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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Delving into the complexity of hereditary spastic paraplegias: how unexpected phenotypes and inheritance modes are revolutionizing their nosology</title><author><name sortKey="Tesson, Christelle" sort="Tesson, Christelle" uniqKey="Tesson C" first="Christelle" last="Tesson">Christelle Tesson</name><affiliation><nlm:aff id="Aff1">INSERM U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 06 UMR_S1127, EPHE, Institut du Cerveau et de la Moelle épinière, CHU Pitié-Salpêtrière, 47 bd de l’Hôpital, 75013 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Koht, Jeanette" sort="Koht, Jeanette" uniqKey="Koht J" first="Jeanette" last="Koht">Jeanette Koht</name><affiliation><nlm:aff id="Aff2">Department of Neurology, Drammen Hospital, Vestre Viken Health Trust, Drammen, Norway</nlm:aff></affiliation></author><author><name sortKey="Stevanin, Giovanni" sort="Stevanin, Giovanni" uniqKey="Stevanin G" first="Giovanni" last="Stevanin">Giovanni Stevanin</name><affiliation><nlm:aff id="Aff1">INSERM U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 06 UMR_S1127, EPHE, Institut du Cerveau et de la Moelle épinière, CHU Pitié-Salpêtrière, 47 bd de l’Hôpital, 75013 Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="Aff3">Département de Génétique et Cytogénétique, APHP, Hôpital de la Pitié-Salpêtrière, 75013 Paris, France</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25758904</idno><idno type="pmc">4424374</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4424374</idno><idno type="RBID">PMC:4424374</idno><idno type="doi">10.1007/s00439-015-1536-7</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000F47</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000F47</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Delving into the complexity of hereditary spastic paraplegias: how unexpected phenotypes and inheritance modes are revolutionizing their nosology</title><author><name sortKey="Tesson, Christelle" sort="Tesson, Christelle" uniqKey="Tesson C" first="Christelle" last="Tesson">Christelle Tesson</name><affiliation><nlm:aff id="Aff1">INSERM U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 06 UMR_S1127, EPHE, Institut du Cerveau et de la Moelle épinière, CHU Pitié-Salpêtrière, 47 bd de l’Hôpital, 75013 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Koht, Jeanette" sort="Koht, Jeanette" uniqKey="Koht J" first="Jeanette" last="Koht">Jeanette Koht</name><affiliation><nlm:aff id="Aff2">Department of Neurology, Drammen Hospital, Vestre Viken Health Trust, Drammen, Norway</nlm:aff></affiliation></author><author><name sortKey="Stevanin, Giovanni" sort="Stevanin, Giovanni" uniqKey="Stevanin G" first="Giovanni" last="Stevanin">Giovanni Stevanin</name><affiliation><nlm:aff id="Aff1">INSERM U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 06 UMR_S1127, EPHE, Institut du Cerveau et de la Moelle épinière, CHU Pitié-Salpêtrière, 47 bd de l’Hôpital, 75013 Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="Aff3">Département de Génétique et Cytogénétique, APHP, Hôpital de la Pitié-Salpêtrière, 75013 Paris, France</nlm:aff></affiliation></author></analytic><series><title level="j">Human Genetics</title><idno type="ISSN">0340-6717</idno><idno type="eISSN">1432-1203</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Hereditary spastic paraplegias (HSP) are rare neurodegenerative diseases sharing the degeneration of the corticospinal tracts as the main pathological characteristic. They are considered one of the most heterogeneous neurological disorders. All modes of inheritance have been described for the 84 different loci and 67 known causative genes implicated up to now. Recent advances in molecular genetics have revealed clinico-genetic heterogeneity of these disorders including their clinical and genetic overlap with other diseases of the nervous system. The systematic analysis of a large set of genes, including exome sequencing, is unmasking unusual phenotypes or inheritance modes associated with mutations in HSP genes and related genes involved in various neurological diseases. A new nosology may emerge after integration and understanding of these new data to replace the current classification. Collectively, functions of the known genes implicate the disturbance of intracellular membrane dynamics and trafficking as the consequence of alterations of cytoskeletal dynamics, lipid metabolism and organelle structures, which represent in fact a relatively small number of cellular processes that could help to find common curative approaches, which are still lacking.</p><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1007/s00439-015-1536-7) contains supplementary material, which is available to authorized users.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Abou Jamra, R" uniqKey="Abou Jamra R">R Abou Jamra</name></author><author><name sortKey="Philippe, O" uniqKey="Philippe O">O Philippe</name></author><author><name sortKey="Raas Rothschild, A" uniqKey="Raas Rothschild A">A Raas-Rothschild</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ajit Bolar, N" uniqKey="Ajit Bolar N">N Ajit Bolar</name></author><author><name sortKey="Vanlander, Av" uniqKey="Vanlander A">AV Vanlander</name></author><author><name sortKey="Wilbrecht, C" uniqKey="Wilbrecht C">C Wilbrecht</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Alazami, Am" uniqKey="Alazami A">AM Alazami</name></author><author><name sortKey="Adly, N" uniqKey="Adly N">N Adly</name></author><author><name sortKey="Al Dhalaan, H" uniqKey="Al Dhalaan H">H Al Dhalaan</name></author><author><name sortKey="Alkuraya, Fs" uniqKey="Alkuraya F">FS Alkuraya</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Al Saif, A" uniqKey="Al Saif A">A Al-Saif</name></author><author><name sortKey="Bohlega, S" uniqKey="Bohlega S">S Bohlega</name></author><author><name sortKey="Al Mohanna, F" uniqKey="Al Mohanna F">F Al-Mohanna</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Anheim, M" uniqKey="Anheim M">M Anheim</name></author><author><name sortKey="Lagier Tourenne, C" uniqKey="Lagier Tourenne C">C Lagier-Tourenne</name></author><author><name sortKey="Stevanin, G" uniqKey="Stevanin G">G Stevanin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Antonicka, H" uniqKey="Antonicka H">H Antonicka</name></author><author><name sortKey="Ostergaard, E" uniqKey="Ostergaard E">E Ostergaard</name></author><author><name sortKey="Sasarman, F" uniqKey="Sasarman F">F Sasarman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Arnoldi, A" uniqKey="Arnoldi A">A Arnoldi</name></author><author><name sortKey="Crimella, C" uniqKey="Crimella C">C Crimella</name></author><author><name sortKey="Tenderini, E" uniqKey="Tenderini E">E Tenderini</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Atorino, L" uniqKey="Atorino L">L Atorino</name></author><author><name sortKey="Silvestri, L" uniqKey="Silvestri L">L Silvestri</name></author><author><name sortKey="Koppen, M" uniqKey="Koppen M">M Koppen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Barbosa, Md" uniqKey="Barbosa M">MD Barbosa</name></author><author><name sortKey="Barrat, Fj" uniqKey="Barrat F">FJ Barrat</name></author><author><name sortKey="Tchernev, Vt" uniqKey="Tchernev V">VT Tchernev</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bauer, P" uniqKey="Bauer P">P Bauer</name></author><author><name sortKey="Leshinsky Silver, E" uniqKey="Leshinsky Silver E">E Leshinsky-Silver</name></author><author><name sortKey="Blumkin, L" uniqKey="Blumkin L">L Blumkin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Beetz, C" uniqKey="Beetz C">C Beetz</name></author><author><name sortKey="Nygren, Aoh" uniqKey="Nygren A">AOH Nygren</name></author><author><name sortKey="Schickel, J" uniqKey="Schickel J">J Schickel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Beetz, C" uniqKey="Beetz C">C Beetz</name></author><author><name sortKey="Schule, R" uniqKey="Schule R">R Schüle</name></author><author><name sortKey="Deconinck, T" uniqKey="Deconinck T">T Deconinck</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Beetz, C" uniqKey="Beetz C">C Beetz</name></author><author><name sortKey="Pieber, Tr" uniqKey="Pieber T">TR Pieber</name></author><author><name sortKey="Hertel, N" uniqKey="Hertel N">N Hertel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Beetz, C" uniqKey="Beetz C">C Beetz</name></author><author><name sortKey="Johnson, A" uniqKey="Johnson A">A Johnson</name></author><author><name sortKey="Schuh, Al" uniqKey="Schuh A">AL Schuh</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bettencourt, C" uniqKey="Bettencourt C">C Bettencourt</name></author><author><name sortKey="Morris, Hr" uniqKey="Morris H">HR Morris</name></author><author><name sortKey="Singleton, Ab" uniqKey="Singleton A">AB Singleton</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Blackstone, C" uniqKey="Blackstone C">C Blackstone</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Blumen, Sc" uniqKey="Blumen S">SC Blumen</name></author><author><name sortKey="Bevan, S" uniqKey="Bevan S">S Bevan</name></author><author><name sortKey="Abu Mouch, S" uniqKey="Abu Mouch S">S Abu-Mouch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bouhlal, Y" uniqKey="Bouhlal Y">Y Bouhlal</name></author><author><name sortKey="Amouri, R" uniqKey="Amouri R">R Amouri</name></author><author><name sortKey="El Euch Fayeche, G" uniqKey="El Euch Fayeche G">G El Euch-Fayeche</name></author><author><name sortKey="Hentati, F" uniqKey="Hentati F">F Hentati</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bouhouche, A" uniqKey="Bouhouche A">A Bouhouche</name></author><author><name sortKey="Benomar, A" uniqKey="Benomar A">A Benomar</name></author><author><name sortKey="Bouslam, N" uniqKey="Bouslam N">N Bouslam</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Boukhris, A" uniqKey="Boukhris A">A Boukhris</name></author><author><name sortKey="Stevanin, G" uniqKey="Stevanin G">G Stevanin</name></author><author><name sortKey="Feki, I" uniqKey="Feki I">I Feki</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Boukhris, A" uniqKey="Boukhris A">A Boukhris</name></author><author><name sortKey="Schule, R" uniqKey="Schule R">R Schule</name></author><author><name sortKey="Loureiro, Jl" uniqKey="Loureiro J">JL Loureiro</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bross, P" uniqKey="Bross P">P Bross</name></author><author><name sortKey="Naundrup, S" uniqKey="Naundrup S">S Naundrup</name></author><author><name sortKey="Hansen, J" uniqKey="Hansen J">J Hansen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Caballero Oteyza, A" uniqKey="Caballero Oteyza A">A Caballero Oteyza</name></author><author><name sortKey="Battalo Lu, E" uniqKey="Battalo Lu E">E Battaloğlu</name></author><author><name sortKey="Ocek, L" uniqKey="Ocek L">L Ocek</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Casari, G" uniqKey="Casari G">G Casari</name></author><author><name sortKey="De Fusco, M" uniqKey="De Fusco M">M De Fusco</name></author><author><name sortKey="Ciarmatori, S" uniqKey="Ciarmatori S">S Ciarmatori</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chang, J" uniqKey="Chang J">J Chang</name></author><author><name sortKey="Lee, S" uniqKey="Lee S">S Lee</name></author><author><name sortKey="Blackstone, C" uniqKey="Blackstone C">C Blackstone</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Citterio, A" uniqKey="Citterio A">A Citterio</name></author><author><name sortKey="Arnoldi, A" uniqKey="Arnoldi A">A Arnoldi</name></author><author><name sortKey="Panzeri, E" uniqKey="Panzeri E">E Panzeri</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cohen, Nr" uniqKey="Cohen N">NR Cohen</name></author><author><name sortKey="Taylor, Js" uniqKey="Taylor J">JS Taylor</name></author><author><name sortKey="Scott, Lb" uniqKey="Scott L">LB Scott</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Collongues, N" uniqKey="Collongues N">N Collongues</name></author><author><name sortKey="Depienne, C" uniqKey="Depienne C">C Depienne</name></author><author><name sortKey="Boehm, N" uniqKey="Boehm N">N Boehm</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Corona, P" uniqKey="Corona P">P Corona</name></author><author><name sortKey="Lamantea, E" uniqKey="Lamantea E">E Lamantea</name></author><author><name sortKey="Greco, M" uniqKey="Greco M">M Greco</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Coutinho, P" uniqKey="Coutinho P">P Coutinho</name></author><author><name sortKey="Barros, J" uniqKey="Barros J">J Barros</name></author><author><name sortKey="Zemmouri, R" uniqKey="Zemmouri R">R Zemmouri</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cremers, Fp" uniqKey="Cremers F">FP Cremers</name></author><author><name sortKey="Pfeiffer, Ra" uniqKey="Pfeiffer R">RA Pfeiffer</name></author><author><name sortKey="Van De Pol, Tj" uniqKey="Van De Pol T">TJ van de Pol</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Crimella, C" uniqKey="Crimella C">C Crimella</name></author><author><name sortKey="Baschirotto, C" uniqKey="Baschirotto C">C Baschirotto</name></author><author><name sortKey="Arnoldi, A" uniqKey="Arnoldi A">A Arnoldi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Crow, Yj" uniqKey="Crow Y">YJ Crow</name></author><author><name sortKey="Zaki, Ms" uniqKey="Zaki M">MS Zaki</name></author><author><name sortKey="Abdel Hamid, Ms" uniqKey="Abdel Hamid M">MS Abdel-Hamid</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="D Mico, A" uniqKey="D Mico A">A D’Amico</name></author><author><name sortKey="Tessa, A" uniqKey="Tessa A">A Tessa</name></author><author><name sortKey="Sabino, A" uniqKey="Sabino A">A Sabino</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dan, P" uniqKey="Dan P">P Dan</name></author><author><name sortKey="Edvardson, S" uniqKey="Edvardson S">S Edvardson</name></author><author><name sortKey="Bielawski, J" uniqKey="Bielawski J">J Bielawski</name></author><author><name sortKey="Hama, H" uniqKey="Hama H">H Hama</name></author><author><name sortKey="Saada, A" uniqKey="Saada A">A Saada</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Daoud, H" uniqKey="Daoud H">H Daoud</name></author><author><name sortKey="Zhou, S" uniqKey="Zhou S">S Zhou</name></author><author><name sortKey="Noreau, A" uniqKey="Noreau A">A Noreau</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De Bot, St" uniqKey="De Bot S">ST De Bot</name></author><author><name sortKey="Schelhaas, Hj" uniqKey="Schelhaas H">HJ Schelhaas</name></author><author><name sortKey="Kamsteeg, E J" uniqKey="Kamsteeg E">E-J Kamsteeg</name></author><author><name sortKey="Van De Warrenburg, Bpc" uniqKey="Van De Warrenburg B">BPC van de Warrenburg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Deluca, Gc" uniqKey="Deluca G">GC Deluca</name></author><author><name sortKey="Ebers, Gc" uniqKey="Ebers G">GC Ebers</name></author><author><name sortKey="Esiri, Mm" uniqKey="Esiri M">MM Esiri</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Deniziak, Ma" uniqKey="Deniziak M">MA Deniziak</name></author><author><name sortKey="Barciszewski, J" uniqKey="Barciszewski J">J Barciszewski</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Denton, Kr" uniqKey="Denton K">KR Denton</name></author><author><name sortKey="Lei, L" uniqKey="Lei L">L Lei</name></author><author><name sortKey="Grenier, J" uniqKey="Grenier J">J Grenier</name></author><author><name sortKey="Rodionov, V" uniqKey="Rodionov V">V Rodionov</name></author><author><name sortKey="Blackstone, C" uniqKey="Blackstone C">C Blackstone</name></author><author><name sortKey="Li, Xj" uniqKey="Li X">XJ Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Depienne, C" uniqKey="Depienne C">C Depienne</name></author><author><name sortKey="Tallaksen, C" uniqKey="Tallaksen C">C Tallaksen</name></author><author><name sortKey="Lephay, Jy" uniqKey="Lephay J">JY Lephay</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Depienne, C" uniqKey="Depienne C">C Depienne</name></author><author><name sortKey="Fedirko, E" uniqKey="Fedirko E">E Fedirko</name></author><author><name sortKey="Forlani, S" uniqKey="Forlani S">S Forlani</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dick, Kj" uniqKey="Dick K">KJ Dick</name></author><author><name sortKey="Eckhardt, M" uniqKey="Eckhardt M">M Eckhardt</name></author><author><name sortKey="Paisan Ruiz, C" uniqKey="Paisan Ruiz C">C Paisán-Ruiz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dor, T" uniqKey="Dor T">T Dor</name></author><author><name sortKey="Cinnamon, Y" uniqKey="Cinnamon Y">Y Cinnamon</name></author><author><name sortKey="Raymond, L" uniqKey="Raymond L">L Raymond</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dumitrescu, Am" uniqKey="Dumitrescu A">AM Dumitrescu</name></author><author><name sortKey="Liao, X H" uniqKey="Liao X">X-H Liao</name></author><author><name sortKey="Best, Tb" uniqKey="Best T">TB Best</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dursun, U" uniqKey="Dursun U">U Dursun</name></author><author><name sortKey="Koroglu, C" uniqKey="Koroglu C">C Koroglu</name></author><author><name sortKey="Kocasoy Orhan, E" uniqKey="Kocasoy Orhan E">E Kocasoy Orhan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ebbing, B" uniqKey="Ebbing B">B Ebbing</name></author><author><name sortKey="Mann, K" uniqKey="Mann K">K Mann</name></author><author><name sortKey="Starosta, A" uniqKey="Starosta A">A Starosta</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Edgar, Jm" uniqKey="Edgar J">JM Edgar</name></author><author><name sortKey="Mclaughlin, M" uniqKey="Mclaughlin M">M McLaughlin</name></author><author><name sortKey="Yool, D" uniqKey="Yool D">D Yool</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Edvardson, S" uniqKey="Edvardson S">S Edvardson</name></author><author><name sortKey="Hama, H" uniqKey="Hama H">H Hama</name></author><author><name sortKey="Shaag, A" uniqKey="Shaag A">A Shaag</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Elliott, Am" uniqKey="Elliott A">AM Elliott</name></author><author><name sortKey="Simard, Lr" uniqKey="Simard L">LR Simard</name></author><author><name sortKey="Coghlan, G" uniqKey="Coghlan G">G Coghlan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Engert, Jc" uniqKey="Engert J">JC Engert</name></author><author><name sortKey="Berube, P" uniqKey="Berube P">P Bérubé</name></author><author><name sortKey="Mercier, J" uniqKey="Mercier J">J Mercier</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Erichsen, Ak" uniqKey="Erichsen A">AK Erichsen</name></author><author><name sortKey="Koht, J" uniqKey="Koht J">J Koht</name></author><author><name sortKey="Stray Pedersen, A" uniqKey="Stray Pedersen A">A Stray-Pedersen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Erlich, Y" uniqKey="Erlich Y">Y Erlich</name></author><author><name sortKey="Edvardson, S" uniqKey="Edvardson S">S Edvardson</name></author><author><name sortKey="Hodges, E" uniqKey="Hodges E">E Hodges</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Esteves, T" uniqKey="Esteves T">T Esteves</name></author><author><name sortKey="Durr, A" uniqKey="Durr A">A Durr</name></author><author><name sortKey="Mundwiller, E" uniqKey="Mundwiller E">E Mundwiller</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Falk, J" uniqKey="Falk J">J Falk</name></author><author><name sortKey="Bonnon, C" uniqKey="Bonnon C">C Bonnon</name></author><author><name sortKey="Girault, J A" uniqKey="Girault J">J-A Girault</name></author><author><name sortKey="Faivre Sarrailh, C" uniqKey="Faivre Sarrailh C">C Faivre-Sarrailh</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Falk, J" uniqKey="Falk J">J Falk</name></author><author><name sortKey="Rohde, M" uniqKey="Rohde M">M Rohde</name></author><author><name sortKey="Bekhite, Mm" uniqKey="Bekhite M">MM Bekhite</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fassier, C" uniqKey="Fassier C">C Fassier</name></author><author><name sortKey="Tarrade, A" uniqKey="Tarrade A">A Tarrade</name></author><author><name sortKey="Peris, L" uniqKey="Peris L">L Peris</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ferreirinha, F" uniqKey="Ferreirinha F">F Ferreirinha</name></author><author><name sortKey="Quattrini, A" uniqKey="Quattrini A">A Quattrini</name></author><author><name sortKey="Pirozzi, M" uniqKey="Pirozzi M">M Pirozzi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fink, Jk" uniqKey="Fink J">JK Fink</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fink, Jk" uniqKey="Fink J">JK Fink</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Finsterer, J" uniqKey="Finsterer J">J Finsterer</name></author><author><name sortKey="Loscher, W" uniqKey="Loscher W">W Löscher</name></author><author><name sortKey="Quasthoff, S" uniqKey="Quasthoff S">S Quasthoff</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fuger, P" uniqKey="Fuger P">P Füger</name></author><author><name sortKey="Sreekumar, V" uniqKey="Sreekumar V">V Sreekumar</name></author><author><name sortKey="Schule, R" uniqKey="Schule R">R Schüle</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Furukawa, Y" uniqKey="Furukawa Y">Y Furukawa</name></author><author><name sortKey="Graf, Wd" uniqKey="Graf W">WD Graf</name></author><author><name sortKey="Wong, H" uniqKey="Wong H">H Wong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ginsberg, D" uniqKey="Ginsberg D">D Ginsberg</name></author><author><name sortKey="Cruz, F" uniqKey="Cruz F">F Cruz</name></author><author><name sortKey="Herschorn, S" uniqKey="Herschorn S">S Herschorn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Goizet, C" uniqKey="Goizet C">C Goizet</name></author><author><name sortKey="Boukhris, A" uniqKey="Boukhris A">A Boukhris</name></author><author><name sortKey="Maltete, D" uniqKey="Maltete D">D Maltete</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Goizet, C" uniqKey="Goizet C">C Goizet</name></author><author><name sortKey="Boukhris, A" uniqKey="Boukhris A">A Boukhris</name></author><author><name sortKey="Mundwiller, E" uniqKey="Mundwiller E">E Mundwiller</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Goizet, C" uniqKey="Goizet C">C Goizet</name></author><author><name sortKey="Depienne, C" uniqKey="Depienne C">C Depienne</name></author><author><name sortKey="Benard, G" uniqKey="Benard G">G Benard</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gonzalez, M" uniqKey="Gonzalez M">M Gonzalez</name></author><author><name sortKey="Mclaughlin, H" uniqKey="Mclaughlin H">H McLaughlin</name></author><author><name sortKey="Houlden, H" uniqKey="Houlden H">H Houlden</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gonzalez Carmona, Ma" uniqKey="Gonzalez Carmona M">MA Gonzalez-Carmona</name></author><author><name sortKey="Sandhoff, R" uniqKey="Sandhoff R">R Sandhoff</name></author><author><name sortKey="Tacke, F" uniqKey="Tacke F">F Tacke</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Goyal, U" uniqKey="Goyal U">U Goyal</name></author><author><name sortKey="Blackstone, C" uniqKey="Blackstone C">C Blackstone</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hamdan, Ff" uniqKey="Hamdan F">FF Hamdan</name></author><author><name sortKey="Gauthier, J" uniqKey="Gauthier J">J Gauthier</name></author><author><name sortKey="Araki, Y" uniqKey="Araki Y">Y Araki</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hammer, Mb" uniqKey="Hammer M">MB Hammer</name></author><author><name sortKey="Eleuch Fayache, G" uniqKey="Eleuch Fayache G">G Eleuch-Fayache</name></author><author><name sortKey="Schottlaender, Lv" uniqKey="Schottlaender L">LV Schottlaender</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hansen, Jj" uniqKey="Hansen J">JJ Hansen</name></author><author><name sortKey="Durr, A" uniqKey="Durr A">A Dürr</name></author><author><name sortKey="Cournu Rebeix, I" uniqKey="Cournu Rebeix I">I Cournu-Rebeix</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Harding, Ae" uniqKey="Harding A">AE Harding</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Harlalka, Gv" uniqKey="Harlalka G">GV Harlalka</name></author><author><name sortKey="Lehman, A" uniqKey="Lehman A">A Lehman</name></author><author><name sortKey="Chioza, B" uniqKey="Chioza B">B Chioza</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hartig, Mb" uniqKey="Hartig M">MB Hartig</name></author><author><name sortKey="Iuso, A" uniqKey="Iuso A">A Iuso</name></author><author><name sortKey="Haack, T" uniqKey="Haack T">T Haack</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hanein, S" uniqKey="Hanein S">S Hanein</name></author><author><name sortKey="Durr, A" uniqKey="Durr A">A Durr</name></author><author><name sortKey="Ribai, P" uniqKey="Ribai P">P Ribai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hanein, S" uniqKey="Hanein S">S Hanein</name></author><author><name sortKey="Martin, E" uniqKey="Martin E">E Martin</name></author><author><name sortKey="Boukhris, A" uniqKey="Boukhris A">A Boukhris</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hazan, J" uniqKey="Hazan J">J Hazan</name></author><author><name sortKey="Fonknechten, N" uniqKey="Fonknechten N">N Fonknechten</name></author><author><name sortKey="Mavel, D" uniqKey="Mavel D">D Mavel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Heffernan, Lf" uniqKey="Heffernan L">LF Heffernan</name></author><author><name sortKey="Simpson, Jc" uniqKey="Simpson J">JC Simpson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hehr, U" uniqKey="Hehr U">U Hehr</name></author><author><name sortKey="Bauer, P" uniqKey="Bauer P">P Bauer</name></author><author><name sortKey="Winner, B" uniqKey="Winner B">B Winner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hewamadduma, C" uniqKey="Hewamadduma C">C Hewamadduma</name></author><author><name sortKey="Mcdermott, C" uniqKey="Mcdermott C">C McDermott</name></author><author><name sortKey="Kirby, J" uniqKey="Kirby J">J Kirby</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hiroko, H" uniqKey="Hiroko H">H Hiroko</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hirst, J" uniqKey="Hirst J">J Hirst</name></author><author><name sortKey="Borner, Ghh" uniqKey="Borner G">GHH Borner</name></author><author><name sortKey="Edgar, J" uniqKey="Edgar J">J Edgar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hodgkinson, Ca" uniqKey="Hodgkinson C">CA Hodgkinson</name></author><author><name sortKey="Bohlega, S" uniqKey="Bohlega S">S Bohlega</name></author><author><name sortKey="Abu Amero, Sn" uniqKey="Abu Amero S">SN Abu-Amero</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ilgaz Aydinlar, E" uniqKey="Ilgaz Aydinlar E">E Ilgaz-Aydinlar</name></author><author><name sortKey="Rolfs, A" uniqKey="Rolfs A">A Rolfs</name></author><author><name sortKey="Serteser, M" uniqKey="Serteser M">M Serteser</name></author><author><name sortKey="Parman, Y" uniqKey="Parman Y">Y Parman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ishiura, H" uniqKey="Ishiura H">H Ishiura</name></author><author><name sortKey="Sako, W" uniqKey="Sako W">W Sako</name></author><author><name sortKey="Yoshida, M" uniqKey="Yoshida M">M Yoshida</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ito, D" uniqKey="Ito D">D Ito</name></author><author><name sortKey="Suzuki, N" uniqKey="Suzuki N">N Suzuki</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jouet, M" uniqKey="Jouet M">M Jouet</name></author><author><name sortKey="Rosenthal, A" uniqKey="Rosenthal A">A Rosenthal</name></author><author><name sortKey="Armstrong, G" uniqKey="Armstrong G">G Armstrong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Karle, Kn" uniqKey="Karle K">KN Karle</name></author><author><name sortKey="Mockel, D" uniqKey="Mockel D">D Möckel</name></author><author><name sortKey="Reid, E" uniqKey="Reid E">E Reid</name></author><author><name sortKey="Schols, L" uniqKey="Schols L">L Schöls</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kasher, Pr" uniqKey="Kasher P">PR Kasher</name></author><author><name sortKey="De Vos, Kj" uniqKey="De Vos K">KJ De Vos</name></author><author><name sortKey="Wharton, Sb" uniqKey="Wharton S">SB Wharton</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Khan, Tn" uniqKey="Khan T">TN Khan</name></author><author><name sortKey="Klar, J" uniqKey="Klar J">J Klar</name></author><author><name sortKey="Tariq, M" uniqKey="Tariq M">M Tariq</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Klebe, S" uniqKey="Klebe S">S Klebe</name></author><author><name sortKey="Depienne, C" uniqKey="Depienne C">C Depienne</name></author><author><name sortKey="Gerber, S" uniqKey="Gerber S">S Gerber</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Klebe, S" uniqKey="Klebe S">S Klebe</name></author><author><name sortKey="Lossos, A" uniqKey="Lossos A">A Lossos</name></author><author><name sortKey="Azzedine, H" uniqKey="Azzedine H">H Azzedine</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Klemm, Rw" uniqKey="Klemm R">RW Klemm</name></author><author><name sortKey="Norton, Jp" uniqKey="Norton J">JP Norton</name></author><author><name sortKey="Cole, Ra" uniqKey="Cole R">RA Cole</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kruer, Mc" uniqKey="Kruer M">MC Kruer</name></author><author><name sortKey="Paisan Ruiz, C" uniqKey="Paisan Ruiz C">C Paisán-Ruiz</name></author><author><name sortKey="Boddaert, N" uniqKey="Boddaert N">N Boddaert</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kurth, I" uniqKey="Kurth I">I Kurth</name></author><author><name sortKey="Pamminger, T" uniqKey="Pamminger T">T Pamminger</name></author><author><name sortKey="Hennings, Jc" uniqKey="Hennings J">JC Hennings</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Landoure, G" uniqKey="Landoure G">G Landouré</name></author><author><name sortKey="Zhu, P P" uniqKey="Zhu P">P-P Zhu</name></author><author><name sortKey="Lourenco, Cm" uniqKey="Lourenco C">CM Lourenço</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Leoni, V" uniqKey="Leoni V">V Leoni</name></author><author><name sortKey="Caccia, C" uniqKey="Caccia C">C Caccia</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liguori, R" uniqKey="Liguori R">R Liguori</name></author><author><name sortKey="Giannoccaro, Mp" uniqKey="Giannoccaro M">MP Giannoccaro</name></author><author><name sortKey="Arnoldi, A" uniqKey="Arnoldi A">A Arnoldi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lin, P" uniqKey="Lin P">P Lin</name></author><author><name sortKey="Li, J" uniqKey="Li J">J Li</name></author><author><name sortKey="Liu, Q" uniqKey="Liu Q">Q Liu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lindsey, Jc" uniqKey="Lindsey J">JC Lindsey</name></author><author><name sortKey="Lusher, Me" uniqKey="Lusher M">ME Lusher</name></author><author><name sortKey="Mcdermott, Cj" uniqKey="Mcdermott C">CJ McDermott</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liu, Y T" uniqKey="Liu Y">Y-T Liu</name></author><author><name sortKey="Laura, M" uniqKey="Laura M">M Laurá</name></author><author><name sortKey="Hersheson, J" uniqKey="Hersheson J">J Hersheson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lossos, A" uniqKey="Lossos A">A Lossos</name></author><author><name sortKey="Stumpfig, C" uniqKey="Stumpfig C">C Stümpfig</name></author><author><name sortKey="Stevanin, G" uniqKey="Stevanin G">G Stevanin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Loureiro, Jl" uniqKey="Loureiro J">JL Loureiro</name></author><author><name sortKey="Brandao, E" uniqKey="Brandao E">E Brandão</name></author><author><name sortKey="Ruano, L" uniqKey="Ruano L">L Ruano</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Luo, Y" uniqKey="Luo Y">Y Luo</name></author><author><name sortKey="Chen, C" uniqKey="Chen C">C Chen</name></author><author><name sortKey="Zhan, Z" uniqKey="Zhan Z">Z Zhan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Macedo Souza, Li" uniqKey="Macedo Souza L">LI Macedo-Souza</name></author><author><name sortKey="Kok, F" uniqKey="Kok F">F Kok</name></author><author><name sortKey="Santos, S" uniqKey="Santos S">S Santos</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Magen, D" uniqKey="Magen D">D Magen</name></author><author><name sortKey="Georgopoulos, C" uniqKey="Georgopoulos C">C Georgopoulos</name></author><author><name sortKey="Bross, P" uniqKey="Bross P">P Bross</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Magre, J" uniqKey="Magre J">J Magré</name></author><author><name sortKey="Delepine, M" uniqKey="Delepine M">M Delépine</name></author><author><name sortKey="Khallouf, E" uniqKey="Khallouf E">E Khallouf</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mannan, Au" uniqKey="Mannan A">AU Mannan</name></author><author><name sortKey="Krawen, P" uniqKey="Krawen P">P Krawen</name></author><author><name sortKey="Sauter, Sm" uniqKey="Sauter S">SM Sauter</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Martin, E" uniqKey="Martin E">E Martin</name></author><author><name sortKey="Schule, R" uniqKey="Schule R">R Schüle</name></author><author><name sortKey="Smets, K" uniqKey="Smets K">K Smets</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mcdermott, Cj" uniqKey="Mcdermott C">CJ McDermott</name></author><author><name sortKey="Dayaratne, Rk" uniqKey="Dayaratne R">RK Dayaratne</name></author><author><name sortKey="Tomkins, J" uniqKey="Tomkins J">J Tomkins</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Meijer, Ia" uniqKey="Meijer I">IA Meijer</name></author><author><name sortKey="Hand, Ck" uniqKey="Hand C">CK Hand</name></author><author><name sortKey="Cossette, P" uniqKey="Cossette P">P Cossette</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Meijer, Ia" uniqKey="Meijer I">IA Meijer</name></author><author><name sortKey="Cossette, P" uniqKey="Cossette P">P Cossette</name></author><author><name sortKey="Roussel, J" uniqKey="Roussel J">J Roussel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mitne Neto, M" uniqKey="Mitne Neto M">M Mitne-Neto</name></author><author><name sortKey="Kok, F" uniqKey="Kok F">F Kok</name></author><author><name sortKey="Beetz, C" uniqKey="Beetz C">C Beetz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Montenegro, G" uniqKey="Montenegro G">G Montenegro</name></author><author><name sortKey="Rebelo, Ap" uniqKey="Rebelo A">AP Rebelo</name></author><author><name sortKey="Connell, J" uniqKey="Connell J">J Connell</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Moreno De Luca, A" uniqKey="Moreno De Luca A">A Moreno-De-Luca</name></author><author><name sortKey="Helmers, Sl" uniqKey="Helmers S">SL Helmers</name></author><author><name sortKey="Mao, H" uniqKey="Mao H">H Mao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Murakami, Y" uniqKey="Murakami Y">Y Murakami</name></author><author><name sortKey="Tawamie, H" uniqKey="Tawamie H">H Tawamie</name></author><author><name sortKey="Maeda, Y" uniqKey="Maeda Y">Y Maeda</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Musumeci, O" uniqKey="Musumeci O">O Musumeci</name></author><author><name sortKey="Bassi, Mt" uniqKey="Bassi M">MT Bassi</name></author><author><name sortKey="Mazzeo, A" uniqKey="Mazzeo A">A Mazzeo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Neveling, K" uniqKey="Neveling K">K Neveling</name></author><author><name sortKey="Martinez Carrera, La" uniqKey="Martinez Carrera L">LA Martinez-Carrera</name></author><author><name sortKey="Holker, I" uniqKey="Holker I">I Hölker</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Novarino, G" uniqKey="Novarino G">G Novarino</name></author><author><name sortKey="Fenstermaker, Ag" uniqKey="Fenstermaker A">AG Fenstermaker</name></author><author><name sortKey="Zaki, Ms" uniqKey="Zaki M">MS Zaki</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Oates, Ec" uniqKey="Oates E">EC Oates</name></author><author><name sortKey="Rossor, Am" uniqKey="Rossor A">AM Rossor</name></author><author><name sortKey="Hafezparast, M" uniqKey="Hafezparast M">M Hafezparast</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ohmi, Y" uniqKey="Ohmi Y">Y Ohmi</name></author><author><name sortKey="Tajima, O" uniqKey="Tajima O">O Tajima</name></author><author><name sortKey="Ohkawa, Y" uniqKey="Ohkawa Y">Y Ohkawa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Orlacchio, A" uniqKey="Orlacchio A">A Orlacchio</name></author><author><name sortKey="Kawarai, T" uniqKey="Kawarai T">T Kawarai</name></author><author><name sortKey="Gaudiello, F" uniqKey="Gaudiello F">F Gaudiello</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Orlacchio, A" uniqKey="Orlacchio A">A Orlacchio</name></author><author><name sortKey="Patrono, C" uniqKey="Patrono C">C Patrono</name></author><author><name sortKey="Gaudiello, F" uniqKey="Gaudiello F">F Gaudiello</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Orlacchio, A" uniqKey="Orlacchio A">A Orlacchio</name></author><author><name sortKey="Babalini, C" uniqKey="Babalini C">C Babalini</name></author><author><name sortKey="Borreca, A" uniqKey="Borreca A">A Borreca</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Orso, G" uniqKey="Orso G">G Orso</name></author><author><name sortKey="Pendin, D" uniqKey="Pendin D">D Pendin</name></author><author><name sortKey="Liu, S" uniqKey="Liu S">S Liu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Orthmann Murphy, Jl" uniqKey="Orthmann Murphy J">JL Orthmann-Murphy</name></author><author><name sortKey="Salsano, E" uniqKey="Salsano E">E Salsano</name></author><author><name sortKey="Abrams, Ck" uniqKey="Abrams C">CK Abrams</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Oz Levi, D" uniqKey="Oz Levi D">D Oz-Levi</name></author><author><name sortKey="Ben Zeev, B" uniqKey="Ben Zeev B">B Ben-Zeev</name></author><author><name sortKey="Ruzzo, Ek" uniqKey="Ruzzo E">EK Ruzzo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Paisan Ruiz, C" uniqKey="Paisan Ruiz C">C Paisan-Ruiz</name></author><author><name sortKey="Dogu, O" uniqKey="Dogu O">O Dogu</name></author><author><name sortKey="Yilmaz, A" uniqKey="Yilmaz A">A Yilmaz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Park, Sh" uniqKey="Park S">SH Park</name></author><author><name sortKey="Zhu, P P" uniqKey="Zhu P">P-P Zhu</name></author><author><name sortKey="Parker, Rl" uniqKey="Parker R">RL Parker</name></author><author><name sortKey="Blackstone, C" uniqKey="Blackstone C">C Blackstone</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Patel, H" uniqKey="Patel H">H Patel</name></author><author><name sortKey="Cross, H" uniqKey="Cross H">H Cross</name></author><author><name sortKey="Proukakis, C" uniqKey="Proukakis C">C Proukakis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Perez Branguli, F" uniqKey="Perez Branguli F">F Pérez-Brangulí</name></author><author><name sortKey="Mishra, Hk" uniqKey="Mishra H">HK Mishra</name></author><author><name sortKey="Prots, I" uniqKey="Prots I">I Prots</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pfeffer, G" uniqKey="Pfeffer G">G Pfeffer</name></author><author><name sortKey="Gorman, Gs" uniqKey="Gorman G">GS Gorman</name></author><author><name sortKey="Griffin, H" uniqKey="Griffin H">H Griffin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Potter, Ka" uniqKey="Potter K">KA Potter</name></author><author><name sortKey="Kern, Mj" uniqKey="Kern M">MJ Kern</name></author><author><name sortKey="Fullbright, G" uniqKey="Fullbright G">G Fullbright</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Proukakis, C" uniqKey="Proukakis C">C Proukakis</name></author><author><name sortKey="Moore, D" uniqKey="Moore D">D Moore</name></author><author><name sortKey="Labrum, R" uniqKey="Labrum R">R Labrum</name></author><author><name sortKey="Wood, Nw" uniqKey="Wood N">NW Wood</name></author><author><name sortKey="Houlden, H" uniqKey="Houlden H">H Houlden</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rahman, M" uniqKey="Rahman M">M Rahman</name></author><author><name sortKey="Haberman, A" uniqKey="Haberman A">A Haberman</name></author><author><name sortKey="Tracy, C" uniqKey="Tracy C">C Tracy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rainier, S" uniqKey="Rainier S">S Rainier</name></author><author><name sortKey="Chai, J H" uniqKey="Chai J">J-H Chai</name></author><author><name sortKey="Tokarz, D" uniqKey="Tokarz D">D Tokarz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rainier, S" uniqKey="Rainier S">S Rainier</name></author><author><name sortKey="Bui, M" uniqKey="Bui M">M Bui</name></author><author><name sortKey="Mark, E" uniqKey="Mark E">E Mark</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Reid, E" uniqKey="Reid E">E Reid</name></author><author><name sortKey="Dearlove, Am" uniqKey="Dearlove A">AM Dearlove</name></author><author><name sortKey="Osborn, O" uniqKey="Osborn O">O Osborn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Reid, E" uniqKey="Reid E">E Reid</name></author><author><name sortKey="Kloos, M" uniqKey="Kloos M">M Kloos</name></author><author><name sortKey="Ashley Koch, A" uniqKey="Ashley Koch A">A Ashley-Koch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Renvoise, B" uniqKey="Renvoise B">B Renvoisé</name></author><author><name sortKey="Stadler, J" uniqKey="Stadler J">J Stadler</name></author><author><name sortKey="Singh, R" uniqKey="Singh R">R Singh</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ribai, P" uniqKey="Ribai P">P Ribai</name></author><author><name sortKey="Stevanin, G" uniqKey="Stevanin G">G Stevanin</name></author><author><name sortKey="Bouslam, N" uniqKey="Bouslam N">N Bouslam</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rismanchi, N" uniqKey="Rismanchi N">N Rismanchi</name></author><author><name sortKey="Soderblom, C" uniqKey="Soderblom C">C Soderblom</name></author><author><name sortKey="Stadler, J" uniqKey="Stadler J">J Stadler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Riviere, J B" uniqKey="Riviere J">J-B Rivière</name></author><author><name sortKey="Ramalingam, S" uniqKey="Ramalingam S">S Ramalingam</name></author><author><name sortKey="Lavastre, V" uniqKey="Lavastre V">V Lavastre</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Romagnolo, A" uniqKey="Romagnolo A">A Romagnolo</name></author><author><name sortKey="Masera, S" uniqKey="Masera S">S Masera</name></author><author><name sortKey="Mattioda, A" uniqKey="Mattioda A">A Mattioda</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rosenthal, A" uniqKey="Rosenthal A">A Rosenthal</name></author><author><name sortKey="Jouet, M" uniqKey="Jouet M">M Jouet</name></author><author><name sortKey="Kenwrick, S" uniqKey="Kenwrick S">S Kenwrick</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ruano, L" uniqKey="Ruano L">L Ruano</name></author><author><name sortKey="Melo, C" uniqKey="Melo C">C Melo</name></author><author><name sortKey="Silva, Mc" uniqKey="Silva M">MC Silva</name></author><author><name sortKey="Coutinho, P" uniqKey="Coutinho P">P Coutinho</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sanchez Ferrero, E" uniqKey="Sanchez Ferrero E">E Sánchez-Ferrero</name></author><author><name sortKey="Coto, E" uniqKey="Coto E">E Coto</name></author><author><name sortKey="Beetz, C" uniqKey="Beetz C">C Beetz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Saugier Veber, P" uniqKey="Saugier Veber P">P Saugier-Veber</name></author><author><name sortKey="Munnich, A" uniqKey="Munnich A">A Munnich</name></author><author><name sortKey="Bonneau, D" uniqKey="Bonneau D">D Bonneau</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schneider, Sa" uniqKey="Schneider S">SA Schneider</name></author><author><name sortKey="Bhatia, Kp" uniqKey="Bhatia K">KP Bhatia</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schule, R" uniqKey="Schule R">R Schüle</name></author><author><name sortKey="Bonin, M" uniqKey="Bonin M">M Bonin</name></author><author><name sortKey="Durr, A" uniqKey="Durr A">A Dürr</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schule, R" uniqKey="Schule R">R Schüle</name></author><author><name sortKey="Schlipf, N" uniqKey="Schlipf N">N Schlipf</name></author><author><name sortKey="Synofzik, M" uniqKey="Synofzik M">M Synofzik</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schule, R" uniqKey="Schule R">R Schüle</name></author><author><name sortKey="Siddique, T" uniqKey="Siddique T">T Siddique</name></author><author><name sortKey="Deng, H X" uniqKey="Deng H">H-X Deng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schuurs Hoeijmakers, Jhm" uniqKey="Schuurs Hoeijmakers J">JHM Schuurs-Hoeijmakers</name></author><author><name sortKey="Geraghty, Mt" uniqKey="Geraghty M">MT Geraghty</name></author><author><name sortKey="Kamsteeg, E J" uniqKey="Kamsteeg E">E-J Kamsteeg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schwartz, Ce" uniqKey="Schwartz C">CE Schwartz</name></author><author><name sortKey="May, Mm" uniqKey="May M">MM May</name></author><author><name sortKey="Carpenter, Nj" uniqKey="Carpenter N">NJ Carpenter</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sedel, F" uniqKey="Sedel F">F Sedel</name></author><author><name sortKey="Fontaine, B" uniqKey="Fontaine B">B Fontaine</name></author><author><name sortKey="Saudubray, Jm" uniqKey="Saudubray J">JM Saudubray</name></author><author><name sortKey="Lyon Caen, O" uniqKey="Lyon Caen O">O Lyon-Caen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Seri, M" uniqKey="Seri M">M Seri</name></author><author><name sortKey="Cusano, R" uniqKey="Cusano R">R Cusano</name></author><author><name sortKey="Forabosco, P" uniqKey="Forabosco P">P Forabosco</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shimazaki, H" uniqKey="Shimazaki H">H Shimazaki</name></author><author><name sortKey="Takiyama, Y" uniqKey="Takiyama Y">Y Takiyama</name></author><author><name sortKey="Ishiura, H" uniqKey="Ishiura H">H Ishiura</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shimazaki, H" uniqKey="Shimazaki H">H Shimazaki</name></author><author><name sortKey="Honda, J" uniqKey="Honda J">J Honda</name></author><author><name sortKey="Naoi, T" uniqKey="Naoi T">T Naoi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Simpson, Ma" uniqKey="Simpson M">MA Simpson</name></author><author><name sortKey="Cross, H" uniqKey="Cross H">H Cross</name></author><author><name sortKey="Proukakis, C" uniqKey="Proukakis C">C Proukakis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sivakumar, K" uniqKey="Sivakumar K">K Sivakumar</name></author><author><name sortKey="Sambuughin, N" uniqKey="Sambuughin N">N Sambuughin</name></author><author><name sortKey="Selenge, B" uniqKey="Selenge B">B Selenge</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Slabicki, M" uniqKey="Slabicki M">M Słabicki</name></author><author><name sortKey="Theis, M" uniqKey="Theis M">M Theis</name></author><author><name sortKey="Krastev, Db" uniqKey="Krastev D">DB Krastev</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Spiegel, R" uniqKey="Spiegel R">R Spiegel</name></author><author><name sortKey="Mandel, H" uniqKey="Mandel H">H Mandel</name></author><author><name sortKey="Saada, A" uniqKey="Saada A">A Saada</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Starling, A" uniqKey="Starling A">A Starling</name></author><author><name sortKey="Rocco, P" uniqKey="Rocco P">P Rocco</name></author><author><name sortKey="Passos Bueno, Mr" uniqKey="Passos Bueno M">MR Passos-Bueno</name></author><author><name sortKey="Hazan, J" uniqKey="Hazan J">J Hazan</name></author><author><name sortKey="Marie, Sk" uniqKey="Marie S">SK Marie</name></author><author><name sortKey="Zatz, M" uniqKey="Zatz M">M Zatz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Steinmuller, R" uniqKey="Steinmuller R">R Steinmüller</name></author><author><name sortKey="Lantigua Cruz, A" uniqKey="Lantigua Cruz A">A Lantigua-Cruz</name></author><author><name sortKey="Garcia Garcia, R" uniqKey="Garcia Garcia R">R Garcia-Garcia</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stevanin, G" uniqKey="Stevanin G">G Stevanin</name></author><author><name sortKey="Paternotte, C" uniqKey="Paternotte C">C Paternotte</name></author><author><name sortKey="Coutinho, P" uniqKey="Coutinho P">P Coutinho</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stevanin, G" uniqKey="Stevanin G">G Stevanin</name></author><author><name sortKey="Santorelli, Fm" uniqKey="Santorelli F">FM Santorelli</name></author><author><name sortKey="Azzedine, H" uniqKey="Azzedine H">H Azzedine</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stevanin, G" uniqKey="Stevanin G">G Stevanin</name></author><author><name sortKey="Azzedine, H" uniqKey="Azzedine H">H Azzedine</name></author><author><name sortKey="Denora, P" uniqKey="Denora P">P Denora</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stevanin, G" uniqKey="Stevanin G">G Stevanin</name></author><author><name sortKey="Ruberg, M" uniqKey="Ruberg M">M Ruberg</name></author><author><name sortKey="Brice, A" uniqKey="Brice A">A Brice</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Svenson, Ik" uniqKey="Svenson I">IK Svenson</name></author><author><name sortKey="Kloos, Mt" uniqKey="Kloos M">MT Kloos</name></author><author><name sortKey="Gaskell, Pc" uniqKey="Gaskell P">PC Gaskell</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Synofzik, M" uniqKey="Synofzik M">M Synofzik</name></author><author><name sortKey="Gonzalez, Ma" uniqKey="Gonzalez M">MA Gonzalez</name></author><author><name sortKey="Lourenco, Cm" uniqKey="Lourenco C">CM Lourenco</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Takiyama, Y" uniqKey="Takiyama Y">Y Takiyama</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tallaksen, Cm" uniqKey="Tallaksen C">CM Tallaksen</name></author><author><name sortKey="Durr, A" uniqKey="Durr A">A Dürr</name></author><author><name sortKey="Brice, A" uniqKey="Brice A">A Brice</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tamagaki, A" uniqKey="Tamagaki A">A Tamagaki</name></author><author><name sortKey="Shima, M" uniqKey="Shima M">M Shima</name></author><author><name sortKey="Tomita, R" uniqKey="Tomita R">R Tomita</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tanyel, Mc" uniqKey="Tanyel M">MC Tanyel</name></author><author><name sortKey="Mancano, Ld" uniqKey="Mancano L">LD Mancano</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tarrade, A" uniqKey="Tarrade A">A Tarrade</name></author><author><name sortKey="Fassier, C" uniqKey="Fassier C">C Fassier</name></author><author><name sortKey="Courageot, S" uniqKey="Courageot S">S Courageot</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tessa, A" uniqKey="Tessa A">A Tessa</name></author><author><name sortKey="Silvestri, G" uniqKey="Silvestri G">G Silvestri</name></author><author><name sortKey="De Leva, Mf" uniqKey="De Leva M">MF de Leva</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tesson, C" uniqKey="Tesson C">C Tesson</name></author><author><name sortKey="Nawara, M" uniqKey="Nawara M">M Nawara</name></author><author><name sortKey="Salih, Mam" uniqKey="Salih M">MAM Salih</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Theofilopoulos, S" uniqKey="Theofilopoulos S">S Theofilopoulos</name></author><author><name sortKey="Griffiths, Wj" uniqKey="Griffiths W">WJ Griffiths</name></author><author><name sortKey="Crick, Pj" uniqKey="Crick P">PJ Crick</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tiranti, V" uniqKey="Tiranti V">V Tiranti</name></author><author><name sortKey="Corona, P" uniqKey="Corona P">P Corona</name></author><author><name sortKey="Greco, M" uniqKey="Greco M">M Greco</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tsang, Hth" uniqKey="Tsang H">HTH Tsang</name></author><author><name sortKey="Edwards, Tl" uniqKey="Edwards T">TL Edwards</name></author><author><name sortKey="Wang, X" uniqKey="Wang X">X Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tsaousidou, Mk" uniqKey="Tsaousidou M">MK Tsaousidou</name></author><author><name sortKey="Ouahchi, K" uniqKey="Ouahchi K">K Ouahchi</name></author><author><name sortKey="Warner, Tt" uniqKey="Warner T">TT Warner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tucci, A" uniqKey="Tucci A">A Tucci</name></author><author><name sortKey="Liu, Y T" uniqKey="Liu Y">Y-T Liu</name></author><author><name sortKey="Preza, E" uniqKey="Preza E">E Preza</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Uhlenberg, B" uniqKey="Uhlenberg B">B Uhlenberg</name></author><author><name sortKey="Schuelke, M" uniqKey="Schuelke M">M Schuelke</name></author><author><name sortKey="Ruschendorf, F" uniqKey="Ruschendorf F">F Rüschendorf</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Valdmanis, Pn" uniqKey="Valdmanis P">PN Valdmanis</name></author><author><name sortKey="Meijer, Ia" uniqKey="Meijer I">IA Meijer</name></author><author><name sortKey="Reynolds, A" uniqKey="Reynolds A">A Reynolds</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Valente, Em" uniqKey="Valente E">EM Valente</name></author><author><name sortKey="Brancati, F" uniqKey="Brancati F">F Brancati</name></author><author><name sortKey="Caputo, V" uniqKey="Caputo V">V Caputo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Varga, R E" uniqKey="Varga R">R-E Varga</name></author><author><name sortKey="Schule, R" uniqKey="Schule R">R Schüle</name></author><author><name sortKey="Fadel, H" uniqKey="Fadel H">H Fadel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vazza, G" uniqKey="Vazza G">G Vazza</name></author><author><name sortKey="Zortea, M" uniqKey="Zortea M">M Zortea</name></author><author><name sortKey="Boaretto, F" uniqKey="Boaretto F">F Boaretto</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Verkerk, Ajmh" uniqKey="Verkerk A">AJMH Verkerk</name></author><author><name sortKey="Schot, R" uniqKey="Schot R">R Schot</name></author><author><name sortKey="Dumee, B" uniqKey="Dumee B">B Dumee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Verny, C" uniqKey="Verny C">C Verny</name></author><author><name sortKey="Guegen, N" uniqKey="Guegen N">N Guegen</name></author><author><name sortKey="Desquiret, V" uniqKey="Desquiret V">V Desquiret</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Votsi, C" uniqKey="Votsi C">C Votsi</name></author><author><name sortKey="Zamba Papanicolaou, E" uniqKey="Zamba Papanicolaou E">E Zamba-Papanicolaou</name></author><author><name sortKey="Middleton, Lt" uniqKey="Middleton L">LT Middleton</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wakil, Sm" uniqKey="Wakil S">SM Wakil</name></author><author><name sortKey="Bohlega, S" uniqKey="Bohlega S">S Bohlega</name></author><author><name sortKey="Hagos, S" uniqKey="Hagos S">S Hagos</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wan, J" uniqKey="Wan J">J Wan</name></author><author><name sortKey="Yourshaw, M" uniqKey="Yourshaw M">M Yourshaw</name></author><author><name sortKey="Mamsa, H" uniqKey="Mamsa H">H Mamsa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, X" uniqKey="Wang X">X Wang</name></author><author><name sortKey="Shaw, Wr" uniqKey="Shaw W">WR Shaw</name></author><author><name sortKey="Tsang, Hth" uniqKey="Tsang H">HTH Tsang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, X" uniqKey="Wang X">X Wang</name></author><author><name sortKey="Yang, Y" uniqKey="Yang Y">Y Yang</name></author><author><name sortKey="Wang, X" uniqKey="Wang X">X Wang</name></author><author><name sortKey="Li, C" uniqKey="Li C">C Li</name></author><author><name sortKey="Jia, J" uniqKey="Jia J">J Jia</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Watts, Gdj" uniqKey="Watts G">GDJ Watts</name></author><author><name sortKey="Wymer, J" uniqKey="Wymer J">J Wymer</name></author><author><name sortKey="Kovach, Mj" uniqKey="Kovach M">MJ Kovach</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wedding, Im" uniqKey="Wedding I">IM Wedding</name></author><author><name sortKey="Koht, J" uniqKey="Koht J">J Koht</name></author><author><name sortKey="Tran, Gt" uniqKey="Tran G">GT Tran</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Werner, Hb" uniqKey="Werner H">HB Werner</name></author><author><name sortKey="Kr Mer Albers, E M" uniqKey="Kr Mer Albers E">E-M Krämer-Albers</name></author><author><name sortKey="Strenzke, N" uniqKey="Strenzke N">N Strenzke</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Windpassinger, C" uniqKey="Windpassinger C">C Windpassinger</name></author><author><name sortKey="Auer Grumbach, M" uniqKey="Auer Grumbach M">M Auer-Grumbach</name></author><author><name sortKey="Irobi, J" uniqKey="Irobi J">J Irobi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yao, D" uniqKey="Yao D">D Yao</name></author><author><name sortKey="Mcgonigal, R" uniqKey="Mcgonigal R">R McGonigal</name></author><author><name sortKey="Barrie, Ja" uniqKey="Barrie J">JA Barrie</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Y Ld R M, Y" uniqKey="Y Ld R M Y">Y Yıldırım</name></author><author><name sortKey="Orhan, Ek" uniqKey="Orhan E">EK Orhan</name></author><author><name sortKey="Iseri, Sau" uniqKey="Iseri S">SAU Iseri</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zanni, G" uniqKey="Zanni G">G Zanni</name></author><author><name sortKey="Scotton, C" uniqKey="Scotton C">C Scotton</name></author><author><name sortKey="Passarelli, C" uniqKey="Passarelli C">C Passarelli</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhao, X" uniqKey="Zhao X">X Zhao</name></author><author><name sortKey="Alvarado, D" uniqKey="Alvarado D">D Alvarado</name></author><author><name sortKey="Rainier, S" uniqKey="Rainier S">S Rainier</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhao, G" uniqKey="Zhao G">G Zhao</name></author><author><name sortKey="Hu, Z" uniqKey="Hu Z">Z Hu</name></author><author><name sortKey="Shen, L" uniqKey="Shen L">L Shen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhu, P P" uniqKey="Zhu P">P-P Zhu</name></author><author><name sortKey="Denton, Kr" uniqKey="Denton K">KR Denton</name></author><author><name sortKey="Pierson, Tm" uniqKey="Pierson T">TM Pierson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zivony Elboum, Y" uniqKey="Zivony Elboum Y">Y Zivony-Elboum</name></author><author><name sortKey="Westbroek, W" uniqKey="Westbroek W">W Westbroek</name></author><author><name sortKey="Kfir, N" uniqKey="Kfir N">N Kfir</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zoller, I" uniqKey="Zoller I">I Zöller</name></author><author><name sortKey="Meixner, M" uniqKey="Meixner M">M Meixner</name></author><author><name sortKey="Hartmann, D" uniqKey="Hartmann D">D Hartmann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zortea, M" uniqKey="Zortea M">M Zortea</name></author><author><name sortKey="Vettori, A" uniqKey="Vettori A">A Vettori</name></author><author><name sortKey="Trevisan, Cp" uniqKey="Trevisan C">CP Trevisan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zuchner, S" uniqKey="Zuchner S">S Züchner</name></author><author><name sortKey="Wang, G" uniqKey="Wang G">G Wang</name></author><author><name sortKey="Tran Viet, K N" uniqKey="Tran Viet K">K-N Tran-Viet</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Hum Genet</journal-id><journal-id journal-id-type="iso-abbrev">Hum. Genet</journal-id><journal-title-group><journal-title>Human Genetics</journal-title></journal-title-group><issn pub-type="ppub">0340-6717</issn><issn pub-type="epub">1432-1203</issn><publisher><publisher-name>Springer Berlin Heidelberg</publisher-name><publisher-loc>Berlin/Heidelberg</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25758904</article-id><article-id pub-id-type="pmc">4424374</article-id><article-id pub-id-type="publisher-id">1536</article-id><article-id pub-id-type="doi">10.1007/s00439-015-1536-7</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review Paper</subject></subj-group></article-categories><title-group><article-title>Delving into the complexity of hereditary spastic paraplegias: how unexpected phenotypes and inheritance modes are revolutionizing their nosology</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Tesson</surname><given-names>Christelle</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Koht</surname><given-names>Jeanette</given-names></name><xref ref-type="aff" rid="Aff2"></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Stevanin</surname><given-names>Giovanni</given-names></name><address><phone>+33.1.57.27.46.49</phone><email>giovanni.stevanin@upmc.fr</email></address><xref ref-type="aff" rid="Aff1"></xref><xref ref-type="aff" rid="Aff3"></xref></contrib><aff id="Aff1"><label></label>INSERM U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 06 UMR_S1127, EPHE, Institut du Cerveau et de la Moelle épinière, CHU Pitié-Salpêtrière, 47 bd de l’Hôpital, 75013 Paris, France</aff><aff id="Aff2"><label></label>Department of Neurology, Drammen Hospital, Vestre Viken Health Trust, Drammen, Norway</aff><aff id="Aff3"><label></label>Département de Génétique et Cytogénétique, APHP, Hôpital de la Pitié-Salpêtrière, 75013 Paris, France</aff></contrib-group><pub-date pub-type="epub"><day>11</day><month>3</month><year>2015</year></pub-date><pub-date pub-type="pmc-release"><day>11</day><month>3</month><year>2015</year></pub-date><pub-date pub-type="ppub"><year>2015</year></pub-date><volume>134</volume><issue>6</issue><fpage>511</fpage><lpage>538</lpage><history><date date-type="received"><day>31</day><month>12</month><year>2014</year></date><date date-type="accepted"><day>23</day><month>2</month><year>2015</year></date></history><permissions><copyright-statement>© The Author(s) 2015</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold>This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.</license-p></license></permissions><abstract id="Abs1"><p>Hereditary spastic paraplegias (HSP) are rare neurodegenerative diseases sharing the degeneration of the corticospinal tracts as the main pathological characteristic. They are considered one of the most heterogeneous neurological disorders. All modes of inheritance have been described for the 84 different loci and 67 known causative genes implicated up to now. Recent advances in molecular genetics have revealed clinico-genetic heterogeneity of these disorders including their clinical and genetic overlap with other diseases of the nervous system. The systematic analysis of a large set of genes, including exome sequencing, is unmasking unusual phenotypes or inheritance modes associated with mutations in HSP genes and related genes involved in various neurological diseases. A new nosology may emerge after integration and understanding of these new data to replace the current classification. Collectively, functions of the known genes implicate the disturbance of intracellular membrane dynamics and trafficking as the consequence of alterations of cytoskeletal dynamics, lipid metabolism and organelle structures, which represent in fact a relatively small number of cellular processes that could help to find common curative approaches, which are still lacking.</p><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1007/s00439-015-1536-7) contains supplementary material, which is available to authorized users.</p></sec></abstract><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© Springer-Verlag Berlin Heidelberg 2015</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1" sec-type="introduction"><title>Introduction</title><p>Hereditary spastic paraplegia (HSP) refers to a group of neurological diseases caused by corticospinal tract degeneration (Tallaksen et al. <xref ref-type="bibr" rid="CR136">2001</xref>; Fink <xref ref-type="bibr" rid="CR49">2003</xref>, <xref ref-type="bibr" rid="CR50">2013</xref>). Approximately, 1 to 10/100,000 people are affected by HSP, depending on the geographical area (Ruano et al. <xref ref-type="bibr" rid="CR119">2014</xref>). Patients suffer from the presence of pyramidal signs predominating in lower limbs (LL), which include spasticity (stiff legs) and exaggerated reflexes, associated to muscular weakness that can progress to spastic paralysis of the legs (paraplegia) (Harding <xref ref-type="bibr" rid="CR64">1983</xref>; Fink <xref ref-type="bibr" rid="CR49">2003</xref>). Pyramidal signs in the upper limbs (UL), as well as distal LL muscle wasting, may appear after long disease durations. Spasticity is usually more severe during gait than at rest. Patients present a swaying, scissor-like, shuffling gait. Age at onset is widely variable, from early childhood to late adulthood. An early sign of spastic paraplegia is the wearing down of the soles of the shoes at the toes and on the inner sides, because of the typical spasticity of adductor muscles and tiptoe gait.</p><p>Historically, cases are distinguished as pure or complicated on clinical grounds (Harding <xref ref-type="bibr" rid="CR64">1983</xref>), even if recent knowledge of these diseases has demonstrated that this is not always correlated with their genetic bases and can vary between patients in the same family. Pure forms are characterized by pyramidal signs, associated with muscle weakness and bladder dysfunction, but patients may also have decreased vibration sense at ankles or pes cavus. Patients rarely need a wheelchair but may use canes during the disease course, and they have usually, except in some clinico-genetic entities, a normal lifespan. In complicated forms, additional neurological signs are observed, such as cerebellar signs, neuropathy, mental/cognitive impairment, epilepsy, extrapyramidal and retinal signs, as well as extra-neurological signs such as gastroesophageal reflux, cataract and abnormal skin pigmentation. In complex forms, the functional handicap and lifespan will depend on the full clinical picture.</p><p>At present, therapeutic options are very limited. For all patients except those with inborn errors of metabolism, rehabilitation therapies with an interdisciplinary approach to maintain autonomy as much as possible, physiotherapy and training are the best treatment options. Regular physical therapy is important to maintain muscle strength and to preserve range of motion and, based on passive tendon stretching, gait and equilibrium rehabilitation. According to the functional repercussion of spasticity, medications such as oral baclofen, intramuscular botulinum toxin or intrathecal baclofen can be of some benefit to patients. Orthopedic options such as special shoes for pes cavus or achilles tendotomy for equinovarus are also proposed to allow a longer autonomous gait. Sphincter disturbances should be investigated by specialists and with a view to possible treatment with anticholinergics, antimuscarinic agents or botulinum toxin injections into the bladder (Fink <xref ref-type="bibr" rid="CR50">2013</xref>; Ginsberg et al. <xref ref-type="bibr" rid="CR54">2013</xref>). Additional symptoms of complex forms can also be treated, such as parkinsonism with levodopa (Anheim et al. <xref ref-type="bibr" rid="CR5">2009</xref>).</p></sec><sec id="Sec2"><title>Exclusion diagnosis</title><p>There are various acquired and genetic causes that should be ruled out in patients with the symptom of spastic paraplegia without a family history (Table <xref rid="Tab1" ref-type="table">1</xref>). Cerebral and spinal magnetic resonance imaging (MRI) investigations are important to rule out common neurological conditions and structural anomalies (e.g., spinal cord compression). For example, a frontal interhemispheric tumor may manifest as progressive spastic paraplegia with sphincter disturbances before other signs such as cognitive deterioration, headache or visual troubles appear. Disease progression, age at onset, additional symptoms and results from other supplementary investigations such as cerebrospinal fluid (CSF) analyses, blood biochemistry and serology, electroneuromyography and ophthalmological examination can give important clues to the diagnosis (Table <xref rid="Tab1" ref-type="table">1</xref>). All these investigations will first exclude acquired causes of spastic paraplegia but will subsequently help with the diagnostic workflow to find the correct genetic diagnosis. Some apparently sporadic cases are in fact masked familial diseases. The absence of a family history in neurogenetic disorders is frequent in clinical practice and several explanations for apparent isolation are reduced penetrance, age-dependent penetrance, variable expressivity, de novo mutation, early death of the transmitting parent or underdiagnosis in pure dominant forms with mild symptoms, autosomal recessive inheritance in small kindreds or, more rarely, X-linked inheritance in affected men. Among other inherited neurogenetic conditions that must be ruled out are leukodystrophies, in the absence of inflammation but in the presence of MRI abnormalities. Biochemical analyses in serum and/or CSF can suggest neurometabolic diseases. Finally, dopa-responsive dystonias (DRD) are a group of autosomal dominant or recessive diseases, which may present with spasticity and can mimic HSP. The dystonic toe is well known and can be misdiagnosed as extensor plantar reflex (Furukawa et al. <xref ref-type="bibr" rid="CR53">2001</xref>). Diurnal fluctuations and high and sustained sensibility to levodopa are characteristic of DRD.<table-wrap id="Tab1"><label>Table 1</label><caption><p>List of the most important differential diagnoses to hereditary spastic paraplegia with suggested supplementary investigations</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left">Type of disease</th><th align="left">Disease</th><th align="left">Investigations</th><th align="left">Characteristics other than spasticity and Babinski sign<sup>b</sup></th></tr></thead><tbody><tr><td align="left" rowspan="5">Structural anomalies and trauma</td><td align="left">Arnold–Chiari malformation</td><td align="left">Brain and spine MRI</td><td align="left">Ataxia, dizziness, unsteadiness</td></tr><tr><td align="left">Tumor</td><td align="left">Brain and spine MRI</td><td align="left">Headache if brain tumor, other focal symptoms</td></tr><tr><td align="left">Spinal cord vascular malformation</td><td align="left">MRI/spinal angiography</td><td align="left">Fluctuating symptoms/sudden onset</td></tr><tr><td align="left">Vertebral disorders with myelopathy</td><td align="left">Spine MRI</td><td align="left">Sensory symptoms, pain</td></tr><tr><td align="left">Spinal cord injury</td><td align="left">Spine MRI</td><td align="left">Sudden onset, trauma</td></tr><tr><td align="left">Inflammatory</td><td align="left">Primary progressive or relapsing-remitting multiple sclerosis</td><td align="left">Brain and spine MRI, CSF investigations including immunoelectrophoresis (evoked responses)</td><td align="left">Symptoms from different topographic regions</td></tr><tr><td align="left" rowspan="2">Neurodegenerative</td><td align="left">Spinocerebellar ataxias</td><td align="left">Genetic screening, brain MRI</td><td align="left">Ataxia</td></tr><tr><td align="left">Amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS)</td><td align="left">Spine and brain MRI, neurography, electromyography, CSF investigations</td><td align="left">Often bulbar signs and rapid progression, weakness, increased reflexes. In ALS; upper and lower motor neuron signs</td></tr><tr><td align="left">Acquired</td><td align="left">Diplegic cerebral palsy (Little disease)</td><td align="left">Brain MRI, antenatal, birth or postnatal history</td><td align="left">Non-progressive</td></tr><tr><td align="left" rowspan="4">Infectious</td><td align="left">Neurosyphilis</td><td align="left">Syphilis serology/CSF investigations</td><td align="left">Acute/subacute, and chronic, laboratory findings, often peripheral nervous system findings</td></tr><tr><td align="left">HTLV-1 infection (tropical spastic paraparesis)</td><td align="left">Serum/CSF HTLV-1 antibodies</td><td align="left">Subacute onset, laboratory findings</td></tr><tr><td align="left">Acquired immune deficiency syndrome (AIDS)</td><td align="left">HIV test</td><td align="left">Subacute onset, laboratory findings</td></tr><tr><td align="left">Neuroborreliosis</td><td align="left">Serology/CSF investigations</td><td align="left">Subacute onset, laboratory findings and/or symptoms from other topographic regions other than upper motor neuron</td></tr><tr><td align="left">Metabolic<sup>a</sup></td><td align="left" colspan="3">Leukodystrophies</td></tr><tr><td align="left" rowspan="17"></td><td align="left"> X-linked adrenoleukodystrophies</td><td align="left">Brain MRI, measurement of very long-chain fatty acids in plasma</td><td align="left">Neuropathy, cognitive decline, white matter changes</td></tr><tr><td align="left"> Metachromatic leukodystrophy (late-onset forms)</td><td align="left">Brain MRI, arylsulphatase A dosage</td><td align="left">Neuropathy, behavioral signs and regression</td></tr><tr><td align="left" colspan="3"> Hereditary CNS demyelinating disease</td></tr><tr><td align="left"> Krabbe leukodystrophy (late-onset forms)</td><td align="left">Brain MRI, galactocerebrosidase deficiency</td><td align="left">Neuropathy, regression</td></tr><tr><td align="left"> Pelizaeus–Merzbacher disease</td><td align="left">Brain MRI</td><td align="left">Nystagmus, ataxia, developmental delay</td></tr><tr><td align="left"> Canavan disease</td><td align="left">Brain MRI, excessive urinary NAA excretion</td><td align="left">Blindness, severe mental defect, megalocephaly</td></tr><tr><td align="left"> Leukoencephalopathy with vanishing white matter</td><td align="left">Brain MRI</td><td align="left">Also known as childhood ataxia with central nervous system hypomyelination (CACH) or vanishing white matter disease</td></tr><tr><td align="left"> Alexander disease</td><td align="left">Brain MRI</td><td align="left">Seizures, megalencephaly, developmental delay; In older patients, bulbar or pseudobulbar signs</td></tr><tr><td align="left"> Sjögren–Larsson syndrome (progressive forms)</td><td align="left">Brain MRI, low fatty aldehyde dehydrogenase activity</td><td align="left">Ichthyosis, mental retardation, macular dystrophy and leukoencephalopathy</td></tr><tr><td align="left"> Refsum disease</td><td align="left">Brain MRI, accumulation of an unusual branched-chain fatty acid, phytanic acid, in blood and tissues</td><td align="left">Retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia</td></tr><tr><td align="left"> Cerebrotendinous xanthomatosis</td><td align="left">Brain MRI, deposits of cholesterol and cholestanol in virtually every tissue</td><td align="left">Cerebellar ataxia beginning after puberty and pseudobulbar phase leading to premature death</td></tr><tr><td align="left">Subacute combined degeneration of the cord and anemia/Lichtheim disease</td><td align="left">Blood cell counts, vitamin B12 dosage, Schilling test (vitamin B12 absorption)</td><td align="left">Neuropathy, anemia</td></tr><tr><td align="left">Amino acid disorders, e.g., Arginase deficiency</td><td align="left">Plasma arginine level, aminoaciduria, genetic screening</td><td align="left">Developmental delay, intellectual disability, seizures, tremor, ataxia, fluctuating symptoms</td></tr><tr><td align="left">Mitochondrial disorders</td><td align="left">Lactate and pyruvate levels in blood and CSF, muscle biopsy</td><td align="left">Dependent of the heteroplasmy levels, symptoms from different organs (multisystemic)</td></tr><tr><td align="left">Abetalipoproteinemia</td><td align="left">Lipoprotein electrophoresis</td><td align="left">Neuropathy, ataxia</td></tr><tr><td align="left">Vitamin E deficiency</td><td align="left">Serum vitamin E level</td><td align="left">Often with neuropathy and ataxia</td></tr><tr><td align="left">Dystonia (including dopa-responsive dystonias)</td><td align="left"><sc>l</sc>-Dopa trial, neurotransmitter investigations in CSF, CSF/serum glucose ratio for GLUT1 deficiency, genetic screening (heterozygous <italic>GCH1</italic> mutations and to a lesser extend biallelic <italic>TH</italic> and <italic>SPR</italic> mutations for dopa-responsive forms, heterozygous <italic>SLC2A1</italic> mutations in DYT9/GLUT1)</td><td align="left">Early-onset, fluctuating symptoms/diurnal variation</td></tr><tr><td align="left" rowspan="2">Brain metal accumulation disorders</td><td align="left">Wilson disease (progressive forms)</td><td align="left">Brain MRI, serum copper and ceruloplasmin, 24-h urine copper; liver tissue biopsy</td><td align="left">Basal ganglia dysfunction symptoms</td></tr><tr><td align="left">Neurodegeneration with brain iron accumulation (NBIA)</td><td align="left">Brain MRI, genetic screening (particularly <italic>PANK2, COASY, PLA2G6, ATP13A2, WDR45</italic> and allelic HSP forms; <italic>FA2H/SPG35, C19orf12/SPG43</italic>)</td><td align="left">Early onset and rapid progression particularly in PANK2 mutated patients, dystonia, central region of hyperintensity in the globus pallidus with surrounding hypointensity on T2-weighted images (“eye-of-the-tiger sign”)</td></tr><tr><td align="left" rowspan="3">Toxic causes</td><td align="left">Neurolathyrism</td><td align="left">Epidemical context, Africa</td><td align="left">Ingestion of certain vegetables of the genus <italic>Lathyrus</italic> (peas…), subacute</td></tr><tr><td align="left">Konzo</td><td align="left">Epidemical context, Africa</td><td align="left">Improper preparation and ingestion of cassava roots, onset less than one week later, non-progressive</td></tr><tr><td align="left">Heavy metals (copper, manganese, lead)</td><td align="left">Brain and spine MRI, CSF investigations</td><td align="left">Diffuse clinical picture, exposure context to heavy metals</td></tr></tbody></table><table-wrap-foot><p><italic>CNS</italic> central nervous system, <italic>CSF</italic> cerebrospinal fluid, <italic>HIV</italic> human immunodeficiency virus, <italic>HTLV-1</italic> Human T cell leukemia/lymphoma virus type 1, <italic>MRI</italic> magnetic resonance imaging, <italic>NAA</italic><italic>N</italic>-acetylaspartic acid</p><p><sup>a</sup>The list is not complete, but the main groups with the most important subgroups are mentioned</p><p><sup>b</sup>Extensor response of the cutaneous plantar reflex</p></table-wrap-foot></table-wrap></p><p>The exploration of rare genetic disorders is an important issue since some diseases associated with spasticity are treatable. In particular, spastic paraparesis can be one of the multiple presentations of inborn errors of metabolism in children and adults and in some cases the symptom spastic paraparesis remains the only symptom for years; therefore, these metabolic causes should be included in the general diagnostic approach to sporadic spastic paraparesis due to treatment options (e.g., diet for argininemia, biotin in biotinidase deficiency) (Tanyel and Mancano <xref ref-type="bibr" rid="CR137">1997</xref>; Sedel et al. <xref ref-type="bibr" rid="CR124">2007</xref>) (<ext-link ext-link-type="uri" xlink:href="http://www.treatable-id.org">www.treatable-id.org</ext-link>).</p></sec><sec id="Sec3"><title>Genetic aspects of HSP</title><p>Genetic analysis of HSP genes can be performed when, according to the clinical symptoms and signs, other important causes have been excluded. HSP genes are denoted Spastic Paraplegia Gene followed by a number according to their order of discovery (SPGn). Up to now, the clinical phenotype and age at onset were critical to prioritize molecular testing because of the heterogeneity of these diseases at the clinical and genetic levels (Supplementary Fig. S1). More than 25 novel causative genes have been reported in 2013–2014 due to next-generation sequencing methods, making this genetic workflow time-consuming (Martin et al. <xref ref-type="bibr" rid="CR91">2013</xref>; Oates et al. <xref ref-type="bibr" rid="CR101">2013</xref>; Boukhris et al. <xref ref-type="bibr" rid="CR18">2013</xref>; Landouré et al. <xref ref-type="bibr" rid="CR82">2013</xref>; Novarino et al. <xref ref-type="bibr" rid="CR100">2014</xref>; Dor et al. <xref ref-type="bibr" rid="CR37">2014</xref>; Esteves et al. <xref ref-type="bibr" rid="CR44">2014</xref>; Crow et al. <xref ref-type="bibr" rid="CR28">2014</xref>), even if there are some genes that are still more frequent than others and may be analyzed first, such as <italic>SPAST</italic> (SPG4) and <italic>KIAA1840</italic> (SPG11) (see below). All classical modes of transmission can be found and there are at least 67 genes that, when mutated, can account for these diseases (Table <xref rid="Tab2" ref-type="table">2</xref>) to which can be added additional genes for which spasticity can be present as part of the clinical presentation (Supplementary Table 1).<table-wrap id="Tab2"><label>Table 2</label><caption><p>HSP genes and their associated phenotypes</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left">SPG no (HUGO) (inheritance)</th><th align="left">Chr<break></break>Gene<break></break>(OMIM no)</th><th align="left">Age at onset (y)</th><th align="left">Pure (P) or Complex (C) forms</th><th align="left">Associated clinical features<break></break>(OMIM no)<break></break>Functional tests, biomarkers</th><th align="left">MRI features</th><th align="left">References</th><th align="left">Allelic disorders<break></break>(OMIM no)<sup>b</sup></th></tr></thead><tbody><tr><td align="left">SPG1<break></break>(X-linked)</td><td align="left">Xq28<break></break><italic>L1CAM</italic><break></break>(308840)</td><td align="left">Congenital</td><td align="left">C</td><td align="left">MASA syndrome (Mental retardation Aphasia Shuffling gait and Adducted thumb) or CRASH syndrome (Corpus callosum hypoplasia Retardation Adducted thumb Spastic paraplegia and Hydrocephalus) (303350)</td><td align="left">Agenesis of the corpus callosum and hydrocephalus</td><td align="left">Rosenthal et al. (<xref ref-type="bibr" rid="CR228">1992</xref>)<break></break>Jouet et al. (<xref ref-type="bibr" rid="CR214">1994</xref>)</td><td align="left">Hydrocephaly (307000);<break></break>Corpus callosum agenesis (304100)</td></tr><tr><td align="left">SPG2<break></break>(X-linked)</td><td align="left">Xq22.2<break></break><italic>PLP1</italic><break></break>(300401)</td><td align="left">Variable</td><td align="left">P or C</td><td align="left">Spastic paraplegia with nystagmus, cerebellar dysfunction, hypotonia, MR and sometimes dementia or seizures (312920)</td><td align="left">WMH</td><td align="left">Cremers et al. (<xref ref-type="bibr" rid="CR204">1987</xref>)<break></break>Saugier-Veber et al. (<xref ref-type="bibr" rid="CR229">1994</xref>)</td><td align="left">Pelizaeus–Merzbacher disease (312080)</td></tr><tr><td align="left">SPG3/SPG3A<break></break>(AD/AR)</td><td align="left">14q22.1<break></break><italic>ATL1</italic><break></break>(606439)</td><td align="left"><1 to 51<break></break>(mainly <10)</td><td align="left">P (C)</td><td align="left">Pure form, rarely with axonal neuropathy or amyotrophy, incomplete penetrance (182600) </td><td align="left">Normal<break></break>(one family with late onset and TCC)</td><td align="left">Zhao et al. (<xref ref-type="bibr" rid="CR249">2001</xref>)</td><td align="left">Hereditary sensory neuropathy type ID, AD (613708)</td></tr><tr><td align="left">SPG4<break></break>(AD)</td><td align="left">2p22.3<break></break><italic>SPAST</italic><break></break>(604277)</td><td align="left">1–80</td><td align="left">P (C)</td><td align="left">Pure, rarely with cognitive impairment or neuropathy; epilepsy, ataxia and ALS in one family, incomplete penetrance (182601)</td><td align="left">Normal<break></break>(WMH in one family)</td><td align="left">Hazan et al. (<xref ref-type="bibr" rid="CR67">1999</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG5/SPG5A<break></break>(AR)</td><td align="left">8q12.3<break></break><italic>CYP7B1</italic><break></break>(603711)</td><td align="left">4–47</td><td align="left">P or C</td><td align="left">Pure or with cerebellar signs, nystagmus, cognitive impairment and amyotrophy (270800)<break></break>27-hydroxy-cholesterol accumulation in blood and CSF</td><td align="left">Normal (rarely WMH)</td><td align="left">Tsaousidou et al. (<xref ref-type="bibr" rid="CR241">2008</xref>)<break></break>Schüle et al. (<xref ref-type="bibr" rid="CR123">2010</xref>)</td><td align="left">Bile acid synthesis defect<break></break>(613812);<break></break>Sensory ataxia</td></tr><tr><td align="left">SPG6<break></break>(AD)</td><td align="left">15q11.2<break></break><italic>NIPA1</italic><break></break>(608145)</td><td align="left">8–37</td><td align="left">P (C)</td><td align="left">Pure, rarely with neuropathy or epilepsy or memory impairment<break></break>(600363)</td><td align="left">Normal</td><td align="left">Rainier et al. (<xref ref-type="bibr" rid="CR225">2003</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG7<break></break>(AR)</td><td align="left">16q24.3<break></break><italic>SPG7</italic><break></break>(602783)</td><td align="left">4–42</td><td align="left">P or C</td><td align="left">Pure or with optic neuropathy or cerebellar ataxia<break></break>(607259)<break></break>Mito DNA deletions, defects in Mito respiration</td><td align="left">Normal or cerebellar atrophy</td><td align="left">Casari et al. (<xref ref-type="bibr" rid="CR20">1998</xref>)<break></break>Wedding et al. (<xref ref-type="bibr" rid="CR150">2014</xref>)</td><td align="left">Optic neuropathy, AD;<break></break>Late-onset ataxia susceptibility, AD</td></tr><tr><td align="left">SPG8<break></break>(AD)</td><td align="left">8q24.13<break></break><italic>KIAA0196</italic><break></break>(610657)</td><td align="left">10–60</td><td align="left">P (C)</td><td align="left">Rarely complex with neuropathy<break></break>(603563)<break></break>Decreased Cho & Cr/NAA peak at PMRS</td><td align="left">Normal, or few white matter abnormalities and atrophy of the thoracic spinal cord</td><td align="left">Valdmanis et al. (<xref ref-type="bibr" rid="CR144">2007</xref>)<break></break>Wang et al. (<xref ref-type="bibr" rid="CR246">2014</xref>)</td><td align="left">Ritscher–Schinzel syndrome, AR (220210)</td></tr><tr><td align="left">SPG9<break></break>(AD)</td><td align="left">10q23.3-q24.2-</td><td align="left">1–30</td><td align="left">C</td><td align="left">Bilateral cataracts, gastroesophageal reflux, neuropathy, amyotrophy (601162)</td><td align="left">Normal (atrophy limited to spinal cord)</td><td align="left">Seri et al. (<xref ref-type="bibr" rid="CR233">1999</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG10<break></break>(AD)</td><td align="left">12q13.3<break></break><italic>KIF5A</italic><break></break>(602821)</td><td align="left">2–51</td><td align="left">P or C</td><td align="left">Pure or with neuropathy (Silver syndrome)<break></break>(604187)</td><td align="left">Normal</td><td align="left">Reid et al. (<xref ref-type="bibr" rid="CR226">2002</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG11<break></break>(AR)</td><td align="left">15q21.1<break></break><italic>KIAA1840</italic><break></break>(610844)</td><td align="left"><1 to 33</td><td align="left">P or C</td><td align="left">Mostly complex with cognitive decline, neuropathy, retinopathy (Kjellin syndrome) and cerebellar signs<break></break>(604360)</td><td align="left">TCC, WMH and cerebellar atrophy</td><td align="left">Stevanin et al. (<xref ref-type="bibr" rid="CR130">2007b</xref>)</td><td align="left">Juvenile amyotrophic lateral sclerosis (ALS-5), Orlacchio et al. (<xref ref-type="bibr" rid="CR223">2010</xref>)</td></tr><tr><td align="left">SPG12<break></break>(AD)</td><td align="left">19q13.32<break></break><italic>RTN2</italic><break></break>(603183)</td><td align="left">7–24</td><td align="left">P</td><td align="left">Pure<break></break>(604805)</td><td align="left">Normal or with WMH</td><td align="left">Montenegro et al. (<xref ref-type="bibr" rid="CR95">2012</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG13<break></break>(AD)</td><td align="left">2q33.1<break></break><italic>HSPD1</italic><break></break>(118190)</td><td align="left">17–68</td><td align="left">P</td><td align="left">Pure<break></break>(605280)</td><td align="left">Normal</td><td align="left">Hansen et al. (<xref ref-type="bibr" rid="CR63">2002</xref>)</td><td align="left">Hypomyelinating leukodystrophy type 4, AR (612233)</td></tr><tr><td align="left">SPG14<break></break>(AR)</td><td align="left">3q27-q28</td><td align="left">~30</td><td align="left">C</td><td align="left">Distal motor neuropathy, mild MR, visual agnosia, and memory deficiency<break></break>(605229)</td><td align="left">Normal</td><td align="left">Vazza et al. (<xref ref-type="bibr" rid="CR243">2000</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG15<break></break>(AR)</td><td align="left">14q24.1<break></break><italic>ZFYVE26</italic><break></break>(612012)</td><td align="left">4–19</td><td align="left">P or C</td><td align="left">Mostly complex with cognitive decline, neuropathy, retinopathy (Kjellin syndrome) and cerebellar signs<break></break>(270700)</td><td align="left">TCC, WMH and cerebellar atrophy</td><td align="left">Hanein et al. (<xref ref-type="bibr" rid="CR211">2008</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG16<break></break>(X-linked)</td><td align="left">Xq11.2</td><td align="left">Early infancy</td><td align="left">P or C</td><td align="left">Pure or complex with quadriplegia, motor aphasia, mild MR, and bowel and bladder dysfunction<break></break>(300266)</td><td align="left">Delayed myelination</td><td align="left">Steinmüller et al. (<xref ref-type="bibr" rid="CR236">1997</xref>)<break></break>Tamagaki et al. (<xref ref-type="bibr" rid="CR238">2000</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG17<break></break>(AD)</td><td align="left">11q12.3<break></break><italic>BSCL2</italic><break></break>(606158)</td><td align="left">2–60</td><td align="left">C</td><td align="left">Silver syndrome: neuropathy, amyotrophy<break></break>(270685)</td><td align="left">Normal</td><td align="left">Magré et al. (<xref ref-type="bibr" rid="CR90">2001</xref>); Windpassinger et al. (<xref ref-type="bibr" rid="CR152">2004</xref>)</td><td align="left">Congenital lipodystrophy type 2, AR (260700); <break></break>Hereditary motor neuropathy type VA, AD (600794); <break></break>Progressive encephalopathy, AR (615924)</td></tr><tr><td align="left">SPG18<break></break>(AR)</td><td align="left">8p11.23<break></break><italic>ERLIN2</italic><break></break>(611605)</td><td align="left"><2</td><td align="left">C</td><td align="left">ID and contractures<break></break>(611225)</td><td align="left">Normal</td><td align="left">Yıldırım et al. (<xref ref-type="bibr" rid="CR154">2011</xref>)</td><td align="left">Juvenile primary lateral sclerosis, AR</td></tr><tr><td align="left">SPG19<break></break>(AD)</td><td align="left">9q33-q34</td><td align="left">36–55</td><td align="left">P</td><td align="left">Pure<break></break>(607152)</td><td align="left">Normal</td><td align="left">Valente et al. (<xref ref-type="bibr" rid="CR242">2002</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG20<break></break>(AR)</td><td align="left">13q12.3<break></break><italic>SPG20/KIAA0610</italic><break></break>(607111)</td><td align="left">Infancy</td><td align="left">C</td><td align="left">Troyer Syndrome: dysarthria, distal amyotrophy in hands and feet, cerebellar signs, mild ID and skeletal abnormalities (short stature)<break></break>(275900)</td><td align="left">WMH</td><td align="left">Patel et al. (<xref ref-type="bibr" rid="CR224">2002</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG21<break></break>(AR)</td><td align="left">15q22.31<break></break><italic>SPG21/ACP33</italic><break></break>(608181)</td><td align="left">Adulthood</td><td align="left">C</td><td align="left">Mast syndrome: speech decline leading to akinetic mutism, personality disturbances, psychotic episodes, cognitive decline and cerebellar dysfunction (incoordination and dysdiadochokinesia). For a Japanese family: cognitive decline and apraxia (248900)</td><td align="left">TCC, WMH and cerebellar atrophy</td><td align="left">Simpson et al. (<xref ref-type="bibr" rid="CR234">2003</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG22<break></break>(X-linked)</td><td align="left">Xq13.2<break></break><italic>SLC16A2</italic><break></break>(300095)</td><td align="left">Early infancy</td><td align="left">C</td><td align="left">Allan–Herndon–Dudley syndrome: spastic quadriplegia, severe MR, central hypotonia, muscle hypoplasia, dystonia, ataxia<break></break>(300523)<break></break>Abnormal relative concentrations of circulating iodothyronines</td><td align="left">Normal or most often delayed myelination with sometimes TCC and mild cortical atrophy</td><td align="left">Dumitrescu et al. (<xref ref-type="bibr" rid="CR207">2004</xref>)<break></break>Schwartz et al. (<xref ref-type="bibr" rid="CR232">2005</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG23<break></break>(AR)</td><td align="left">1q24-q32</td><td align="left">Infancy</td><td align="left">C</td><td align="left">Lison syndrome: abnormal skin and hair pigmentation, ± dysmorphisms, skeletal deformities, MR or sensorimotor neuropathy<break></break>(270750)</td><td align="left">Normal or slight enlargement of the ventricles with ± microcephaly</td><td align="left">Blumen et al. (<xref ref-type="bibr" rid="CR201">2003</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG24<break></break>(AR)</td><td align="left">13q14</td><td align="left">Infancy</td><td align="left">P</td><td align="left">Pure<break></break>(607584)</td><td align="left">Normal</td><td align="left">Hodgkinson et al. (<xref ref-type="bibr" rid="CR212">2002</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG25<break></break>(AR)</td><td align="left">6q23-24.1</td><td align="left">30–46</td><td align="left">C</td><td align="left">Mild sensorimotor neuropathy<break></break>(608220)</td><td align="left">Spinal disc herniation with minor spondylosis</td><td align="left">Zortea et al. (<xref ref-type="bibr" rid="CR251">2002</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG26<break></break>(AR)</td><td align="left">12q13.3<break></break><italic>B4GALNT1</italic><break></break>(601873)</td><td align="left">2–19</td><td align="left">C</td><td align="left">ID, cerebellar ataxia, peripheral neuropathy, and one family presents behavioral problems<break></break>(609195)<break></break>Decreased GM2 and increased GM3 in fibroblasts. Low testosterone level in men</td><td align="left">Normal or after long disease duration cortical and subcortical atrophy and/or WMH</td><td align="left">Boukhris et al. (<xref ref-type="bibr" rid="CR18">2013</xref>)<break></break>Harlalka et al. (<xref ref-type="bibr" rid="CR65">2013</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG27<break></break>(AR)</td><td align="left">10q22.1-q24.1</td><td align="left">P: 25–45<break></break>C: 2–7</td><td align="left">P or C</td><td align="left">Pure or with sensorimotor polyneuropathy and sometimes with MR, cerebellar signs and skeletal abnormalities<break></break>(609041)</td><td align="left">Normal or mild cortical<break></break>and cerebellar atrophy</td><td align="left">Meijer et al. (<xref ref-type="bibr" rid="CR220">2004</xref>)<break></break>Ribai et al. (<xref ref-type="bibr" rid="CR227">2006</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG28<break></break>(AR)</td><td align="left">14q22.1<break></break><italic>DDHD1</italic><break></break>(614603)</td><td align="left">7–15</td><td align="left">P or C</td><td align="left">Pure or with cerebellar oculomotor disturbances or axonal neuropathy<break></break>(609340)<break></break>Ventricular lactate accumulation and reduction of PCr/Pi ratio in muscles</td><td align="left">Normal</td><td align="left">Tesson et al. (<xref ref-type="bibr" rid="CR239">2012</xref>)<break></break>Liguori et al. (<xref ref-type="bibr" rid="CR216">2014</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG29<break></break>(AD)</td><td align="left">1p31.1-21.1</td><td align="left">Infancy</td><td align="left">C</td><td align="left">Neonatal hyperbilirubinemia, hearing impairment due to auditory neuropathy and persistent vomiting due to hiatal hernia<break></break>(609727)</td><td align="left">Normal</td><td align="left">Orlacchio et al. (<xref ref-type="bibr" rid="CR221">2005</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG30<break></break>(AR)</td><td align="left">2q37.3<break></break><italic>KIF1A</italic><break></break>(601255)</td><td align="left">10–39</td><td align="left">P or C</td><td align="left">Pure or with sensory neuropathy and cerebellar ataxia<break></break>(610357)</td><td align="left">Normal or mild cerebellar atrophy</td><td align="left">Erlich et al. (<xref ref-type="bibr" rid="CR43">2011</xref>); Klebe et al. (<xref ref-type="bibr" rid="CR79">2012b</xref>)</td><td align="left">Complex MR with axial hypotonia, spasticity and cerebellar atrophy, AD (614255); <break></break>Sensory and autonomic neuropathy, AR (614213)</td></tr><tr><td align="left">SPG31<break></break>(AD)</td><td align="left">2p11.2<break></break><italic>REEP1</italic><break></break>(609139)</td><td align="left">Variable</td><td align="left">P or C</td><td align="left">Pure or sometimes complex with neuropathy<break></break>(610250)</td><td align="left">Normal</td><td align="left">Züchner et al. (<xref ref-type="bibr" rid="CR158">2006</xref>)</td><td align="left">Distal hereditary motor neuropathy type VB, AD (614751)</td></tr><tr><td align="left">SPG32<break></break>(AR)</td><td align="left">14q12-q21</td><td align="left">6–7</td><td align="left">C</td><td align="left">Mild MR<break></break>(611252)</td><td align="left">Cerebellar atrophy and pontine dysraphia, moderate TCC</td><td align="left">Stevanin et al. (<xref ref-type="bibr" rid="CR237">2007a</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG33<break></break>(AD)</td><td align="left">10q24.2<break></break><italic>ZFYVE27</italic><break></break>(610244)</td><td align="left">42–50</td><td align="left">P</td><td align="left">Pure<break></break>(610248)</td><td align="left">ND</td><td align="left">Mannan et al. (<xref ref-type="bibr" rid="CR219">2006</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG34<break></break>(X-linked)</td><td align="left">Xq24-q25</td><td align="left">16–25</td><td align="left">P</td><td align="left">Pure<break></break>(300750)</td><td align="left">ND</td><td align="left">Macedo-Souza et al. (<xref ref-type="bibr" rid="CR218">2008</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG35<break></break>(AR)</td><td align="left">16q23.1<break></break><italic>FA2H</italic><break></break>(611026)</td><td align="left">2–17 one family with late onset</td><td align="left">C</td><td align="left">Dystonia, LL amyotrophy, seizures, cerebellar signs, cognitive decline and optic atrophy<break></break>(612319)<break></break>Reduced hydroxylated fatty acid sphingomyelin in fibroblasts and erythrocytes</td><td align="left">Leukodystrophy, hypointensities of globus pallidus, TCC and cerebellar atrophy</td><td align="left">Edvardson et al. (<xref ref-type="bibr" rid="CR40">2008</xref>)<break></break>Dan et al. (<xref ref-type="bibr" rid="CR205">2011</xref>)</td><td align="left">Leukodystrophy/NBIA, AR</td></tr><tr><td align="left">SPG36<break></break>(AD)</td><td align="left">12q23-24</td><td align="left">14–33</td><td align="left">C</td><td align="left">Peripheral sensorimotor neuropathy<break></break>(613096)</td><td align="left">Normal</td><td align="left">Schüle et al. (<xref ref-type="bibr" rid="CR230">2009a</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG37<break></break>(AD)</td><td align="left">8p21.1-q13.3</td><td align="left">8–60</td><td align="left">P</td><td align="left">Pure<break></break>(611945)</td><td align="left">Normal</td><td align="left">Hanein et al. (<xref ref-type="bibr" rid="CR210">2007</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG38<break></break>(AD)</td><td align="left">4p16-p15</td><td align="left">16–19</td><td align="left">P</td><td align="left">Clinical features similar to SPG4<break></break>(612335)</td><td align="left">ND</td><td align="left">Orlacchio et al. (<xref ref-type="bibr" rid="CR222">2008</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG39<break></break>(AR)</td><td align="left">19p13.2<break></break><italic>PNPLA6</italic><break></break>(603197)</td><td align="left">Infancy, adolescence</td><td align="left">C</td><td align="left">Muscle wasting and motor axonopathy of the LL and UL<break></break>(612020)</td><td align="left">Normal</td><td align="left">Rainier et al. (<xref ref-type="bibr" rid="CR113">2008</xref>); Synofzik et al. (<xref ref-type="bibr" rid="CR134">2014</xref>)</td><td align="left">Boucher-Neuhauser syndrome (215470); <break></break>Gordon Holmes syndrome; <break></break>Spastic ataxia</td></tr><tr><td align="left">SPG41<break></break>(AD)</td><td align="left">11p14.1-11p.2</td><td align="left">Mean 17 ± 3</td><td align="left">P</td><td align="left">Pure<break></break>(613364)</td><td align="left">Normal</td><td align="left">Zhao et al. (<xref ref-type="bibr" rid="CR248">2008</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG42<break></break>(AD)</td><td align="left">3q25.31<break></break><italic>SLC33A1</italic><break></break>(603690)</td><td align="left">4–42</td><td align="left">P</td><td align="left">Pure<break></break>(612539)</td><td align="left">Normal</td><td align="left">Lin et al. (<xref ref-type="bibr" rid="CR217">2008</xref>)</td><td align="left">Congenital cataracts, hearing loss and neurodegeneration, AR (614482)</td></tr><tr><td align="left">SPG43<break></break>(AR)</td><td align="left">19p13.11-q12<break></break><italic>C19orf12</italic><break></break>(614297)</td><td align="left">7–12</td><td align="left">C</td><td align="left">Neuropathy and severe atrophy and decreased sensation in the arms and legs<break></break>(615043)</td><td align="left">Normal</td><td align="left">Landouré et al. (<xref ref-type="bibr" rid="CR82">2013</xref>)</td><td align="left">NBIA4 (614298); <break></break>Pallido-pyramidal syndrome</td></tr><tr><td align="left">SPG44<break></break>(AR)</td><td align="left">1q42.13<break></break><italic>GJC2</italic><break></break>(608803)</td><td align="left">1st or 2nd decade</td><td align="left">C</td><td align="left">Dysarthria, cerebellar ataxia, mental impairment<break></break>(613206)<break></break>Reduced Cho/NAA and Cho/Cr ratios</td><td align="left">WMH</td><td align="left">Uhlenberg et al. (<xref ref-type="bibr" rid="CR143">2004</xref>)<break></break>Orthmann-Murphy et al. (<xref ref-type="bibr" rid="CR104">2009</xref>)</td><td align="left">Pelizaeus–Merzbacher-like hypomyelinating leukodystrophy (608804); <break></break>Hereditary lymphedema, AD (613480)</td></tr><tr><td align="left">SPG45<break></break>(AR)</td><td align="left">10q24.3-q25.1</td><td align="left">Infancy</td><td align="left">C</td><td align="left">MR and ocular signs<break></break>(613162)</td><td align="left">ND</td><td align="left">Dursun et al. (<xref ref-type="bibr" rid="CR208">2009</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG46<break></break>(AR)</td><td align="left">9p13.3<break></break><italic>GBA2</italic><break></break>(609471)</td><td align="left">1–16</td><td align="left">C</td><td align="left">Cerebellar ataxia, cataract and mental impairment, infertility in males<break></break>(614409)<break></break>GBA2 activity abolished in lymphoblasts and leukocytes</td><td align="left">TCC, cerebral and cerebellar atrophy</td><td align="left">Martin et al. (<xref ref-type="bibr" rid="CR91">2013</xref>)</td><td align="left">Spastic ataxia</td></tr><tr><td align="left">SPG47<break></break>(AR)</td><td align="left">1p13.2<break></break><italic>AP4B1</italic><break></break>(607245)</td><td align="left">Birth</td><td align="left">C</td><td align="left">Severe ID, absent speech, shy character, stereotypic laughter, muscular hypotonia, microcephaly, foot deformity, decreased muscle mass and growth retardation<break></break>(614066)</td><td align="left">Periventricular WMH and TCC</td><td align="left">Abou Jamra et al. (<xref ref-type="bibr" rid="CR1">2011</xref>)<break></break>Bauer et al. (<xref ref-type="bibr" rid="CR200">2012</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG48<break></break>(AR)</td><td align="left">7p22.1<break></break><italic>AP5Z1</italic><break></break>(613653)</td><td align="left">2–50</td><td align="left">P or C</td><td align="left">Pure or with cognitive impairment or MR<break></break>(613647)</td><td align="left">Normal or TCC and WMH</td><td align="left">Słabicki et al. (<xref ref-type="bibr" rid="CR235">2010</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG49<sup>a</sup><break></break>(denoted SPG56 by OMIM)<break></break>(AR)</td><td align="left">4q25<break></break><italic>CYP2U1</italic><sup>a</sup><break></break>(615030)</td><td align="left"><1–8</td><td align="left">P or C</td><td align="left">Mental impairment, dysarthria, dystonia and infraclinical axonal neuropathy<break></break>(615030)</td><td align="left">Normal or TCC, WMH and basal ganglion calcifications</td><td align="left">Tesson et al. (<xref ref-type="bibr" rid="CR239">2012</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG50<break></break>(AR)</td><td align="left">7q22.1<break></break><italic>AP4M1</italic><break></break>(602292)</td><td align="left">Infancy</td><td align="left">C</td><td align="left">Tetraplegic cerebral palsy with MR<break></break>(612936)</td><td align="left">WMH and cerebellar atrophy</td><td align="left">Verkerk et al. (<xref ref-type="bibr" rid="CR244">2009</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG51<break></break>(AR)</td><td align="left">15q21.2<break></break><italic>AP4E1</italic><break></break>(607244)</td><td align="left">Infancy</td><td align="left">C</td><td align="left">Similar to SPG47<break></break>(613744)</td><td align="left"></td><td align="left">Abou Jamra et al. (<xref ref-type="bibr" rid="CR1">2011</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG52<break></break>(AR)</td><td align="left">14q12<break></break><italic>AP4S1</italic><break></break>(607243)</td><td align="left">Infancy</td><td align="left">C</td><td align="left">Similar to SPG47<break></break>(614067)</td><td align="left"></td><td align="left">Abou Jamra et al. (<xref ref-type="bibr" rid="CR1">2011</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG53<break></break>(AR)</td><td align="left">8p22<break></break><italic>VPS37A</italic><break></break>(609927)</td><td align="left">1–2</td><td align="left">C</td><td align="left">Developmental and motor delay, delays in cognition and speech, marked kyphosis<break></break>(614898)</td><td align="left">Normal or mild WMH and mild ventriculomegaly</td><td align="left">Zivony-Elboum et al. (<xref ref-type="bibr" rid="CR250">2012</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG54<break></break>(AR)</td><td align="left">8p11.23<break></break><italic>DDHD2</italic><break></break>(615003)</td><td align="left"><2</td><td align="left">C</td><td align="left">ID or developmental delay, dysarthria, cerebellar signs and short stature<break></break>(615033)<break></break>Pathologic lipid peak at 1.3 ppm in brain</td><td align="left">TCC, WMH and spinal syrinx</td><td align="left">Schuurs-Hoeijmakers et al. (<xref ref-type="bibr" rid="CR231">2012</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG55<break></break>(AR)</td><td align="left">12q24.31<break></break><italic>C12orf65</italic><break></break>(613541)</td><td align="left">2–7</td><td align="left">C</td><td align="left">Optic atrophy, muscle atrophy and neuropathy or ID, neuropathy and ophthalmoplegia<break></break>(615035)<break></break>Decreased complex I and IV and sometimes V of the respiratory chain</td><td align="left">Normal or TCC and WMH</td><td align="left">Shimazaki et al. (<xref ref-type="bibr" rid="CR125">2012</xref>)</td><td align="left">Combined oxidative phosphorylation deficiency 7 (Leigh syndrome)<break></break>(613543)</td></tr><tr><td align="left">SPG56<sup>a</sup><break></break>(AR)</td><td align="left">4q25<break></break><italic>CYP2U1</italic><sup>a</sup><break></break>(615030)</td><td align="left"></td><td align="left"></td><td align="left">According to OMIM see SPG49<sup>a</sup></td><td align="left"></td><td align="left"></td><td align="left"></td></tr><tr><td align="left">SPG57<break></break>(AR)</td><td align="left">3q12.2<break></break><italic>TFG</italic><break></break>(602498)</td><td align="left">Infancy</td><td align="left">C</td><td align="left">Optic atrophy and axonal demyelinating motor neuropathy<break></break>(615658)</td><td align="left">Normal</td><td align="left">Ishiura et al. (<xref ref-type="bibr" rid="CR73">2012</xref>)<break></break>Beetz et al. (<xref ref-type="bibr" rid="CR13">2013</xref>)</td><td align="left">Chondosarcoma extrasqueletal myxoid, fused genes NR4A3/TFG (612237); <break></break>Motor and sensory neuropathy, AD (604484)</td></tr><tr><td align="left">SPG58<break></break>(AR, AD?)</td><td align="left">17p13.2<break></break><italic>KIF1C</italic><break></break>(603060)</td><td align="left">2–4</td><td align="left">P or C</td><td align="left">Mostly complex with ataxia, dysarthria, extrapyramidal chorea, hypotonia, developmental delay or MR and sometimes short stature. Mild phenotype at heterozygous state</td><td align="left">Normal or WMH</td><td align="left">Dor et al. (<xref ref-type="bibr" rid="CR37">2014</xref>)<break></break>Novarino et al. (<xref ref-type="bibr" rid="CR100">2014</xref>)<break></break>Caballero Oteyza et al. (<xref ref-type="bibr" rid="CR203">2014</xref>)</td><td align="left">Spastic ataxia SPAX2 (611302)</td></tr><tr><td align="left">SPG59<break></break>(AR)</td><td align="left">15q21.2<break></break><italic>USP8</italic><break></break>(603158)</td><td align="left">Infancy</td><td align="left">C</td><td align="left">Nystagmus, pes equinovarus and mild MR</td><td align="left">Normal</td><td align="left">Novarino et al. (<xref ref-type="bibr" rid="CR100">2014</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG60<break></break>(AR)</td><td align="left">3p22.2<break></break><italic>WDR48</italic><break></break>(612167)</td><td align="left">Infancy</td><td align="left">C</td><td align="left">Nystagmus and neuropathy</td><td align="left">Normal</td><td align="left">Novarino et al. (<xref ref-type="bibr" rid="CR100">2014</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG61<break></break>(AR)</td><td align="left">16p12.3<break></break><italic>ARL6IP1</italic><break></break>(603158)</td><td align="left">Infancy</td><td align="left">C</td><td align="left">Motor and sensory polyneuropathy with acropathy mutilation<break></break>(615685)</td><td align="left">Normal or mild dilatation of lateral ventricles</td><td align="left">Novarino et al. (<xref ref-type="bibr" rid="CR100">2014</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG62<break></break>(AR)</td><td align="left">10q24.31<break></break><italic>ERLIN1</italic><break></break>(611604)</td><td align="left">Infancy</td><td align="left">P</td><td align="left">Pure</td><td align="left">Normal</td><td align="left">Novarino et al. (<xref ref-type="bibr" rid="CR100">2014</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG63<break></break>(AR)</td><td align="left">1p13.3<break></break><italic>AMPD2</italic><break></break>(102771)</td><td align="left">Infancy</td><td align="left">C</td><td align="left">Short stature<break></break>615686</td><td align="left">WMH, TCC</td><td align="left">Novarino et al. (<xref ref-type="bibr" rid="CR100">2014</xref>)</td><td align="left">Pontocerebellar hypoplasia<break></break>(615809)</td></tr><tr><td align="left">SPG64<break></break>(AR)</td><td align="left">10q24.1<break></break><italic>ENTPD1</italic><break></break>(601752)</td><td align="left">1–4</td><td align="left">C</td><td align="left">Amyotrophy, cerebellar signs, moderate ID, aggressiveness, delayed puberty and microcephaly<break></break>(615683)</td><td align="left">WMH</td><td align="left">Novarino et al. (<xref ref-type="bibr" rid="CR100">2014</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG65<break></break>(AR)</td><td align="left">10q24.32 q24.33<break></break><italic>NT5C2</italic><break></break>(600417)</td><td align="left">Infancy</td><td align="left">P or C</td><td align="left">Amyotrophy, pes equinovarus and learning disability<break></break>(613162)</td><td align="left">TCC, WMH or delayed myelination</td><td align="left">Novarino et al. (<xref ref-type="bibr" rid="CR100">2014</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG66<break></break>(AR)</td><td align="left">5q32<break></break><italic>ARSI</italic><break></break>(610009)</td><td align="left">Infancy</td><td align="left">C</td><td align="left">Amyotrophy, pes equinovarus and severe sensory/motor polyneuropathy</td><td align="left">Corpus callosum and cerebellar hypoplasia, colpocephaly</td><td align="left">Novarino et al. (<xref ref-type="bibr" rid="CR100">2014</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG67<break></break>(AR)</td><td align="left">2q33.1<break></break><italic>PGAP1</italic><break></break>(611655)</td><td align="left"><1–4</td><td align="left">C</td><td align="left">Amyotrophy</td><td align="left">Corpus callosum agenesis, vermis hypoplasia, defective myelination</td><td align="left">Novarino et al. (<xref ref-type="bibr" rid="CR100">2014</xref>)</td><td align="left">Complex MR<break></break>(615802)</td></tr><tr><td align="left">SPG68<break></break>(AR)</td><td align="left">11q13.1<break></break><italic>FLRT1</italic><break></break>(604806)</td><td align="left">2–3</td><td align="left">C</td><td align="left">Optic atrophy, nystagmus, mild amyotrophy and peripheral neuropathy</td><td align="left">Normal</td><td align="left">Novarino et al. (<xref ref-type="bibr" rid="CR100">2014</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG69<break></break>(AR)</td><td align="left">1q31<break></break><italic>RAB3GAP2</italic><break></break>(609275)</td><td align="left"><1</td><td align="left">C</td><td align="left">Dysarthria, cataract, deafness and ID</td><td align="left">Normal</td><td align="left">Novarino et al. (<xref ref-type="bibr" rid="CR100">2014</xref>)</td><td align="left">Martsolf syndrome: (212720); <break></break>Warburg micro syndrome 2<break></break>(614225)</td></tr><tr><td align="left">SPG70<break></break>(AR)</td><td align="left">12q13.3<break></break><italic>MARS</italic><break></break>(156560)</td><td align="left"><1</td><td align="left">C</td><td align="left">Amyotrophy and Achilles tendon contracture</td><td align="left">ND</td><td align="left">Novarino et al. (<xref ref-type="bibr" rid="CR100">2014</xref>)</td><td align="left">Infantile liver failure syndrome (615486); <break></break>Charcot–Marie–Tooth disease like presentation, AD</td></tr><tr><td align="left">SPG71<break></break>(AR)</td><td align="left">5p13.3<break></break><italic>ZFR</italic><break></break>(615635)</td><td align="left">Infancy</td><td align="left">P</td><td align="left">Pure</td><td align="left">TCC</td><td align="left">Novarino et al. (<xref ref-type="bibr" rid="CR100">2014</xref>)</td><td align="left"></td></tr><tr><td align="left">SPG72<break></break>(AR/AD)</td><td align="left">5q31.2<break></break><italic>REEP2</italic><break></break>(609347)</td><td align="left">3–4</td><td align="left">P</td><td align="left">Pure<break></break>(615625)</td><td align="left">ND</td><td align="left">Esteves et al. (<xref ref-type="bibr" rid="CR44">2014</xref>)</td><td align="left"></td></tr><tr><td align="left">No SPG<break></break>(AR)</td><td align="left">1q21.3<break></break><italic>ADAR1</italic><break></break>(146920)</td><td align="left">2</td><td align="left">P</td><td align="left">Pure<break></break>Increased interferon level</td><td align="left">Normal</td><td align="left">Crow et al. (<xref ref-type="bibr" rid="CR28">2014</xref>)</td><td align="left">Aicardi–Goutière syndrome (615010); <break></break>Dyschromatosis symmetrica<break></break>AD (127400)</td></tr><tr><td align="left">No SPG<break></break>(AR/AD)</td><td align="left">9q22.32<break></break><italic>BICD2</italic><break></break>(609797)</td><td align="left">Infancy</td><td align="left">P or C</td><td align="left">Pure (AD) or complex with amyotrophy (AR)</td><td align="left">Normal</td><td align="left">Neveling et al. (<xref ref-type="bibr" rid="CR99">2013</xref>)<break></break>Oates et al. (<xref ref-type="bibr" rid="CR101">2013</xref>)<break></break>Novarino et al. (<xref ref-type="bibr" rid="CR100">2014</xref>)</td><td align="left">Spinal muscular atrophy<break></break>AD (615290)</td></tr><tr><td align="left">No SPG<break></break>(AR)</td><td align="left">5p15.2<break></break><italic>CCT5</italic><break></break>(610150)</td><td align="left">Infancy</td><td align="left">C</td><td align="left">Mutilating sensory neuropathy<break></break>(256840)</td><td align="left">ND</td><td align="left">Bouhouche et al. (<xref ref-type="bibr" rid="CR202">2006</xref>)</td><td align="left"></td></tr><tr><td align="left">No SPG<break></break>(AR)</td><td align="left">9p13.2<break></break><italic>EXOSC3</italic><break></break>(606489)</td><td align="left">Infancy</td><td align="left">C</td><td align="left">Mild cognitive impairment, nystagmus and distal amyotrophy</td><td align="left">Cerebellar atrophy or hypoplasia, and enlarged cisterna magna</td><td align="left">Wan et al. (<xref ref-type="bibr" rid="CR148">2012</xref>)<break></break>Zanni et al. (<xref ref-type="bibr" rid="CR155">2013</xref>)</td><td align="left">Pontocerebellar hypoplasia<break></break>(614678)</td></tr><tr><td align="left">No SPG<break></break>(AR)</td><td align="left">5p15.1<break></break><italic>FAM134B</italic><break></break>(613114)</td><td align="left">2–3</td><td align="left">C</td><td align="left">Motor and sensory neuropathy with ulcerations of limbs</td><td align="left">Normal</td><td align="left">Kurth et al. (<xref ref-type="bibr" rid="CR215">2009</xref>)<break></break>Ilgaz-Aydinlar et al. (<xref ref-type="bibr" rid="CR213">2014</xref>)</td><td align="left">Sensory and autonomic neuropathy (HSAN2B)<break></break>(613115)</td></tr><tr><td align="left">No SPG<break></break>(AR)</td><td align="left">1q42.13<break></break>IBA57<break></break>(615316)</td><td align="left">3–12</td><td align="left">C</td><td align="left">Distal amyotrophy, peripheral neuropathy optic nerve atrophy and reduced visual acuity (SPOAN-like phenotype)</td><td align="left">Normal or WMH foci sometimes with TCC and cerebellar atrophy.</td><td align="left">Lossos et al. (<xref ref-type="bibr" rid="CR86">2015</xref>)</td><td align="left">Multiple mitochondrial dysfunctions syndrome<break></break>(615330), Ajit Bolar et al. (<xref ref-type="bibr" rid="CR2">2013</xref>)</td></tr><tr><td align="left">No SPG<break></break>(AR)</td><td align="left">2q24.2<break></break><italic>IFIH1</italic><break></break>(606951)</td><td align="left">2</td><td align="left">P</td><td align="left">Pure<break></break>Increased Interferon level</td><td align="left">Normal</td><td align="left">Crow et al. (<xref ref-type="bibr" rid="CR28">2014</xref>)</td><td align="left">Aicardi–Goutière syndrome<break></break>(615846)</td></tr><tr><td align="left">No SPG<break></break>(AR)</td><td align="left">1q42.3<break></break><italic>LYST</italic><break></break>(606897)</td><td align="left">Late (48–58)</td><td align="left">C</td><td align="left">Cerebellar ataxia, peripheral neuropathy and large peroxidase-positive granules in granulocytes</td><td align="left">Mild cerebellar atrophy</td><td align="left">Shimazaki et al. (<xref ref-type="bibr" rid="CR126">2014</xref>)</td><td align="left">Chediak–Higashi syndrome<break></break>(214500)</td></tr><tr><td align="left">No SPG<break></break>(AR)</td><td align="left">19q13.1<break></break><italic>MAG</italic><break></break>(159460)</td><td align="left">Infancy</td><td align="left">C</td><td align="left">Cerebellar signs, nystagmus, and amyotrophy</td><td align="left">Normal</td><td align="left">Novarino et al. (<xref ref-type="bibr" rid="CR100">2014</xref>)</td><td align="left"></td></tr><tr><td align="left">No SPG<break></break>(Mito)</td><td align="left"><italic>MT</italic>-<italic>ATP6</italic><break></break>(516060)</td><td align="left">30–50</td><td align="left">P or C</td><td align="left">Pure or with neuropathy, cerebellar signs and cardiomyopathy</td><td align="left">ND</td><td align="left">Verny et al. (<xref ref-type="bibr" rid="CR245">2011</xref>)</td><td align="left">Leigh syndrome (551500); <break></break>Leber optic atrophy (535000); <break></break>Infantile bilateral striatal necrosis (500003); <break></break>Epilepsy and lactic acidosis<break></break>Infantile cardiomyopathy</td></tr><tr><td align="left">No SPG<break></break>(Mito)</td><td align="left"><italic>MT</italic>-<italic>CO3</italic><break></break>(516050)</td><td align="left">Infancy</td><td align="left">C</td><td align="left">Spastic paraparesis, ophthalmoparesis and lactic acidosis</td><td align="left">Basal ganglia hyperintensities (Leigh syndrome-like) and mild cerebral and cerebellar atrophy</td><td align="left">Tiranti et al. (<xref ref-type="bibr" rid="CR240">2000</xref>)</td><td align="left"></td></tr><tr><td align="left">No SPG<break></break>(Mito)</td><td align="left"><italic>MT</italic>-<italic>TI</italic><break></break>(590045)</td><td align="left">Adulthood</td><td align="left">P or C</td><td align="left">Pure with low heteroplasmy levels. Complex with high heteroplasmy levels, with ataxia, deafness, epilepsy, cardiomyopathy and hypogonadism</td><td align="left">ND</td><td align="left">Corona et al. (<xref ref-type="bibr" rid="CR25">2002</xref>)</td><td align="left"></td></tr><tr><td align="left">No SPG<break></break>(AR)</td><td align="left">13q14.3<break></break><italic>RNASEH2B</italic><break></break>(610326)</td><td align="left">18–21 months</td><td align="left">P</td><td align="left">Pure</td><td align="left">Normal</td><td align="left">Crow et al. (<xref ref-type="bibr" rid="CR28">2014</xref>)</td><td align="left">Aicardi–Goutière syndrome (610181)</td></tr><tr><td align="left">No SPG<break></break>(AR)</td><td align="left">13q11<break></break><italic>SACS</italic><break></break>(604490)</td><td align="left">Infancy</td><td align="left">C</td><td align="left">Spastic ataxia of Charlevoix Saguenay: early childhood onset of cerebellar ataxia, pyramidal tract signs and peripheral neuropathy, ± retinal striations on fundoscopy and thickening of the retinal nerve fiber layer on OCT</td><td align="left">Atrophy of the superior cerebellar vermis, hyperintensity of corticospinal tracts</td><td align="left">Engert et al. (<xref ref-type="bibr" rid="CR209">2000</xref>)</td><td align="left"></td></tr><tr><td align="left">No SPG<sup>a</sup> (denoted SPG49<sup>a</sup> by OMIM)<break></break>(AR)</td><td align="left">14q32.31<break></break><italic>TECPR2</italic><sup>a</sup><break></break>(615000)</td><td align="left">Infancy</td><td align="left">C</td><td align="left">Severe ID, rigid ataxic gait, brachycephalic microcephaly, fluctuating central hypoventilation, gastroesophageal reflux disease, wake apnea, areflexia and dysmorphic features<break></break>(615031)</td><td align="left">Ventriculomegaly, TCC, cerebral and cerebellar atrophy</td><td align="left">Oz-Levi et al. (<xref ref-type="bibr" rid="CR105">2012</xref>)</td><td align="left"></td></tr><tr><td align="left">No SPG<break></break>(AD)</td><td align="left">9p13<break></break><italic>VCP</italic><break></break>(601023)</td><td align="left">54–57</td><td align="left">C</td><td align="left">Case report: hereditary spastic paraplegia with Paget’s disease of bone.</td><td align="left">Normal</td><td align="left">Watts et al. (<xref ref-type="bibr" rid="CR247">2004</xref>) De bot et al. (<xref ref-type="bibr" rid="CR206">2012</xref>)</td><td align="left">Inclusion body myopathy (167320); <break></break>Amyotrophic lateral sclerosis (613954)</td></tr></tbody></table><table-wrap-foot><p><italic>AD</italic> autosomal dominant, <italic>ALS</italic> amyotrophic lateral sclerosis, <italic>AR</italic> autosomal recessive, <italic>Chr</italic> chromosome, <italic>Cho/Cr and Cho/NAA</italic> ratio choline to creatine or to NAA, <italic>CSF</italic> cerebrospinal fluid, <italic>GM2/3</italic> gangliosides monosialic 2 and 3, <italic>ID</italic> intellectual disability, <italic>LL</italic> lower limb, <italic>Mito</italic> mitochondrial, <italic>MR</italic> mental retardation, <italic>MRI</italic> magnetic resonance imaging, <italic>NAA</italic><italic>N</italic>-acetyl aspartate, <italic>nb</italic> number, <italic>NBIA</italic> neuronal brain iron accumulation disorders, <italic>ND</italic> not described, <italic>OCT</italic> ocular coherence tomography, <italic>PCr/Pi</italic> ratio of phosphocreatine to inorganic phosphate, <italic>PPM</italic> parts per million, <italic>PMRS</italic> proton magnetic resonance spectrometry, <italic>SPOAN</italic> spastic paraplegia, optic atrophy and neuropathy, <italic>TCC</italic> thin corpus callosum, <italic>UL</italic> upper limb, <italic>WMH</italic> white matter hyperintensity, <italic>y</italic> years</p><p><sup>a</sup>According to the HUGO nomenclature, SPG49 has been associated with <italic>CYP2U1</italic> mutations and SPG56 has not been associated to a specific gene. According to the OMIM numbering, SPG49 has been associated to <italic>TECPR2</italic> mutations and SPG56 to <italic>CYP2U1</italic> mutations</p><p><sup>b</sup>Inheritance mode is indicated when it differs from the one described in families with spasticity</p></table-wrap-foot></table-wrap></p><p>Autosomal dominant (AD) forms of HSP are mainly pure forms with ages at onset that can range from infancy to late adulthood. Mutations in <italic>SPAST</italic> (SPG4), <italic>ATL1</italic> (SPG3), <italic>KIF5A</italic> (SPG10) and <italic>REEP1</italic> (SPG31) are described as being responsible for around 50 % of all cases (Fig. <xref rid="Fig1" ref-type="fig">1</xref>) (Finsterer et al. <xref ref-type="bibr" rid="CR51">2012</xref>). <italic>SPAST</italic> point mutations and exonic rearrangements have been implicated in 10–40 % of the HSP patients (Hazan et al. <xref ref-type="bibr" rid="CR67">1999</xref>; Meijer et al. <xref ref-type="bibr" rid="CR93">2002</xref>; Beetz et al. <xref ref-type="bibr" rid="CR10">2006</xref>; Loureiro et al. <xref ref-type="bibr" rid="CR87">2013</xref>) and in up to 12 % of sporadic forms (Depienne et al. <xref ref-type="bibr" rid="CR34">2006</xref>).<fig id="Fig1"><label>Fig. 1</label><caption><p>Relative frequencies of the main autosomal dominant (<bold>a</bold>) and recessive (<bold>b</bold>) mutations in the SPATAX (<ext-link ext-link-type="uri" xlink:href="http://spatax.wordpress.com/">http://spatax.wordpress.com/</ext-link>) cohort (Goizet et al. <xref ref-type="bibr" rid="CR55">2009a</xref>, <xref ref-type="bibr" rid="CR56">b</xref>, <xref ref-type="bibr" rid="CR57">2011</xref>; Stevanin et al. <xref ref-type="bibr" rid="CR131">2008a</xref>; Tesson et al. (<xref ref-type="bibr" rid="CR239">2012</xref>); unpublished data)</p></caption><graphic xlink:href="439_2015_1536_Fig1_HTML" id="MO1"></graphic></fig></p><p>The autosomal recessive (AR) forms appear to be particularly prevalent where consanguinity is common such as in the Middle East or Mediterranean countries (Coutinho et al. <xref ref-type="bibr" rid="CR26">1999</xref>; Boukhris et al. <xref ref-type="bibr" rid="CR17">2009</xref>; Ruano et al. <xref ref-type="bibr" rid="CR119">2014</xref>), and lesser frequent in central Europe, Japan (Takiyama <xref ref-type="bibr" rid="CR135">2014</xref>) and USA (with the exception of communities such as the Amish). They are also more complex in clinical terms, associated with greater genetic heterogeneity (Table <xref rid="Tab2" ref-type="table">2</xref>) with an onset of symptoms that is generally early. Only two forms are associated with pure HSP, but this likely results from the assignment of few families each: SPG71 and SPG72. In complex forms, the associated signs may be subtle but important indicators of the mutated gene, such as cerebellar atrophy or cerebellar ataxia with optic atrophy in SPG7, developmental delay and short stature in SPG20 (Troyer syndrome), dysarthria, distal amyotrophy, premature aging and cognitive decline in SPG21 (Mast syndrome), peripheral neuropathy and abnormal skin and hair pigmentation in SPG23 (Lison syndrome) (Table <xref rid="Tab2" ref-type="table">2</xref>). Mental retardation or intellectual deterioration, thin corpus callosum (TCC) and axonal neuropathy are highly suggestive of SPG11 (Stevanin et al. <xref ref-type="bibr" rid="CR131">2008a</xref>). Finally, spastic ataxia with dysarthria, nystagmus and retinal striations is suggestive of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Mutations in the <italic>CYP7B1</italic> (SPG5), <italic>SPG7</italic>, <italic>KIAA1840</italic> (SPG11) and <italic>ZFYVE26</italic> (SPG15) genes are among the most frequently found but their relative frequencies vary according to the geographical origin (Stevanin et al. <xref ref-type="bibr" rid="CR131">2008a</xref>; Paisan-Ruiz et al. <xref ref-type="bibr" rid="CR106">2008</xref>; Erichsen et al. <xref ref-type="bibr" rid="CR42">2009</xref>; Goizet et al. <xref ref-type="bibr" rid="CR55">2009a</xref>; Schüle et al. <xref ref-type="bibr" rid="CR122">2009b</xref>; Arnoldi et al. <xref ref-type="bibr" rid="CR7">2012</xref>; Klebe et al. <xref ref-type="bibr" rid="CR78">2012a</xref>; Pfeffer et al. <xref ref-type="bibr" rid="CR109">2014</xref>) (Fig. <xref rid="Fig1" ref-type="fig">1</xref>). Point mutations or rearrangements in <italic>KIAA1840</italic> (SPG11) have been shown to account for approximately 20 % of AR-HSP (Stevanin et al. <xref ref-type="bibr" rid="CR131">2008a</xref>).</p><p>X-linked forms are rare and include two clinical entities well recognized by pediatricians (Table <xref rid="Tab2" ref-type="table">2</xref>): SPG1, caused by mutations in the neural cell adhesion molecule <italic>L1CAM</italic> gene, and SPG2, which results from mutations in the gene encoding the proteolipid protein (<italic>PLP1</italic>), a myelin component. SPG2 can also account for late-onset cases in women (Sivakumar et al. <xref ref-type="bibr" rid="CR127">1999</xref>).</p></sec><sec id="Sec4"><title>Phenotype–genotype correlations in HSP</title><p>Many studies have failed in the past to determine reliable phenotype–genotype correlations. However, the systematic analysis of a large set of genes, including exome sequencing, is regularly unmasking unusual phenotypes and inheritance modes associated with mutations in HSP genes and the nature of the mutation in some of them can now be correlated to a specific phenotype.</p><sec id="Sec5"><title>Instances where similar mutations are associated with a wide spectrum of HSP phenotypes; extension of the clinical picture previously observed</title><p>There are good examples of variable phenotypes among HSP subtypes, as SPG4 in which age at onset can vary from early childhood to asymptomatic status at old ages. As more families are reported with a mutation in a specific gene, the full spectrum of each genetic entity extends and there are now fewer than ten HSP loci/genes associated exclusively with pure forms of the disease, most of them accounting for single or only a few families so far (Table <xref rid="Tab2" ref-type="table">2</xref>; Supplementary Table 1). This was the case, for example, with SPG10, which was initially thought to be a pure form but now also accounts for 10 % of the complex AD families (Goizet et al. <xref ref-type="bibr" rid="CR56">2009b</xref>). In SPG7, the occurrence of cerebellar ataxia and/or atrophy (Klebe et al. <xref ref-type="bibr" rid="CR78">2012a</xref>) or progressive external ophthalmoplegia (Wedding et al. <xref ref-type="bibr" rid="CR150">2014</xref>; Pfeffer et al. <xref ref-type="bibr" rid="CR109">2014</xref>) suggests that the analysis of this gene should be extended to other phenotypes. Patients with isolated optic neuropathy should also be tested for mutations on <italic>SPG7</italic> (Klebe et al. <xref ref-type="bibr" rid="CR78">2012a</xref>).</p></sec><sec id="Sec6"><title>Instances where the nature of the mutations of a specific HSP gene can determine the inheritance model and/or associated phenotype</title><p>One of the recent advances in HSP genetics is the identification of various modes of inheritance of the mutations in single HSP genes. This is what occurs for <italic>REEP2</italic> mutations that have recently been implicated in three families with recessive or dominant transmission of a pure HSP, namely SPG72 (Novarino et al. <xref ref-type="bibr" rid="CR100">2014</xref>; Esteves et al. <xref ref-type="bibr" rid="CR44">2014</xref>). In one Portuguese family with AR inheritance, two mutations segregated in trans including a splice site mutation leading to a loss of function of the corresponding allele and a missense mutation responsible for reduced binding capacities to membranes of the protein formed from the second allele. In a French autosomal dominant family, the disease segregated with a heterozygous missense mutation that had a dominant negative effect on the capacity of the wild-type protein to bind membranes. In both cases, AD and AR mutations led to a complete loss of membrane binding capacities of the REEP2 protein with consequences for the tubular structure of the endoplasmic reticulum (ER) (Esteves et al. <xref ref-type="bibr" rid="CR44">2014</xref>). Recently, position p.Arg415 of Atlastin-1 (SPG3A) was shown to be a hotspot for missense mutations, first associated with incomplete penetrance with an AD inheritance pattern (D’Amico et al. <xref ref-type="bibr" rid="CR29">2004</xref>), and then with AR transmission (Varga et al. <xref ref-type="bibr" rid="CR145">2013</xref>) (Khan et al. <xref ref-type="bibr" rid="CR77">2014</xref>). Similarly, an unusual recessive or dominant inheritance has been suggested in <italic>SPAST</italic> (SPG4, Lindsey et al. <xref ref-type="bibr" rid="CR84">2000</xref>) and <italic>SPG7</italic> (McDermott et al. <xref ref-type="bibr" rid="CR92">2001</xref>; Sánchez-Ferrero et al. <xref ref-type="bibr" rid="CR120">2013</xref>), respectively.</p><p>The nature of the mutation and/or its localization in the protein can sometimes impact both the inheritance model and the phenotype at the same time, so that the nature of the mutation can predict the phenotype. This was observed with <italic>KIF1A</italic> (SPG30), in which missense homozygous mutations located in the kinesin motor domain account for a relatively pure HSP (Erlich et al. <xref ref-type="bibr" rid="CR43">2011</xref>; Klebe et al. <xref ref-type="bibr" rid="CR79">2012b</xref>), whereas heterozygous mutations located in the ATP binding site of KIF1A were found in patients with severe mental retardation with axial hypotonia, peripheral spasticity and mild atrophy of cerebellum and or corpus callosum, a phenotype reminiscent of SPG11 (Hamdan et al. <xref ref-type="bibr" rid="CR61">2011</xref>; Chang et al. <xref ref-type="bibr" rid="CR21">2014</xref>). Homozygous <italic>KIF1A</italic> frameshift mutations lead to hereditary sensory neuropathy type IIC (Rivière et al. <xref ref-type="bibr" rid="CR117">2011</xref>). Similarly, heterozygous mutations in <italic>HSPD1</italic> lead to SPG13 (Hansen et al. <xref ref-type="bibr" rid="CR63">2002</xref>), but homozygous missense mutations of the same gene are implicated in hypomyelinating leukodystrophy type 4 (Magen et al. <xref ref-type="bibr" rid="CR89">2008</xref>). Mutations in <italic>TFG</italic> are responsible for SPG57, an AR-HSP associated with optic atrophy and neuropathy (Beetz et al. <xref ref-type="bibr" rid="CR13">2013</xref>) but can also be responsible for AD motor and sensory neuropathy (Ishiura et al. <xref ref-type="bibr" rid="CR73">2012</xref>). Interestingly, the <italic>TFG</italic> mutations affect different domains of the protein: the coil–coil domain in the HSP family, the P/Q rich domain in the family with neuropathy, suggesting different pathological mechanisms. In addition, one patient with neuropathy had ubiquitin- and TDP43-positive cytoplasmic neuronal inclusions reminiscent of amyotrophic lateral sclerosis (ALS) (Supplementary Table 2), suggesting a toxic gain of function effect resulting in a dominant inheritance pattern. In contrast, biallelic mutations affect the capacity of TFG to self-assemble and then probably lead to a loss of function (Beetz et al. <xref ref-type="bibr" rid="CR13">2013</xref>). This is also the case with <italic>REEP1</italic>, in which frameshift mutations or missense mutations that abolish ER targeting and affect the capacity of the protein to bind ATL1 (Falk et al. <xref ref-type="bibr" rid="CR45">2002</xref>; Beetz et al. <xref ref-type="bibr" rid="CR12">2012</xref>) lead to HSP (Züchner et al. <xref ref-type="bibr" rid="CR158">2006</xref>; Beetz et al. <xref ref-type="bibr" rid="CR11">2008</xref>; Hewamadduma et al. <xref ref-type="bibr" rid="CR70">2009</xref>; Goizet et al. <xref ref-type="bibr" rid="CR57">2011</xref>), whereas in-frame deletions do not impact the capacity of the protein to bind ATL1 and lead to hereditary motor neuropathy type V (Beetz et al. <xref ref-type="bibr" rid="CR12">2012</xref>).</p></sec><sec id="Sec7"><title>Instances where the mutations of a specific HSP gene lead to overlapping diseases</title><p>During the past few years, it has appeared that HSP and other neurological conditions are at opposite ends of a continuum of overlapping diseases. The clinical overlap of HSP with peripheral neuropathies, cerebellar ataxias or mental disabilities is not new since mutated HSP patients can have a clinical presentation associating symptoms specific to these groups of disorders. ARSACS is a good illustration of this clinical overlap between ataxias and spastic paraplegias (Bouhlal et al. <xref ref-type="bibr" rid="CR16">2011</xref>). It is sometimes difficult to decide which symptom is most prominent in the clinical presentation and this may also depend on the physician’s expertise. The overlap between HSP and ataxias was again recently highlighted by mutations in <italic>GBA2</italic> (SPG46), which have been found in patients with spastic ataxia associated with cataract, having ataxia (Hammer et al. <xref ref-type="bibr" rid="CR62">2013</xref>; Votsi et al. <xref ref-type="bibr" rid="CR146">2014</xref>) or spasticity (Martin et al. <xref ref-type="bibr" rid="CR91">2013</xref>; Citterio et al. <xref ref-type="bibr" rid="CR22">2014</xref>) as the prominent clinical feature. Point mutations and exonic deletions in <italic>KIF1C</italic> have both been reported in HSP (Novarino et al. <xref ref-type="bibr" rid="CR100">2014</xref>) and spastic ataxia (Dor et al. <xref ref-type="bibr" rid="CR37">2014</xref>), illustrating the fact that both diseases are part of the same clinical spectrum. <italic>PNPLA6</italic> mutations are found in patients with a wide range of phenotypes: Gordon Holmes spinocerebellar syndrome (ataxia with brisk reflexes and hypogonadism), Boucher-Neuhäuser syndrome (ataxia with chorioretinal dystrophy and hypogonadism), isolated cerebellar ataxia and isolated spastic paraplegia (SPG39) (Rainier et al. <xref ref-type="bibr" rid="CR113">2008</xref>; Synofzik et al. <xref ref-type="bibr" rid="CR134">2014</xref>).</p><p>Regarding motor neuron diseases and polyneuropathies (Fig. <xref rid="Fig2" ref-type="fig">2</xref>), HSP genes have been found mutated in patients with (i) peripheral nerve affections such as Charcot–Marie–Tooth (CMT) neuropathies, (ii) first and secondary motor neuron degeneration, such as ALS, and (iii) lower motor neuron disorders such as spinal muscular atrophy (SMA). For example, <italic>KIAA1840</italic><italic>(SPG11)</italic> mutations may mimic ALS5 when muscle wasting is marked in absence of other complicated signs, or complex HSP in presence of cerebellar and cognitive signs (Stevanin et al. <xref ref-type="bibr" rid="CR130">2007b</xref>, <xref ref-type="bibr" rid="CR131">2008a</xref>; Orlacchio et al. <xref ref-type="bibr" rid="CR223">2010</xref>; Daoud et al. <xref ref-type="bibr" rid="CR30">2012</xref>; Romagnolo et al. <xref ref-type="bibr" rid="CR118">2014</xref>). Similarly, mutations in <italic>TFG</italic> can also be associated with HSP (SPG57) and ALS-like presentations (Ishiura et al. <xref ref-type="bibr" rid="CR73">2012</xref>; Beetz et al. <xref ref-type="bibr" rid="CR13">2013</xref>). <italic>BIDC2</italic> mutations are mainly responsible for SMA phenotypes but can cause HSP as well (Neveling et al. <xref ref-type="bibr" rid="CR99">2013</xref>; Oates et al. <xref ref-type="bibr" rid="CR101">2013</xref>). <italic>ERLIN2</italic> mutations are responsible for SPG18 (Yıldırım et al. <xref ref-type="bibr" rid="CR154">2011</xref>; Alazami et al. <xref ref-type="bibr" rid="CR3">2011</xref>; Wakil et al. <xref ref-type="bibr" rid="CR147">2013</xref>) but also account for juvenile primary lateral sclerosis, another neurodegenerative disorder of the upper motor neuron overlapping HSP phenotype (Al-Saif et al. <xref ref-type="bibr" rid="CR4">2012</xref>). Finally, missense mutations in <italic>KIF5A</italic> affecting the kinesin motor domain, or in <italic>MARS</italic> (SPG70) encoding the methionyl-tRNA synthase essential for protein biosynthesis (Deniziak and Barciszewski <xref ref-type="bibr" rid="CR32">2001</xref>), are responsible for pure (Reid et al. <xref ref-type="bibr" rid="CR114">2000</xref>) or complex forms of HSP with neuropathy or amyotrophy (Tessa et al. <xref ref-type="bibr" rid="CR139">2008</xref>; Goizet et al. <xref ref-type="bibr" rid="CR56">2009b</xref>; Musumeci et al. <xref ref-type="bibr" rid="CR98">2011</xref>; Crimella et al. <xref ref-type="bibr" rid="CR27">2012</xref>; Collongues et al. <xref ref-type="bibr" rid="CR24">2013</xref>; Novarino et al. <xref ref-type="bibr" rid="CR100">2014</xref>; Liu et al. <xref ref-type="bibr" rid="CR85">2014</xref>) but also CMT (Crimella et al. <xref ref-type="bibr" rid="CR27">2012</xref>; Gonzalez et al. <xref ref-type="bibr" rid="CR58">2013</xref>; Liu et al. <xref ref-type="bibr" rid="CR85">2014</xref>). In <italic>MARS</italic>, the mutations identified in CMT-like disease and in HSP patients are located in different domains.<fig id="Fig2"><label>Fig. 2</label><caption><p>Clinico-genetic entities associated with hereditary spastic paraplegia (HSP) according to the motor neuron phenotypic presentation. When mutated, HSP genes can be associated with various phenotypes that overlap with upper and lower motor neuron diseases</p></caption><graphic xlink:href="439_2015_1536_Fig2_HTML" id="MO2"></graphic></fig></p><p>Other examples are the <italic>FA2H</italic> and <italic>C9ORF12</italic> genes, which can be found mutated in patients with neuronal brain iron accumulation (NBIA) or spastic paraplegia (Edvardson et al. <xref ref-type="bibr" rid="CR40">2008</xref>; Schneider and Bhatia <xref ref-type="bibr" rid="CR121">2010</xref>; Dick et al. <xref ref-type="bibr" rid="CR36">2010</xref>; Kruer et al. <xref ref-type="bibr" rid="CR81">2010</xref>; Hartig et al. <xref ref-type="bibr" rid="CR66">2011</xref>; Landouré et al. <xref ref-type="bibr" rid="CR82">2013</xref>). There are also two genes in which mutations are associated with complex HSP but also account for pontocerebellar hypoplasia: <italic>AMPD2</italic> (SPG63) and <italic>EXOSC3</italic> (Wan et al. <xref ref-type="bibr" rid="CR148">2012</xref>; Zanni et al. <xref ref-type="bibr" rid="CR155">2013</xref>; Novarino et al. <xref ref-type="bibr" rid="CR100">2014</xref>). <italic>GJC2</italic> accounts for complex HSP associated with dysarthria, cerebellar ataxia and mental impairment (Orthmann-Murphy et al. <xref ref-type="bibr" rid="CR104">2009</xref>) and hypomyelinating leukodystrophy Pelizaeus–Merzbacher-like disease (Uhlenberg et al. <xref ref-type="bibr" rid="CR143">2004</xref>). Similarly, <italic>PGAP1</italic> and <italic>C12ORF65</italic> have been reported mutated in encephalomyopathies (Antonicka et al. <xref ref-type="bibr" rid="CR6">2010</xref>; Murakami et al. <xref ref-type="bibr" rid="CR97">2014</xref>), but they are also mutated in patients with complex HSP (Shimazaki et al. <xref ref-type="bibr" rid="CR125">2012</xref>; Tucci et al. <xref ref-type="bibr" rid="CR142">2013</xref>; Spiegel et al. <xref ref-type="bibr" rid="CR128">2014</xref>; Novarino et al. <xref ref-type="bibr" rid="CR100">2014</xref>).</p></sec><sec id="Sec8"><title>Instances where mutations can either account for HSP or multisystemic disorders</title><p>Several genes mutated in HSP can also be responsible for multisystemic disorders in which spasticity can be part of the phenotype or even absent. Some of these genes cause developmental disorders such as those involving mutations in genes coding for adaptor protein complex 4 (AP4) (SPG47, 50, 51 and 52) (Moreno-De-Luca et al. <xref ref-type="bibr" rid="CR96">2011</xref>; Abou Jamra et al. <xref ref-type="bibr" rid="CR1">2011</xref>). <italic>KIAA0196</italic> is mutated in pure AD-HSP (SPG8) patients (Valdmanis et al. <xref ref-type="bibr" rid="CR144">2007</xref>), but also in complex cases in which the spasticity decreased upon levodopa treatment (Bettencourt et al. <xref ref-type="bibr" rid="CR14">2013</xref>), and recently a homozygous splice site mutation leading to exon 27 skipping was involved in Ritscher–Schinzel syndrome, a developmental syndrome with craniofacial abnormalities, congenital heart defects and cerebellar brain malformations (Elliott et al. <xref ref-type="bibr" rid="CR41">2013</xref>).</p><p>Biallelic mutations in <italic>IBA57</italic>, encoding a Fe/S mitochondrial protein assembly factor, can be responsible for a slowly progressive childhood-onset HSP (Lossos et al. <xref ref-type="bibr" rid="CR86">2015</xref>), up to multiple mitochondrial dysfunction syndrome 3 (MMDS3; OMIM #615330), a severe lethal encephalopathy with multiple malformations, myopathy and hyperglycinemia (Ajit Bolar et al. <xref ref-type="bibr" rid="CR2">2013</xref>). Mutations in <italic>LYST</italic> were first described in Chediak–Higashi syndrome, a disease characterized by decreased pigmentation, photophobia, nystagmus and abnormal susceptibility to infection (Barbosa et al. <xref ref-type="bibr" rid="CR9">1997</xref>). Recently, one mutation was reported in a family with late-onset complex HSP with cerebellar ataxia, peripheral neuropathy and large peroxidase-positive granules in granulocytes (Shimazaki et al. <xref ref-type="bibr" rid="CR126">2014</xref>).</p><p>Finally, biallelic mutations in <italic>BSCL2</italic> are responsible for congenital generalized lipodystrophy type 2, characterized by severe lipoatrophy, insulin resistance, hypertriglyceridemia and mental retardation (Magré et al. <xref ref-type="bibr" rid="CR90">2001</xref>). In contrast, heterozygous missense mutations in its <italic>N</italic>-glycosylation motif (p.Asn88Ser and p.Ser90Leu) result in a toxic gain of function by ER-stress-mediated cell death responsible for motor neuron diseases, including SPG17 and hereditary motor neuropathy type V (Windpassinger et al. <xref ref-type="bibr" rid="CR152">2004</xref>; Ito and Suzuki <xref ref-type="bibr" rid="CR74">2009</xref>).</p></sec><sec id="Sec9"><title>Modifying factors</title><p>One striking observation is the large interfamilial but also intrafamilial phenotypic variability regarding age at onset and disease severity between patients, particularly in autosomal dominant HSP subtypes. Some SPG4 patients within the same family and carrying the same mutation may indeed remain asymptomatic throughout their life whereas others have an early onset and are severely affected and may present with additional features such as cognitive impairment and peripheral neuropathy. One major issue is therefore the identification of environmental or genetic modifiers in HSP. This has been especially studied in <italic>SPAST</italic>-positive patients; three modifier variants have been suggested so far: the rare p.Ser44Leu and p.Pro45Gln polymorphisms in <italic>SPAST</italic> and the p.Gly563Ala polymorphism located in <italic>HSPD1</italic> (HSP60/SPG13) (Svenson et al. <xref ref-type="bibr" rid="CR133">2004</xref>; Bross et al. <xref ref-type="bibr" rid="CR19">2008</xref>). Large population studies are still lacking to validate these findings.</p><p>Phenotypic variability is well known in mitochondrial disorders. The mitochondrial <italic>MT</italic>-<italic>TI</italic> mutation segregating in a HSP family is associated with a disease severity that is correlated to the level of heteroplasmy: from pure HSP in the proband showing 55 % heteroplasmy levels in muscles, to a multisystemic disorder with cardiomyopathy in the brother with heteroplasmy levels of 90 % (Corona et al. <xref ref-type="bibr" rid="CR25">2002</xref>).</p><p>Sex-dependent penetrance or severity has been suggested for <italic>SPAST</italic> mutations on the basis of a significant excess of affected males (Starling et al. <xref ref-type="bibr" rid="CR129">2002</xref>; Proukakis et al. <xref ref-type="bibr" rid="CR111">2011</xref>) and/or an earlier age at onset (Mitne-Neto et al. <xref ref-type="bibr" rid="CR94">2007</xref>) This was also suggested for <italic>ATL1</italic> mutations (Varga et al. <xref ref-type="bibr" rid="CR145">2013</xref>; Luo et al. <xref ref-type="bibr" rid="CR88">2014</xref>).</p><p>In other cases, a variant may be pathogenic when inherited as a recessive trait but may become a susceptibility factor for other neurological conditions at the heterozygous state. Recent observations in the gene encoding paraplegin are striking. SPG7 patients usually have pure or complex forms of HSP, mainly associated with cerebellar signs and optic atrophy. Interestingly, heterozygous carriers of <italic>SPG7</italic> truncating mutations can develop a late-onset cerebellar syndrome/atrophy without spasticity, suggesting a predisposition for late-onset neurodegenerative disorders of heterozygous SPG7 carriers, mimicking an autosomal dominant inheritance when children are carrying two causative mutations. Moreover, patients with the heterozygous p.Asp411Ala mutation were reported with optic atrophy without ataxia or spasticity in a large autosomal dominant kindred. <italic>SPG7</italic> has, therefore, to be considered in patients with late-onset cerebellar signs or optic atrophy, even in the absence of spasticity (Klebe et al. <xref ref-type="bibr" rid="CR78">2012a</xref>).</p></sec></sec><sec id="Sec10"><title>Genetic diagnosis of HSP</title><p>A genetic diagnosis workflow to be used in routine diagnosis is proposed in Supplementary Fig. 1 when new technologies are still not available. In sporadic and AD cases, <italic>ATL1</italic> and <italic>SPAST</italic> genes should be tested first depending on age at onset. Of note, up to 12 % of sporadic cases are mutated in the <italic>SPAST</italic> gene (Depienne et al. <xref ref-type="bibr" rid="CR34">2006</xref>; Beetz et al. <xref ref-type="bibr" rid="CR10">2006</xref>) while up to 40 % are mutated among autosomal dominant forms. Since 50 % of the mutations in SPG4 are larger deletions, duplications or complex genomic rearrangements (Beetz et al. <xref ref-type="bibr" rid="CR10">2006</xref>; Depienne et al. <xref ref-type="bibr" rid="CR35">2007</xref>), a dedicated technique (array-CGH, MLPA) has to be used in parallel. In AR cases, the genes to be tested are based on the associated phenotype. Indeed, the relative frequency of SPG11 varies according to phenotype (Stevanin et al. <xref ref-type="bibr" rid="CR131">2008a</xref>). SPG11 accounts for <1 % of patients with a pure phenotype, 4.5 % of cases with spastic paraplegia and cognitive impairment without thinning of the corpus callosum (TCC), but up to 59 % of persons with early-onset progressive spasticity with mild intellectual disability and/or cognitive decline associated with TCC. The other HSP genes are analyzed depending on the inheritance mode, the clinical presentation and the results of additional examinations.</p><p>However, the number of causative genes is growing very rapidly thanks to the improvement of sequencing techniques, and the classical testing of one gene after the other is progressively being replaced by diagnostic kits allowing multiple genes to be tested in parallel. Access to all SPG variants with such techniques may open opportunities to analyze their modifier effects in addition to the causative mutation in the near future. This may also represent a challenge for the interpretation of their effects since multiple variants with potential effects will likely be identified in more than one candidate gene. The development of common databases and of bioinformatics but also biological pipelines for analysis of the pathogenic effects will be required and will sometimes complicate the diagnosis workflow.</p><p>When a mutation is identified, genetic counseling and prenatal and presymptomatic testing are possible options.</p></sec><sec id="Sec11"><title>Physiopathology of HSP</title><p>Known HSP genes encode proteins involved mainly in ER morphogenesis, microtubule dynamics and transport, mitochondrial quality control, lipid metabolism and endosomal/lysosomal functions (Table <xref rid="Tab3" ref-type="table">3</xref>), and collectively suggest that HSP might be caused by impaired cellular trafficking (Stevanin et al. <xref ref-type="bibr" rid="CR132">2008b</xref>; Blackstone <xref ref-type="bibr" rid="CR15">2012</xref>).<table-wrap id="Tab3"><label>Table 3</label><caption><p>Functions of the proteins encoded by the genes involved in hereditary spastic paraplegia</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left">SPG no<break></break>(HUGO nomenclature)</th><th align="left"><italic>Gene</italic><break></break>(<italic>OMIM no</italic>)</th><th align="left">Chromosome</th><th align="left">Protein</th><th align="left">Protein function</th></tr></thead><tbody><tr><td align="left">SPG1</td><td align="left"><italic>L1CAM</italic><break></break>(308840)</td><td align="left">Xq28</td><td align="left">L1 cell adhesion molecule</td><td align="left">Axonal guidance</td></tr><tr><td align="left">SPG2</td><td align="left"><italic>PLP1</italic><break></break>(300401)</td><td align="left">Xq22.2</td><td align="left">Proteolipid protein 1</td><td align="left">Myelin component<break></break>Oligodendrocyte progenitor cell migration</td></tr><tr><td align="left">SPG3<break></break>SPG3A</td><td align="left"><italic>ATL1</italic><break></break>(606439)</td><td align="left">14q22.1</td><td align="left">Atlastin GTPase 1</td><td align="left">Formation of the tubular ER<break></break>Dendritic morphogenesis<break></break>Inhibit BMP signaling</td></tr><tr><td align="left">SPG4</td><td align="left"><italic>SPAST</italic><break></break>(604277)</td><td align="left">2p22.3</td><td align="left">Spastin</td><td align="left">Microtubule dynamics, BMP signaling</td></tr><tr><td align="left">SPG5/SPG5A</td><td align="left"><italic>CYP7B1</italic><break></break>(603711)</td><td align="left">8q12.3</td><td align="left">Cytochrome P450, family 7, subfamily B, polypeptide 1</td><td align="left">Hydroxylase, cholesterol and neurosteroïd metabolism</td></tr><tr><td align="left">SPG6</td><td align="left"><italic>NIPA1</italic><break></break>(608145)</td><td align="left">15q11.2</td><td align="left">NIPA1/non-imprinted in Prader Willi/Angelman syndrome 1</td><td align="left">Mg<sup>2+</sup> transporter<break></break>Inhibitor of BMP pathway</td></tr><tr><td align="left">SPG7</td><td align="left"><italic>SPG7</italic><break></break>(602783)</td><td align="left">16q24.3</td><td align="left">Paraplegin</td><td align="left">Component of the m-AAA protease</td></tr><tr><td align="left">SPG8</td><td align="left"><italic>KIAA0196</italic><break></break>(610657)</td><td align="left">8q24.13</td><td align="left">Strumpellin</td><td align="left">Actin remodeling</td></tr><tr><td align="left">SPG10</td><td align="left"><italic>KIF5A</italic><break></break>(602821)</td><td align="left">12q13.3</td><td align="left">Kinesin heavy chain isoform 5A</td><td align="left">Motor protein, axonal transport</td></tr><tr><td align="left">SPG11</td><td align="left"><italic>KIAA1840</italic><break></break>(610844)</td><td align="left">15q21.1</td><td align="left">Spatacsin</td><td align="left">Lysosome shaping</td></tr><tr><td align="left">SPG12</td><td align="left"><italic>RTN2</italic><break></break>(603183)</td><td align="left">19q13.32</td><td align="left">Reticulon 2</td><td align="left">ER shaping</td></tr><tr><td align="left">SPG13</td><td align="left"><italic>HSPD1</italic><break></break>(118190)</td><td align="left">2q33.1</td><td align="left">Heat shock 60 kDa protein 1/chaperonin</td><td align="left">Mitochondrial chaperone</td></tr><tr><td align="left">SPG15</td><td align="left"><italic>ZFYVE26</italic><break></break>(612012)</td><td align="left">14q24.1</td><td align="left">Spastizin</td><td align="left">Lysosome shaping, cytokinesis, autophagy</td></tr><tr><td align="left">SPG17</td><td align="left"><italic>BSCL2</italic><break></break>(606158)</td><td align="left">11q12.3</td><td align="left">Seipin</td><td align="left">ER protein, scaffolding protein for lipid metabolism and lipid droplet formation</td></tr><tr><td align="left">SPG18</td><td align="left"><italic>ERLIN2</italic><break></break>(611605)</td><td align="left">8p11.23</td><td align="left">SPFH2</td><td align="left">ER-associated degradation pathway (ERAD)</td></tr><tr><td align="left">SPG20</td><td align="left"><italic>KIAA0610</italic><break></break>(607111)</td><td align="left">13q12.3</td><td align="left">Spartin</td><td align="left">Cytokinesis, BMP signaling, Lipid droplet maintenance, Mitochondrial Ca<sup>2+</sup> homeostasis</td></tr><tr><td align="left">SPG21</td><td align="left"><italic>ACP33</italic><break></break>(608181)</td><td align="left">15q22.31</td><td align="left">Maspardin</td><td align="left">Associated predominantly with markers for the trans-Golgi and endocytic compartments</td></tr><tr><td align="left">SPG22</td><td align="left"><italic>SLC16A2</italic><break></break>(300095)</td><td align="left">Xq13.2</td><td align="left">Solute carrier family 16 (monocarboxylic acid transporter) member 2</td><td align="left">Thyroid hormone transporter</td></tr><tr><td align="left">SPG26</td><td align="left"><italic>B4GALNT1</italic><break></break>(601873)</td><td align="left">12q13.3</td><td align="left">Beta-1,4-<italic>N</italic>-acetyl-galactosaminyl transferase 1</td><td align="left">Ganglioside metabolism</td></tr><tr><td align="left">SPG28</td><td align="left"><italic>DDHD1</italic><break></break>(614603)</td><td align="left">14q22.1</td><td align="left">DDHD domain containing 1</td><td align="left">Phospholipase A1, lipid metabolism</td></tr><tr><td align="left">SPG30</td><td align="left"><italic>KIF1A</italic><break></break>(601255)</td><td align="left">2q37.3</td><td align="left">Kinesin family member 1A</td><td align="left">Motor protein, axonal anterograde transport</td></tr><tr><td align="left">SPG31</td><td align="left"><italic>REEP1</italic><break></break>(609139)</td><td align="left">2p11.2</td><td align="left">Receptor expression-enhancing protein 1</td><td align="left">ER-shaping, mitochondrial functions?</td></tr><tr><td align="left">SPG33</td><td align="left"><italic>ZFYVE27</italic><break></break>(610244)</td><td align="left">10q24.2</td><td align="left">ZFYVE27/Zinc Finger, FYVE domain containing 27/Protrudin</td><td align="left">ER morphology<break></break>Neurite outgrowth</td></tr><tr><td align="left">SPG35</td><td align="left"><italic>FA2H</italic><break></break>(611026)</td><td align="left">16q23.1</td><td align="left">Fatty acid 2-hydroxylase</td><td align="left">Myelin stability<break></break>Cell differentiation</td></tr><tr><td align="left">SPG39</td><td align="left"><italic>PNPLA6</italic><break></break>(603197)</td><td align="left">19p13.2</td><td align="left">Patatin-like phospholipase domain containing 6/neuropathy target esterase (NTE)</td><td align="left">Lipid metabolism<break></break>Membrane curvature</td></tr><tr><td align="left">SPG42</td><td align="left"><italic>SLC33A1</italic><break></break>(603690)</td><td align="left">3q25.31</td><td align="left">Solute carrier family 33 Acetyl-CoA transporter, member 1</td><td align="left">Acetyl-CoA transporter</td></tr><tr><td align="left">SPG43</td><td align="left"><italic>C19orf12</italic><break></break>(614297)</td><td align="left">19p13.11-q12</td><td align="left">Chromosome 19 open reading frame 12</td><td align="left">–</td></tr><tr><td align="left">SPG44</td><td align="left"><italic>GJC2</italic><break></break>(608803)</td><td align="left">1q42.13</td><td align="left">Gap junction protein, gamma 2, 47 kDa</td><td align="left">Oligodendrocyte connexin</td></tr><tr><td align="left">SPG46</td><td align="left"><italic>GBA2</italic><break></break>(609471)</td><td align="left">9p13.3</td><td align="left">Glucocerebrosidase 2</td><td align="left">Lipid metabolism</td></tr><tr><td align="left">SPG47</td><td align="left"><italic>AP4B1</italic><break></break>(607245)</td><td align="left">1p13.2</td><td align="left">Adaptor-related protein complex 4, beta 1 subunit</td><td align="left">Membrane trafficking</td></tr><tr><td align="left">SPG48</td><td align="left"><italic>AP5Z1</italic><break></break>(613653)</td><td align="left">7p22.1</td><td align="left">Adaptor-related protein complex 5, zeta 1 subunit</td><td align="left">Membrane trafficking</td></tr><tr><td align="left">SPG49<sup>a</sup><break></break>(denoted SPG56<sup>a</sup> by OMIM)</td><td align="left"><italic>CYP2U1</italic><sup>a</sup><break></break>(615030)</td><td align="left">4q25</td><td align="left">Cytochrome P450, family 2, subfamily U, polypeptide 1</td><td align="left">Lipid metabolism</td></tr><tr><td align="left">SPG50</td><td align="left"><italic>AP4M1</italic><break></break>(602292)</td><td align="left">7q22.1</td><td align="left">Adaptor-related protein complex 4, mu 1 subunit</td><td align="left">Membrane trafficking</td></tr><tr><td align="left">SPG51</td><td align="left"><italic>AP4E1</italic><break></break>(607244)</td><td align="left">15q21.2</td><td align="left">Adaptor-related protein complex 4, epsilon 1 subunit</td><td align="left">Membrane trafficking</td></tr><tr><td align="left">SPG52</td><td align="left"><italic>AP4S1</italic><break></break>(607243)</td><td align="left">14q12</td><td align="left">Adaptor-related protein complex 4, sigma 1 subunit</td><td align="left">Membrane trafficking</td></tr><tr><td align="left">SPG53</td><td align="left"><italic>VPS37A</italic><break></break>(609927)</td><td align="left">8p22</td><td align="left">Vacuolar protein sorting 37 homolog A</td><td align="left">Member of the ESCRT-I complex</td></tr><tr><td align="left">SPG54</td><td align="left"><italic>DDHD2</italic><break></break>(615003)</td><td align="left">8p11.23</td><td align="left">DDHD domain containing 2</td><td align="left">Phospholipase, lipid metabolism</td></tr><tr><td align="left">SPG55</td><td align="left"><italic>C12orf65</italic><break></break>(613541)</td><td align="left">12q24.31</td><td align="left">Chromosome 12 open reading frame 65</td><td align="left">Member of the mediated ribosome rescue system in mitochondria</td></tr><tr><td align="left">SPG56<sup>a</sup></td><td align="left"><italic>CYP2U1</italic><sup>a</sup><break></break>(615030)</td><td align="left">4q25</td><td align="left">See SPG49<sup>a</sup> and <italic>TECPR2</italic><sup>a</sup></td><td align="left"></td></tr><tr><td align="left">SPG57</td><td align="left"><italic>TFG</italic><break></break>(602498)</td><td align="left">3q12.2</td><td align="left">TRK-fused gene</td><td align="left">ER morphology, vesicle transport between ER and Golgi</td></tr><tr><td align="left">SPG58</td><td align="left"><italic>KIF1C</italic><break></break>(603060)</td><td align="left">17p13.2</td><td align="left">Kinesin family member 1C</td><td align="left">Motor protein, retrograde Golgi to ER transport</td></tr><tr><td align="left">SPG59</td><td align="left"><italic>USP8</italic><break></break>(603158)</td><td align="left">15q21.2</td><td align="left">Ubiquitin specific peptidase 8</td><td align="left">Deubiquitination enzyme</td></tr><tr><td align="left">SPG60</td><td align="left"><italic>WDR48</italic><break></break>(612167)</td><td align="left">3p22.2</td><td align="left">WD repeat domain 48</td><td align="left">Deubiquitination regulation</td></tr><tr><td align="left">SPG61</td><td align="left"><italic>ARL6IP1</italic><break></break>(603158)</td><td align="left">16p12.3</td><td align="left">ADP-ribosylation factor-like 6 interacting protein 1</td><td align="left">ER morphology</td></tr><tr><td align="left">SPG62</td><td align="left"><italic>ERLIN1</italic><break></break>(611604)</td><td align="left">10q24.31</td><td align="left">ER lipid raft associated 1</td><td align="left">ER-associated degradation</td></tr><tr><td align="left">SPG63</td><td align="left"><italic>AMPD2</italic><break></break>(102771)</td><td align="left">1p13.3</td><td align="left">Adenosine monophosphate deaminase 2</td><td align="left">Deaminates AMP to IMP in purine nucleotide metabolism</td></tr><tr><td align="left">SPG64</td><td align="left"><italic>ENTPD1</italic><break></break>(601752)</td><td align="left">10q24.1</td><td align="left">Ectonucleosidase triphosphate diphosphorylase 1</td><td align="left">Hydrolyzes ATP and other nucleotides to regulate purinergic transmission</td></tr><tr><td align="left">SPG65</td><td align="left"><italic>NT5C2</italic><break></break>(600417)</td><td align="left">10q24.32 q24.33</td><td align="left">Cytosolic 5′-nucleotidase</td><td align="left">Hydrolyses IMP in both purine/pyrimidine nucleotide metabolism</td></tr><tr><td align="left">SPG66</td><td align="left"><italic>ARSI</italic><break></break>(610009)</td><td align="left">5q32</td><td align="left">Arysulfatase I</td><td align="left">Hydrolyses sulfate esters, hormone biosynthesis</td></tr><tr><td align="left">SPG67</td><td align="left"><italic>PGAP1</italic><break></break>(611655)</td><td align="left">2q33.1</td><td align="left">GPI inositol deacylase</td><td align="left">GPI-AP sorting by ERES</td></tr><tr><td align="left">SPG68</td><td align="left"><italic>FLRT1</italic><break></break>(604806)</td><td align="left">11q13.1</td><td align="left">Fibronectin leucine rich transmembrane protein 1</td><td align="left">FGF pathway</td></tr><tr><td align="left">SPG69</td><td align="left"><italic>RAB3GAP2</italic><break></break>(609275)</td><td align="left">1q31</td><td align="left">RAB3 GTPase activating protein subunit 2</td><td align="left">ER morphology</td></tr><tr><td align="left">SPG70</td><td align="left"><italic>MARS</italic><break></break>(156560)</td><td align="left">12q13.3</td><td align="left">Methionyl-tRNA synthetase</td><td align="left">Cytosolic methionyl-tRNA synthetase</td></tr><tr><td align="left">SPG71</td><td align="left"><italic>ZFR</italic><break></break>(615635)</td><td align="left">5p13.3</td><td align="left">Zinc finger RNA binding protein</td><td align="left">–</td></tr><tr><td align="left">SPG72</td><td align="left"><italic>REEP2</italic><break></break>(609347)</td><td align="left">5q31.2</td><td align="left">Receptor expression-enhancing protein 2</td><td align="left">ER shaping</td></tr><tr><td align="left">No SPG</td><td align="left"><italic>ADAR1</italic><break></break>(146920)</td><td align="left">1q21.3</td><td align="left">Adenosine deaminase RNA-specific</td><td align="left">RNA metabolism</td></tr><tr><td align="left">No SPG</td><td align="left"><italic>BICD2</italic><break></break>(609797)</td><td align="left">9q22.32</td><td align="left">Bicaudal D homologue 2</td><td align="left">Adaptor protein of the dynein–dynactin motor complex</td></tr><tr><td align="left">No SPG</td><td align="left"><italic>CCT5</italic><break></break>(610150)</td><td align="left">5p15.2</td><td align="left">Chaperonin containing TCP1, subunit 5</td><td align="left">Cytosolic chaperonin</td></tr><tr><td align="left">No SPG</td><td align="left"><italic>EXOSC3</italic><break></break>(606489)</td><td align="left">9p13.2</td><td align="left">Exosome component 3</td><td align="left">Core component of the RNA exosome complex</td></tr><tr><td align="left">No SPG</td><td align="left"><italic>FAM134B</italic><break></break>(613114)</td><td align="left">5p15.1</td><td align="left">FAM134B</td><td align="left">Golgi protein</td></tr><tr><td align="left">No SPG</td><td align="left"><italic>IFIH1</italic><break></break>(606951)</td><td align="left">2q24.2</td><td align="left">Interferon-induced helicase C domain containing protein 1</td><td align="left">Interferon signaling</td></tr><tr><td align="left">No SPG</td><td align="left"><italic>LYST</italic><break></break>(606897)</td><td align="left">1q42.3</td><td align="left">Lysosomal trafficking regulator protein</td><td align="left">Lysosome fusion/fission regulation</td></tr><tr><td align="left">No SPG</td><td align="left"><italic>MAG</italic><break></break>(159460)</td><td align="left">19q13.1</td><td align="left">Myelin-associated glycoprotein</td><td align="left">Myelination</td></tr><tr><td align="left">No SPG</td><td align="left"><italic>MT</italic>-<italic>ATP6</italic><break></break>(516060)</td><td align="left"><italic>Mitochondrial</italic></td><td align="left">Complex V, ATP synthase, subunit ATPase 6</td><td align="left">Respiratory chain complex V subunit</td></tr><tr><td align="left">No SPG</td><td align="left"><italic>MT</italic>-<italic>CO3</italic><break></break>(516050)</td><td align="left"><italic>Mitochondrial</italic></td><td align="left">Cytochrome c oxydase III/Complex IV</td><td align="left">Respiratory chain complex IV subunit</td></tr><tr><td align="left">No SPG</td><td align="left"><italic>MT</italic>-<italic>TI</italic><break></break>(590045)</td><td align="left"><italic>Mitochondrial</italic></td><td align="left">Isoleucine transfer RNA (Mitochondrial)</td><td align="left">Mitochondria</td></tr><tr><td align="left">No SPG</td><td align="left"><italic>RNASEH2B</italic><break></break>(610326)</td><td align="left">13q14.3</td><td align="left">Ribonuclease H2 subunit B</td><td align="left">Metabolism of ribonucleotides</td></tr><tr><td align="left">No SPG</td><td align="left"><italic>SACS</italic><break></break>(604490)</td><td align="left">13q11</td><td align="left">Sacsin</td><td align="left">Chaperone</td></tr><tr><td align="left">No SPG (denoted SPG49<sup>a</sup> by OMIM)</td><td align="left"><italic>TECPR2</italic><sup>a</sup><break></break>(615000)</td><td align="left">14q32.31</td><td align="left">Tectonin beta-propeller repeat containing 2</td><td align="left">Autophagy pathway</td></tr><tr><td align="left">No SPG</td><td align="left"><italic>VCP</italic><break></break>(601023)</td><td align="left">9p13</td><td align="left">Valosin-containing protein</td><td align="left">Member of the AAA+ family; Role in the ubiquitin-proteasome system</td></tr><tr><td align="left">No SPG</td><td align="left"><italic>IBA57</italic><break></break>(615316)</td><td align="left">1q42</td><td align="left">Iron–sulfur cluster assembly homolog</td><td align="left">Part of the iron–sulfur cluster (ISC) assembly machinery in mitochondria</td></tr></tbody></table><table-wrap-foot><p><italic>(m)AAA</italic> (mitochondrial) ATPase associated with diverse cellular activities, <italic>BMP</italic> bone morphogenetic pathway, <italic>ER</italic> endoplasmic reticulum, <italic>ERES</italic> ER exit sites, <italic>ESCRT</italic> endosomal sorting complexes required for transport, <italic>FGF</italic> fibroblast growth factor, <italic>GPI-AP</italic> glycosylphosphatidylinositol-anchor protein, <italic>IMP</italic> inositol monophosphate</p><p><sup>a</sup>According to the HUGO nomenclature, SPG49 has been associated with <italic>CYP2U1</italic> mutations and SPG56 has not been associated to a specific gene. According to the OMIM numbering, SPG49 has been associated to <italic>TECPR2</italic> mutations and SPG56 to <italic>CYP2U1</italic> mutations</p></table-wrap-foot></table-wrap></p><p>Clear evidence of impaired trafficking comes from the involvement of KIF5A (SPG10), KIF1A (SPG30) and KIF1C (SAX2/SPAX2/SPG58), which are motor proteins (kinesins) involved in organelle/vesicle trafficking. In KIF5A, heterozygous missense mutations in the motor domain are associated with a reduced velocity along microtubules in gliding assays (Ebbing et al. <xref ref-type="bibr" rid="CR38">2008</xref>). There is also other evidence of trafficking disturbances in HSP. Neurons from knockout (KO) mice for <italic>Spast</italic> present with a marked impairment of microtubule dynamics along axons, accompanied by axonal swelling and cargo stalling (Tarrade et al. <xref ref-type="bibr" rid="CR138">2006</xref>; Kasher et al. <xref ref-type="bibr" rid="CR76">2009</xref>; Fassier et al. <xref ref-type="bibr" rid="CR47">2013</xref>). Spastin (SPAST/SPG4) is a microtubule-severing protein, which links cytoskeletal dynamics to membrane remodeling in several cellular processes. Abnormal axonal swellings have been also reported in <italic>Plp1</italic>, <italic>Fa2h</italic> and <italic>Kif5a</italic> KO mice and/or fly models (Edgar et al. <xref ref-type="bibr" rid="CR39">2004</xref>; Potter et al. <xref ref-type="bibr" rid="CR110">2011</xref>; Füger et al. <xref ref-type="bibr" rid="CR52">2012</xref>; Karle et al. <xref ref-type="bibr" rid="CR75">2012</xref>). Axon swellings with accumulation of membranous material in axons have also been observed in <italic>Spg7</italic> KO mice (Ferreirinha et al. <xref ref-type="bibr" rid="CR48">2004</xref>) and in nerve biopsies of SPG11 patients (Hehr et al. <xref ref-type="bibr" rid="CR69">2007</xref>). Finally, axonal trafficking of vesicles was shown to be impaired in neurons derived from induced pluripotent stem cells (IPSC) of SPG11 patients (Pérez-Brangulí et al. <xref ref-type="bibr" rid="CR108">2014</xref>).</p><p>The best known example of mitochondrial dysfunction in HSP is related to the SPG7 subtype. The corresponding gene is the first to have been identified in HSPs, in 1998 (Casari et al. <xref ref-type="bibr" rid="CR20">1998</xref>) and encodes paraplegin. Paraplegin is a conserved subunit of the ATP-dependent m-AAA protease of the inner membrane of the mitochondria involved in the quality control of multiple proteins of the respiratory pathway. SPG7 is associated with multiple mitochondrial DNA deletions, suggesting that functions of other mitochondrial proteins involved in either mitochondrial DNA replication itself or pathways of mitochondrial quality control are altered (Wedding et al. <xref ref-type="bibr" rid="CR150">2014</xref>). As a consequence, SPG7 patients present with reduced mitochondrial respiration rates and increased sensitivity to oxidative stress (Atorino et al. <xref ref-type="bibr" rid="CR8">2003</xref>). <italic>Spg7</italic> KO mice show axonal swellings with accumulation of membranous material and mitochondria in distal axons (Ferreirinha et al. <xref ref-type="bibr" rid="CR48">2004</xref>) reminiscent of what is observed in <italic>Spg4/Spast</italic> KO mice and therefore making the link between mitochondrial alterations and intracellular trafficking defects. Recently, reduced levels and activities of mitochondrial 4Fe-4S mitochondrial proteins have been observed in a family with a combination of spastic paraplegia, optic atrophy, and peripheral neuropathy (SPOAN) due to <italic>IBA57</italic> mutations (Lossos et al. <xref ref-type="bibr" rid="CR86">2015</xref>). Finally, impaired mitochondrial motility was shown in neurons derived from iPSC of SPG3A patients (Zhu et al. <xref ref-type="bibr" rid="CR156">2014</xref>), again linking trafficking and mitochondrial functions; mitochondrial distribution is dependent on microtubule cytoskeleton and tubular ER functions.</p><p>The number of HSP proteins involved in the functions of the ER is growing. Six genes related to these functions are mutated in HSP (Goyal and Blackstone <xref ref-type="bibr" rid="CR60">2013</xref>). Atlastin-1 is a GTPase able to promote ER tubule homotypic fusion by forming trans-oligomeric complexes between two adjacent ER tubules (Orso et al. <xref ref-type="bibr" rid="CR103">2009</xref>). Rismanchi et al. (<xref ref-type="bibr" rid="CR116">2008</xref>) showed ER morphology effects of the mutant atlastin-1 while ER-Golgi trafficking was largely unaffected. Another subgroup of proteins acts in ER shaping: ARL6IP1 (SPG61), reticulon 2 (SPG12), REEP1 (SPG31), REEP2 (SPG72) and RAB3GAP2 (Montenegro et al. <xref ref-type="bibr" rid="CR95">2012</xref>; Novarino et al. <xref ref-type="bibr" rid="CR100">2014</xref>; Esteves et al. <xref ref-type="bibr" rid="CR44">2014</xref>). Of note, spastin, atlastin-1 and REEP1 have been found to interact with each other and to act on microtubule interactions with the tubules of the ER (Park et al. <xref ref-type="bibr" rid="CR107">2010</xref>).</p><p>The secretory pathway is also altered. Spatacsin (SPG11) and spastizin (SPG15) account for proteins involved in the formation of lysosomes (Chang et al. <xref ref-type="bibr" rid="CR21">2014</xref>) and interact with components of the AP5 complex involved in membrane sorting of late endosomes (Hirst et al. <xref ref-type="bibr" rid="CR72">2013</xref>). Another adaptor protein complex, AP4, is also involved in neurodevelopmental diseases overlapping with HSP: SPG50, SPG51, SPG47 and SPG52 (Moreno-De-Luca et al. <xref ref-type="bibr" rid="CR96">2011</xref>; Abou Jamra et al. <xref ref-type="bibr" rid="CR1">2011</xref>). Accumulation of giant lysosomes and autophagosomes was observed in patient’s cells and in a Drosophila KO for <italic>Lyst</italic>, suggesting that LYST plays a role in homotypic fusion of these organelles (Rahman et al. <xref ref-type="bibr" rid="CR112">2012</xref>). BICD2 is an adaptor protein necessary for retrograde transport of vesicles from ER to Golgi (Heffernan and Simpson <xref ref-type="bibr" rid="CR68">2014</xref>). Finally, the NIPA1 protein (SPG6) is a neuron-specific transmembrane protein principally localized in the early endosomal compartment and on the plasma membrane, and its ortholog in Drosophila (Spict) was shown to interact with bone morphogenetic protein (BMP) receptors and promote their internalization from the membrane (Wang et al. <xref ref-type="bibr" rid="CR149">2007</xref>). BMP signaling is necessary for normal microtubule cytoskeleton assembly, and <italic>NIPA1</italic> mutants are less efficient in the lysosomal degradation of BMP receptors, therefore, interfering with distal axonal functions (Tsang et al. <xref ref-type="bibr" rid="CR141">2009</xref>).</p><p>There are some subtypes of HSP that affect multiple brain regions and are associated with an early onset of the symptoms, which include psychomotor delay. These disorders include the SPGs affecting the AP4 complex as well as SPG1 and SPG2. In SPG3A and SPG11, the early onset of the disease may also suggest an abnormal development but information is lacking to confirm this point. A good example of abnormal development is SPG1. L1CAM function is necessary for correct formation of the corticospinal tract. Indeed, mice lacking <italic>L1cam</italic> mimic the human phenotype and present with defects in axonal guidance in the corticospinal tracts and reduced decussation (Cohen et al. <xref ref-type="bibr" rid="CR23">1998</xref>). Of note, abnormal development leading to psychomotor delay has also been suspected in HSP due to mutations in <italic>PGAP1</italic> (SPG67) (Novarino et al. <xref ref-type="bibr" rid="CR100">2014</xref>).</p><p>Some genes expressed almost exclusively in glial cells have been identified in HSP, such as <italic>SLC16A2</italic> coding for MCT8, a thyroid hormone transporter expressed by astrocytes during embryonic development in mammals. Several other proteins involved in HSP are expressed predominantly in non-neuronal cells, such as MAG and PLP1, two components of myelin, and FA2H, an enzyme involved in the hydroxylation of sphingolipids, galactolipids and other fatty acids (Hiroko <xref ref-type="bibr" rid="CR71">2010</xref>). Mice lacking <italic>Fa2h</italic> show a degeneration of myelin sheaths at 18 months (Zöller et al. <xref ref-type="bibr" rid="CR157">2008</xref>). PLP1/DM20 is expressed in oligodendrocytes and oligodendrocyte progenitor cells (OPC). Despite normal myelination, mice lacking <italic>Plp1</italic> have physically fragile myelin and a decrease of its cholesterol content (Werner et al. <xref ref-type="bibr" rid="CR151">2013</xref>). It can be suggested that PLP1/DM20 may stabilize and maintain the myelin sheath. Moreover, these mice have an alteration of fast retrograde and anterograde transport (Edgar et al. <xref ref-type="bibr" rid="CR39">2004</xref>).</p><p>Lipid metabolism is an emerging pathway in HSP, but its importance is growing daily and has opened an entirely novel perspective on the pathogenesis of this group of diseases. There is increasing evidence that lipids have critical roles as signaling mediators and effectors, and that lipid composition of neuronal membranes affects crucial processes such as exocytosis and ion channel functions, and contributes to the formation of membrane domains. As an example, the loss of the B4GALNT1, an enzyme of the catabolism of complex gangliosides, changes the cholesterol and phospholipid content of membranes (Ohmi et al. <xref ref-type="bibr" rid="CR102">2011</xref>). <italic>B4galnt1</italic> KO mice show an age-dependent neurodegenerative phenotype, central and peripheral axonal degeneration, reduced myelin volume and loss of axo-glial junctions. This phenotype was rescued by <italic>B4GALNT1</italic> expression in neurons but not by <italic>B4GALNT1</italic> glial expression, indicating that neuronal rather that glial gangliosides are important for integrity of the CNS (Yao et al. <xref ref-type="bibr" rid="CR153">2014</xref>). On the other hand, <italic>SPG5</italic> encodes an enzyme of the bilic acid and neurosteroid formation (CYP7B1). SPG5 physiopathology may result from an accumulation of toxic substrates and the absence of neurosteroids (Leoni and Caccia <xref ref-type="bibr" rid="CR83">2011</xref>; Theofilopoulos et al. <xref ref-type="bibr" rid="CR140">2014</xref>). In <italic>Gba2</italic> KO mice, the accumulation of glucocerebrosides has been shown in brain, liver and testis (Gonzalez-Carmona et al. <xref ref-type="bibr" rid="CR59">2012</xref>), but only infertility has been explored in these mice and whether this accumulation is toxic in the brain is not proved. Lipid storage may also be affected in some of these diseases since Atlastin-1, REEP1, Spartin and Seipin modulate lipid droplet structures (Renvoisé et al. <xref ref-type="bibr" rid="CR115">2012</xref>; Klemm et al. <xref ref-type="bibr" rid="CR80">2013</xref>; Falk et al. <xref ref-type="bibr" rid="CR46">2014</xref>).</p><p>Altogether, the functional knowledge gained from the known functions of the HSP genes and from the analysis of various animal models of these diseases suggest that the pathology results from disturbance of intracellular membrane trafficking and may account for the ‘dying-back’ mechanism observed in neuropathological human cases (Supplementary Table 2) (Deluca et al. <xref ref-type="bibr" rid="CR31">2004</xref>). The relationship between most of the genes involved in HSP has recently been pinpointed by the publication of an HSP interactome that may be useful to incriminate further causative genes in the future (Novarino et al. <xref ref-type="bibr" rid="CR100">2014</xref>). Very recently, nucleotide metabolism and autophagy were also novel functions reported as possibly altered in HSP (Oz-Levi et al. <xref ref-type="bibr" rid="CR105">2012</xref>; Novarino et al. <xref ref-type="bibr" rid="CR100">2014</xref>).</p></sec><sec id="Sec12" sec-type="conclusion"><title>Conclusions</title><p>The increasing number of genes and the extension of the clinical picture associated with each genetic entity are building a new nosology that may modify the way molecular diagnosis and treatment of these diseases is done. Although it is often impossible to identify the mutated HSP gene in an individual patient on the basis of clinical criteria, the relative frequencies and clinical characteristics still help to elaborate an effective diagnostic strategy after careful exclusion of other causes. The strategy is simple in certain cases because of the high relative frequencies of two major genes: SPG4, which represents up to 40 % of pure AD forms, and SPG11, which accounts for up to 59 % of cases with a TCC transmitted in an AR manner. However, numerous studies have shown that the classic subdivision of HSP into pure and complex forms, still in use in clinical practice, is imperfect. In addition, the clinical and genetic overlap of various neurodegenerative diseases suggests that HSP is (or indeed the HSPs are) in a continuum with other neurological diseases and that the phenotype of a given patient will depend on multiple factors, including the mutated gene, the nature of the mutation and its location in the protein, the zygosity of the mutation, modifier variants and the environment. When considering all factors, it becomes clear that the dogma linking one gene to one phenotype has to be replaced by one patient—one disease, which will fit with personalized medicine in the future. On the other hand, there is indication for a possible unification of genetic forms from the cell biological and, thus, potentially therapeutic point of view. In particular, the functions of several recently identified HSP proteins suggest that they may participate in the same molecular pathway of lipid metabolism, which may lead to common therapies. Interestingly, disturbances in lipid metabolism also offered the unprecedented opportunity to identify biomarkers for HSP, as in SPG5 (25 and 27 hydroxy-cholesterol) (Schüle et al. <xref ref-type="bibr" rid="CR123">2010</xref>) and SPG26 (testosterone or GM2/GM3 levels) (Boukhris et al. <xref ref-type="bibr" rid="CR18">2013</xref>; Harlalka et al. <xref ref-type="bibr" rid="CR65">2013</xref>) (Table <xref rid="Tab2" ref-type="table">2</xref>; Supplementary Table 1), prerequisite for therapeutic trials. Finally, elucidation of the underlying pathogenic mechanisms will also help to develop more effective therapeutic agents. Preclinical trials in <italic>Spast</italic> KO flies and mice (ex vivo) and SPG4 human embryonic stem cells indicated that microtubule-binding agents might have therapeutic value (Fassier et al. <xref ref-type="bibr" rid="CR47">2013</xref>; Denton et al. <xref ref-type="bibr" rid="CR33">2014</xref>). Similarly, these drugs proved to be efficient in rescuing axon growth defects in SPG3A iPSC (Zhu et al. <xref ref-type="bibr" rid="CR156">2014</xref>) which open therapeutic avenues for HSP subtypes related to abnormal trafficking.</p></sec><sec sec-type="supplementary-material"><title>Electronic supplementary material</title><sec id="Sec13"><supplementary-material content-type="local-data" id="MOESM1"><media xlink:href="439_2015_1536_MOESM1_ESM.pdf"><caption><p>Supplementary material 1 (PDF 2642 kb)</p></caption></media></supplementary-material></sec></sec></body><back><ack><p>The authors are grateful to Drs. Odile Boesflug-Tanguy, Christel Depienne, Frédéric Darios, Cyril Goizet, Annick Toutain and Khalid H. El-Hachimi for helpful discussions. The authors’ work was partially funded by the French National Agency for Research (to GS), the European Union (Omics call of the 7th framework program, NEUROMICS, to GS; E-rare program, NEUROLIPID, to GS), the Tom Wahlig Foundation, the VERUM Foundation (to GS), the Vestre Viken Health trust (to JK) and the program “Investissements d’Avenir” ANR-10-IAIHU-06 (to GS). CT was the recipient of a PhD fellowship from the French Ministry for Research from the Doctoral School of the Ecole Pratique des Hautes Etudes.</p><sec id="d30e6947"><title>Conflict of interest</title><p>The authors declare that they have no conflict of interest.</p></sec></ack><ref-list id="Bib1"><title>References</title><ref id="CR1"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Abou Jamra</surname><given-names>R</given-names></name><name><surname>Philippe</surname><given-names>O</given-names></name><name><surname>Raas-Rothschild</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature</article-title><source>Am J Hum Genet</source><year>2011</year><volume>88</volume><fpage>788</fpage><lpage>795</lpage><pub-id pub-id-type="pmid">21620353</pub-id></element-citation></ref><ref id="CR2"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ajit Bolar</surname><given-names>N</given-names></name><name><surname>Vanlander</surname><given-names>AV</given-names></name><name><surname>Wilbrecht</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>Mutation of the iron-sulfur cluster assembly gene IBA57 cause severe myopathy and encephalopathy</article-title><source>Hum Mol Genet</source><year>2013</year><volume>22</volume><fpage>2590</fpage><lpage>2602</lpage><pub-id pub-id-type="pmid">23462291</pub-id></element-citation></ref><ref id="CR3"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Alazami</surname><given-names>AM</given-names></name><name><surname>Adly</surname><given-names>N</given-names></name><name><surname>Al Dhalaan</surname><given-names>H</given-names></name><name><surname>Alkuraya</surname><given-names>FS</given-names></name></person-group><article-title>A nullimorphic ERLIN2 mutation defines a complicated hereditary spastic paraplegia locus (SPG18)</article-title><source>Neurogenetics</source><year>2011</year><volume>12</volume><fpage>333</fpage><lpage>336</lpage><pub-id pub-id-type="pmid">21796390</pub-id></element-citation></ref><ref id="CR4"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Al-Saif</surname><given-names>A</given-names></name><name><surname>Bohlega</surname><given-names>S</given-names></name><name><surname>Al-Mohanna</surname><given-names>F</given-names></name></person-group><article-title>Loss of ERLIN2 function leads to juvenile primary lateral sclerosis</article-title><source>Ann Neurol</source><year>2012</year><volume>72</volume><fpage>510</fpage><lpage>516</lpage><pub-id pub-id-type="pmid">23109145</pub-id></element-citation></ref><ref id="CR5"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Anheim</surname><given-names>M</given-names></name><name><surname>Lagier-Tourenne</surname><given-names>C</given-names></name><name><surname>Stevanin</surname><given-names>G</given-names></name><etal></etal></person-group><article-title>SPG11 spastic paraplegia. A new cause of juvenile parkinsonism</article-title><source>J Neurol</source><year>2009</year><volume>256</volume><fpage>104</fpage><lpage>108</lpage><pub-id pub-id-type="pmid">19224311</pub-id></element-citation></ref><ref id="CR6"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Antonicka</surname><given-names>H</given-names></name><name><surname>Ostergaard</surname><given-names>E</given-names></name><name><surname>Sasarman</surname><given-names>F</given-names></name><etal></etal></person-group><article-title>Mutations in C12orf65 in patients with encephalomyopathy and a mitochondrial translation defect</article-title><source>Am J Hum Genet</source><year>2010</year><volume>87</volume><fpage>115</fpage><lpage>122</lpage><pub-id pub-id-type="pmid">20598281</pub-id></element-citation></ref><ref id="CR7"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Arnoldi</surname><given-names>A</given-names></name><name><surname>Crimella</surname><given-names>C</given-names></name><name><surname>Tenderini</surname><given-names>E</given-names></name><etal></etal></person-group><article-title>Clinical phenotype variability in patients with hereditary spastic paraplegia type 5 associated with CYP7B1 mutations</article-title><source>Clin Genet</source><year>2012</year><volume>81</volume><issue>2</issue><fpage>150</fpage><lpage>157</lpage><pub-id pub-id-type="pmid">21214876</pub-id></element-citation></ref><ref id="CR8"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Atorino</surname><given-names>L</given-names></name><name><surname>Silvestri</surname><given-names>L</given-names></name><name><surname>Koppen</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Loss of m-AAA protease in mitochondria causes complex I deficiency and increased sensitivity to oxidative stress in hereditary spastic paraplegia</article-title><source>J Cell Biol</source><year>2003</year><volume>163</volume><fpage>777</fpage><lpage>787</lpage><pub-id pub-id-type="pmid">14623864</pub-id></element-citation></ref><ref id="CR9"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Barbosa</surname><given-names>MD</given-names></name><name><surname>Barrat</surname><given-names>FJ</given-names></name><name><surname>Tchernev</surname><given-names>VT</given-names></name><etal></etal></person-group><article-title>Identification of mutations in two major mRNA isoforms of the Chediak–Higashi syndrome gene in human and mouse</article-title><source>Hum Mol Genet</source><year>1997</year><volume>6</volume><fpage>1091</fpage><lpage>1098</lpage><pub-id pub-id-type="pmid">9215680</pub-id></element-citation></ref><ref id="CR200"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bauer</surname><given-names>P</given-names></name><name><surname>Leshinsky-Silver</surname><given-names>E</given-names></name><name><surname>Blumkin</surname><given-names>L</given-names></name><etal></etal></person-group><article-title>Mutation in the AP4B1 gene cause hereditary spastic paraplegia type 47 (SPG47)</article-title><source>Neurogenetics</source><year>2012</year><volume>13</volume><fpage>73</fpage><lpage>76</lpage><pub-id pub-id-type="pmid">22290197</pub-id></element-citation></ref><ref id="CR10"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Beetz</surname><given-names>C</given-names></name><name><surname>Nygren</surname><given-names>AOH</given-names></name><name><surname>Schickel</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia</article-title><source>Neurology</source><year>2006</year><volume>67</volume><fpage>1926</fpage><lpage>1930</lpage><pub-id pub-id-type="pmid">17035675</pub-id></element-citation></ref><ref id="CR11"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Beetz</surname><given-names>C</given-names></name><name><surname>Schüle</surname><given-names>R</given-names></name><name><surname>Deconinck</surname><given-names>T</given-names></name><etal></etal></person-group><article-title>REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31</article-title><source>Brain</source><year>2008</year><volume>131</volume><fpage>1078</fpage><lpage>1086</lpage><pub-id pub-id-type="pmid">18321925</pub-id></element-citation></ref><ref id="CR12"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Beetz</surname><given-names>C</given-names></name><name><surname>Pieber</surname><given-names>TR</given-names></name><name><surname>Hertel</surname><given-names>N</given-names></name><etal></etal></person-group><article-title>Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V</article-title><source>Am J Hum Genet</source><year>2012</year><volume>91</volume><fpage>139</fpage><lpage>145</lpage><pub-id pub-id-type="pmid">22703882</pub-id></element-citation></ref><ref id="CR13"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Beetz</surname><given-names>C</given-names></name><name><surname>Johnson</surname><given-names>A</given-names></name><name><surname>Schuh</surname><given-names>AL</given-names></name><etal></etal></person-group><article-title>Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure</article-title><source>Proc Natl Acad Sci</source><year>2013</year><volume>110</volume><fpage>5091</fpage><lpage>5096</lpage><pub-id pub-id-type="pmid">23479643</pub-id></element-citation></ref><ref id="CR14"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bettencourt</surname><given-names>C</given-names></name><name><surname>Morris</surname><given-names>HR</given-names></name><name><surname>Singleton</surname><given-names>AB</given-names></name><etal></etal></person-group><article-title>Exome sequencing expands the mutational spectrum of SPG8 in a family with spasticity responsive to <sc>l</sc>-DOPA treatment</article-title><source>J Neurol</source><year>2013</year><volume>260</volume><fpage>2414</fpage><lpage>2416</lpage><pub-id pub-id-type="pmid">23881105</pub-id></element-citation></ref><ref id="CR15"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Blackstone</surname><given-names>C</given-names></name></person-group><article-title>Cellular pathways of hereditary spastic paraplegia</article-title><source>Annu Rev Neurosci</source><year>2012</year><volume>35</volume><fpage>25</fpage><lpage>47</lpage><pub-id pub-id-type="pmid">22540978</pub-id></element-citation></ref><ref id="CR201"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Blumen</surname><given-names>SC</given-names></name><name><surname>Bevan</surname><given-names>S</given-names></name><name><surname>Abu-Mouch</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>A locus for complicated hereditary spastic paraplegia maps to chromosome 1q24-q32</article-title><source>Ann Neurol</source><year>2003</year><volume>54</volume><fpage>796</fpage><lpage>803</lpage><pub-id pub-id-type="pmid">14681889</pub-id></element-citation></ref><ref id="CR16"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bouhlal</surname><given-names>Y</given-names></name><name><surname>Amouri</surname><given-names>R</given-names></name><name><surname>El Euch-Fayeche</surname><given-names>G</given-names></name><name><surname>Hentati</surname><given-names>F</given-names></name></person-group><article-title>Autosomal recessive spastic ataxia of Charlevoix-Saguenay: an overview</article-title><source>Parkinsonism Relat Disord</source><year>2011</year><volume>17</volume><fpage>418</fpage><lpage>422</lpage><pub-id pub-id-type="pmid">21450511</pub-id></element-citation></ref><ref id="CR202"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bouhouche</surname><given-names>A</given-names></name><name><surname>Benomar</surname><given-names>A</given-names></name><name><surname>Bouslam</surname><given-names>N</given-names></name><etal></etal></person-group><article-title>Mutation in the epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct5) gene causes autosomal recessive mutilating sensory neuropathy with spastic paraplegia</article-title><source>J Med Genet</source><year>2006</year><volume>43</volume><fpage>441</fpage><lpage>443</lpage><pub-id pub-id-type="pmid">16399879</pub-id></element-citation></ref><ref id="CR17"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Boukhris</surname><given-names>A</given-names></name><name><surname>Stevanin</surname><given-names>G</given-names></name><name><surname>Feki</surname><given-names>I</given-names></name><etal></etal></person-group><article-title>Tunisian hereditary spastic paraplegias: clinical variability supported by genetic heterogeneity</article-title><source>Clin Genet</source><year>2009</year><volume>75</volume><issue>6</issue><fpage>527</fpage><lpage>536</lpage><pub-id pub-id-type="pmid">19438933</pub-id></element-citation></ref><ref id="CR18"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Boukhris</surname><given-names>A</given-names></name><name><surname>Schule</surname><given-names>R</given-names></name><name><surname>Loureiro</surname><given-names>JL</given-names></name><etal></etal></person-group><article-title>Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia</article-title><source>Am J Hum Genet</source><year>2013</year><volume>93</volume><fpage>118</fpage><lpage>123</lpage><pub-id pub-id-type="pmid">23746551</pub-id></element-citation></ref><ref id="CR19"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bross</surname><given-names>P</given-names></name><name><surname>Naundrup</surname><given-names>S</given-names></name><name><surname>Hansen</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>The Hsp60-(p. V98I) mutation associated with hereditary spastic paraplegia SPG13 compromises chaperonin function both in vitro and in vivo</article-title><source>J Biol Chem</source><year>2008</year><volume>283</volume><fpage>15694</fpage><lpage>15700</lpage><pub-id pub-id-type="pmid">18400758</pub-id></element-citation></ref><ref id="CR203"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Caballero Oteyza</surname><given-names>A</given-names></name><name><surname>Battaloğlu</surname><given-names>E</given-names></name><name><surname>Ocek</surname><given-names>L</given-names></name><etal></etal></person-group><article-title>Motor protein mutations cause a new form of hereditary spastic paraplegia</article-title><source>Neurology</source><year>2014</year><volume>82</volume><issue>22</issue><fpage>2007</fpage><lpage>2016</lpage><pub-id pub-id-type="pmid">24808017</pub-id></element-citation></ref><ref id="CR20"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Casari</surname><given-names>G</given-names></name><name><surname>De Fusco</surname><given-names>M</given-names></name><name><surname>Ciarmatori</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease</article-title><source>Cell</source><year>1998</year><volume>93</volume><fpage>973</fpage><lpage>983</lpage><pub-id pub-id-type="pmid">9635427</pub-id></element-citation></ref><ref id="CR21"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chang</surname><given-names>J</given-names></name><name><surname>Lee</surname><given-names>S</given-names></name><name><surname>Blackstone</surname><given-names>C</given-names></name></person-group><article-title>Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation</article-title><source>J Clin Invest.</source><year>2014</year><volume>124</volume><issue>12</issue><fpage>5249</fpage><lpage>5262</lpage><pub-id pub-id-type="pmid">25365221</pub-id></element-citation></ref><ref id="CR22"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Citterio</surname><given-names>A</given-names></name><name><surname>Arnoldi</surname><given-names>A</given-names></name><name><surname>Panzeri</surname><given-names>E</given-names></name><etal></etal></person-group><article-title>Mutations in CYP2U1, DDHD2 and GBA2 genes are rare causes of complicated forms of hereditary spastic paraparesis</article-title><source>J Neurol</source><year>2014</year><volume>261</volume><issue>2</issue><fpage>373</fpage><lpage>381</lpage><pub-id pub-id-type="pmid">24337409</pub-id></element-citation></ref><ref id="CR23"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cohen</surname><given-names>NR</given-names></name><name><surname>Taylor</surname><given-names>JS</given-names></name><name><surname>Scott</surname><given-names>LB</given-names></name><etal></etal></person-group><article-title>Errors in corticospinal axon guidance in mice lacking the neural cell adhesion molecule L1</article-title><source>Curr Biol</source><year>1998</year><volume>8</volume><fpage>26</fpage><lpage>33</lpage><pub-id pub-id-type="pmid">9427628</pub-id></element-citation></ref><ref id="CR24"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Collongues</surname><given-names>N</given-names></name><name><surname>Depienne</surname><given-names>C</given-names></name><name><surname>Boehm</surname><given-names>N</given-names></name><etal></etal></person-group><article-title>Novel SPG10 mutation associated with dysautonomia, spinal cord atrophy, and skin biopsy abnormality</article-title><source>Eur J Neurol</source><year>2013</year><volume>20</volume><fpage>398</fpage><lpage>401</lpage><pub-id pub-id-type="pmid">22788249</pub-id></element-citation></ref><ref id="CR25"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Corona</surname><given-names>P</given-names></name><name><surname>Lamantea</surname><given-names>E</given-names></name><name><surname>Greco</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Novel heteroplasmic mtDNA mutation in a family with heterogeneous clinical presentations</article-title><source>Ann Neurol</source><year>2002</year><volume>51</volume><fpage>118</fpage><lpage>122</lpage><pub-id pub-id-type="pmid">11782991</pub-id></element-citation></ref><ref id="CR26"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Coutinho</surname><given-names>P</given-names></name><name><surname>Barros</surname><given-names>J</given-names></name><name><surname>Zemmouri</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>Clinical heterogeneity of autosomal recessive spastic paraplegias: analysis of 106 patients in 46 families</article-title><source>Arch Neurol</source><year>1999</year><volume>56</volume><fpage>943</fpage><lpage>949</lpage><pub-id pub-id-type="pmid">10448799</pub-id></element-citation></ref><ref id="CR204"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cremers</surname><given-names>FP</given-names></name><name><surname>Pfeiffer</surname><given-names>RA</given-names></name><name><surname>van de Pol</surname><given-names>TJ</given-names></name><etal></etal></person-group><article-title>An interstitial duplication of the X chromosome in a male allows physical fine mapping of probes from the Xq13-q22 region</article-title><source>Hum Genet</source><year>1987</year><volume>77</volume><fpage>23</fpage><lpage>27</lpage><pub-id pub-id-type="pmid">3476455</pub-id></element-citation></ref><ref id="CR27"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Crimella</surname><given-names>C</given-names></name><name><surname>Baschirotto</surname><given-names>C</given-names></name><name><surname>Arnoldi</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Mutations in the motor and stalk domains of KIF5A in spastic paraplegia type 10 and in axonal Charcot-Marie-Tooth type 2</article-title><source>Clin Genet</source><year>2012</year><volume>82</volume><fpage>157</fpage><lpage>164</lpage><pub-id pub-id-type="pmid">21623771</pub-id></element-citation></ref><ref id="CR28"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Crow</surname><given-names>YJ</given-names></name><name><surname>Zaki</surname><given-names>MS</given-names></name><name><surname>Abdel-Hamid</surname><given-names>MS</given-names></name><etal></etal></person-group><article-title>Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia</article-title><source>Neuropediatrics</source><year>2014</year><volume>45</volume><issue>6</issue><fpage>386</fpage><lpage>393</lpage><pub-id pub-id-type="pmid">25243380</pub-id></element-citation></ref><ref id="CR29"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>D’Amico</surname><given-names>A</given-names></name><name><surname>Tessa</surname><given-names>A</given-names></name><name><surname>Sabino</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Incomplete penetrance in an SPG3A-linked family with a new mutation in the atlastin gene</article-title><source>Neurology</source><year>2004</year><volume>62</volume><fpage>2138</fpage><lpage>2139</lpage><pub-id pub-id-type="pmid">15184642</pub-id></element-citation></ref><ref id="CR205"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dan</surname><given-names>P</given-names></name><name><surname>Edvardson</surname><given-names>S</given-names></name><name><surname>Bielawski</surname><given-names>J</given-names></name><name><surname>Hama</surname><given-names>H</given-names></name><name><surname>Saada</surname><given-names>A</given-names></name></person-group><article-title>2-Hydroxylated sphingomyelin profiles in cells from patients with mutated fatty acid 2-hydroxylase</article-title><source>Lipids Health Dis</source><year>2011</year><volume>10</volume><fpage>84</fpage><pub-id pub-id-type="pmid">21599921</pub-id></element-citation></ref><ref id="CR30"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Daoud</surname><given-names>H</given-names></name><name><surname>Zhou</surname><given-names>S</given-names></name><name><surname>Noreau</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Exome sequencing reveals SPG11 mutations causing juvenile ALS</article-title><source>Neurobiol Aging</source><year>2012</year><volume>33</volume><issue>839</issue><fpage>e5</fpage><lpage>e9</lpage><pub-id pub-id-type="pmid">22154821</pub-id></element-citation></ref><ref id="CR206"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>De Bot</surname><given-names>ST</given-names></name><name><surname>Schelhaas</surname><given-names>HJ</given-names></name><name><surname>Kamsteeg</surname><given-names>E-J</given-names></name><name><surname>van de Warrenburg</surname><given-names>BPC</given-names></name></person-group><article-title>Hereditary spastic paraplegia caused by a mutation in the VCP gene</article-title><source>Brain J Neurol</source><year>2012</year><volume>135</volume><fpage>e223; author reply e224</fpage></element-citation></ref><ref id="CR31"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Deluca</surname><given-names>GC</given-names></name><name><surname>Ebers</surname><given-names>GC</given-names></name><name><surname>Esiri</surname><given-names>MM</given-names></name></person-group><article-title>The extent of axonal loss in the long tracts in hereditary spastic paraplegia</article-title><source>Neuropathol Appl Neurobiol</source><year>2004</year><volume>30</volume><fpage>576</fpage><lpage>584</lpage><pub-id pub-id-type="pmid">15540998</pub-id></element-citation></ref><ref id="CR32"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Deniziak</surname><given-names>MA</given-names></name><name><surname>Barciszewski</surname><given-names>J</given-names></name></person-group><article-title>Methionyl-tRNA synthetase</article-title><source>Acta Biochim Pol</source><year>2001</year><volume>48</volume><fpage>337</fpage><lpage>350</lpage><pub-id pub-id-type="pmid">11732605</pub-id></element-citation></ref><ref id="CR33"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Denton</surname><given-names>KR</given-names></name><name><surname>Lei</surname><given-names>L</given-names></name><name><surname>Grenier</surname><given-names>J</given-names></name><name><surname>Rodionov</surname><given-names>V</given-names></name><name><surname>Blackstone</surname><given-names>C</given-names></name><name><surname>Li</surname><given-names>XJ</given-names></name></person-group><article-title>Loss of spastin function results in disease-specific axonal defects in human pluripotent stem cell-based models of hereditary spastic paraplegia</article-title><source>Stem Cells</source><year>2014</year><volume>32</volume><issue>2</issue><fpage>414</fpage><lpage>423</lpage><pub-id pub-id-type="pmid">24123785</pub-id></element-citation></ref><ref id="CR34"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Depienne</surname><given-names>C</given-names></name><name><surname>Tallaksen</surname><given-names>C</given-names></name><name><surname>Lephay</surname><given-names>JY</given-names></name><etal></etal></person-group><article-title>Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases</article-title><source>J Med Genet</source><year>2006</year><volume>43</volume><fpage>259</fpage><lpage>265</lpage><pub-id pub-id-type="pmid">16055926</pub-id></element-citation></ref><ref id="CR35"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Depienne</surname><given-names>C</given-names></name><name><surname>Fedirko</surname><given-names>E</given-names></name><name><surname>Forlani</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Exon deletions of SPG4 are a frequent cause of hereditary spastic paraplegia</article-title><source>J Med Genet</source><year>2007</year><volume>44</volume><fpage>281</fpage><lpage>284</lpage><pub-id pub-id-type="pmid">17098887</pub-id></element-citation></ref><ref id="CR36"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dick</surname><given-names>KJ</given-names></name><name><surname>Eckhardt</surname><given-names>M</given-names></name><name><surname>Paisán-Ruiz</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35)</article-title><source>Hum Mutat</source><year>2010</year><volume>31</volume><fpage>E1251</fpage><lpage>E1260</lpage><pub-id pub-id-type="pmid">20104589</pub-id></element-citation></ref><ref id="CR37"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dor</surname><given-names>T</given-names></name><name><surname>Cinnamon</surname><given-names>Y</given-names></name><name><surname>Raymond</surname><given-names>L</given-names></name><etal></etal></person-group><article-title>KIF1C mutations in two families with hereditary spastic paraparesis and cerebellar dysfunction</article-title><source>J Med Genet</source><year>2014</year><volume>51</volume><fpage>137</fpage><lpage>142</lpage><pub-id pub-id-type="pmid">24319291</pub-id></element-citation></ref><ref id="CR207"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dumitrescu</surname><given-names>AM</given-names></name><name><surname>Liao</surname><given-names>X-H</given-names></name><name><surname>Best</surname><given-names>TB</given-names></name><etal></etal></person-group><article-title>A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene</article-title><source>Am J Hum Genet</source><year>2004</year><volume>74</volume><fpage>168</fpage><lpage>175</lpage><pub-id pub-id-type="pmid">14661163</pub-id></element-citation></ref><ref id="CR208"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dursun</surname><given-names>U</given-names></name><name><surname>Koroglu</surname><given-names>C</given-names></name><name><surname>Kocasoy Orhan</surname><given-names>E</given-names></name><etal></etal></person-group><article-title>Autosomal recessive spastic paraplegia (SPG45) with mental retardation maps to 10q24.3-q25.1</article-title><source>Neurogenetics</source><year>2009</year><volume>10</volume><fpage>325</fpage><lpage>331</lpage><pub-id pub-id-type="pmid">19415352</pub-id></element-citation></ref><ref id="CR38"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ebbing</surname><given-names>B</given-names></name><name><surname>Mann</surname><given-names>K</given-names></name><name><surname>Starosta</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Effect of spastic paraplegia mutations in KIF5A kinesin on transport activity</article-title><source>Hum Mol Genet</source><year>2008</year><volume>17</volume><fpage>1245</fpage><lpage>1252</lpage><pub-id pub-id-type="pmid">18203753</pub-id></element-citation></ref><ref id="CR39"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Edgar</surname><given-names>JM</given-names></name><name><surname>McLaughlin</surname><given-names>M</given-names></name><name><surname>Yool</surname><given-names>D</given-names></name><etal></etal></person-group><article-title>Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia</article-title><source>J Cell Biol</source><year>2004</year><volume>166</volume><fpage>121</fpage><lpage>131</lpage><pub-id pub-id-type="pmid">15226307</pub-id></element-citation></ref><ref id="CR40"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Edvardson</surname><given-names>S</given-names></name><name><surname>Hama</surname><given-names>H</given-names></name><name><surname>Shaag</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Mutations in the fatty acid 2-hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia</article-title><source>Am J Hum Genet</source><year>2008</year><volume>83</volume><fpage>643</fpage><lpage>648</lpage><pub-id pub-id-type="pmid">19068277</pub-id></element-citation></ref><ref id="CR41"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Elliott</surname><given-names>AM</given-names></name><name><surname>Simard</surname><given-names>LR</given-names></name><name><surname>Coghlan</surname><given-names>G</given-names></name><etal></etal></person-group><article-title>A novel mutation in KIAA0196: identification of a gene involved in Ritscher-Schinzel/3C syndrome in a First Nations cohort</article-title><source>J Med Genet</source><year>2013</year><volume>50</volume><fpage>819</fpage><lpage>822</lpage><pub-id pub-id-type="pmid">24065355</pub-id></element-citation></ref><ref id="CR209"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Engert</surname><given-names>JC</given-names></name><name><surname>Bérubé</surname><given-names>P</given-names></name><name><surname>Mercier</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>ARSACS, a spastic ataxia common in northeastern Québec, is caused by mutations in a new gene encoding an 11.5-kb ORF</article-title><source>Nat Genet</source><year>2000</year><volume>24</volume><fpage>120</fpage><lpage>125</lpage><pub-id pub-id-type="pmid">10655055</pub-id></element-citation></ref><ref id="CR42"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Erichsen</surname><given-names>AK</given-names></name><name><surname>Koht</surname><given-names>J</given-names></name><name><surname>Stray-Pedersen</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: a population-based study</article-title><source>Brain</source><year>2009</year><volume>132</volume><fpage>1577</fpage><lpage>1588</lpage><pub-id pub-id-type="pmid">19339254</pub-id></element-citation></ref><ref id="CR43"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Erlich</surname><given-names>Y</given-names></name><name><surname>Edvardson</surname><given-names>S</given-names></name><name><surname>Hodges</surname><given-names>E</given-names></name><etal></etal></person-group><article-title>Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis</article-title><source>Genome Res</source><year>2011</year><volume>21</volume><fpage>658</fpage><lpage>664</lpage><pub-id pub-id-type="pmid">21487076</pub-id></element-citation></ref><ref id="CR44"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Esteves</surname><given-names>T</given-names></name><name><surname>Durr</surname><given-names>A</given-names></name><name><surname>Mundwiller</surname><given-names>E</given-names></name><etal></etal></person-group><article-title>Loss of association of REEP2 with membranes leads to hereditary spastic paraplegia</article-title><source>Am J Hum Genet</source><year>2014</year><volume>94</volume><fpage>268</fpage><lpage>277</lpage><pub-id pub-id-type="pmid">24388663</pub-id></element-citation></ref><ref id="CR45"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Falk</surname><given-names>J</given-names></name><name><surname>Bonnon</surname><given-names>C</given-names></name><name><surname>Girault</surname><given-names>J-A</given-names></name><name><surname>Faivre-Sarrailh</surname><given-names>C</given-names></name></person-group><article-title>F3/contactin, a neuronal cell adhesion molecule implicated in axogenesis and myelination</article-title><source>Biol Cell</source><year>2002</year><volume>94</volume><fpage>327</fpage><lpage>334</lpage><pub-id pub-id-type="pmid">12500940</pub-id></element-citation></ref><ref id="CR46"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Falk</surname><given-names>J</given-names></name><name><surname>Rohde</surname><given-names>M</given-names></name><name><surname>Bekhite</surname><given-names>MM</given-names></name><etal></etal></person-group><article-title>Functional mutation analysis provides evidence for a role of REEP1 in lipid droplet biology</article-title><source>Hum Mutat</source><year>2014</year><volume>35</volume><fpage>497</fpage><lpage>504</lpage><pub-id pub-id-type="pmid">24478229</pub-id></element-citation></ref><ref id="CR47"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fassier</surname><given-names>C</given-names></name><name><surname>Tarrade</surname><given-names>A</given-names></name><name><surname>Peris</surname><given-names>L</given-names></name><etal></etal></person-group><article-title>Microtubule-targeting drugs rescue axonal swellings in cortical neurons from spastin knockout mice</article-title><source>Dis Model Mech</source><year>2013</year><volume>6</volume><fpage>72</fpage><lpage>83</lpage><pub-id pub-id-type="pmid">22773755</pub-id></element-citation></ref><ref id="CR48"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ferreirinha</surname><given-names>F</given-names></name><name><surname>Quattrini</surname><given-names>A</given-names></name><name><surname>Pirozzi</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport</article-title><source>J Clin Invest</source><year>2004</year><volume>113</volume><fpage>231</fpage><lpage>242</lpage><pub-id pub-id-type="pmid">14722615</pub-id></element-citation></ref><ref id="CR49"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fink</surname><given-names>JK</given-names></name></person-group><article-title>The hereditary spastic paraplegias: nine genes and counting</article-title><source>Arch Neurol</source><year>2003</year><volume>60</volume><issue>8</issue><fpage>1045</fpage><lpage>1049</lpage><pub-id pub-id-type="pmid">12925358</pub-id></element-citation></ref><ref id="CR50"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fink</surname><given-names>JK</given-names></name></person-group><article-title>Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms</article-title><source>Acta Neuropathol</source><year>2013</year><volume>126</volume><issue>3</issue><fpage>307</fpage><lpage>328</lpage><pub-id pub-id-type="pmid">23897027</pub-id></element-citation></ref><ref id="CR51"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Finsterer</surname><given-names>J</given-names></name><name><surname>Löscher</surname><given-names>W</given-names></name><name><surname>Quasthoff</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance</article-title><source>J Neurol Sci</source><year>2012</year><volume>318</volume><fpage>1</fpage><lpage>18</lpage><pub-id pub-id-type="pmid">22554690</pub-id></element-citation></ref><ref id="CR52"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Füger</surname><given-names>P</given-names></name><name><surname>Sreekumar</surname><given-names>V</given-names></name><name><surname>Schüle</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>Spastic paraplegia mutation N256S in the neuronal microtubule motor KIF5A disrupts axonal transport in a Drosophila HSP model</article-title><source>PLoS Genet</source><year>2012</year><volume>8</volume><fpage>e1003066</fpage><pub-id pub-id-type="pmid">23209432</pub-id></element-citation></ref><ref id="CR53"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Furukawa</surname><given-names>Y</given-names></name><name><surname>Graf</surname><given-names>WD</given-names></name><name><surname>Wong</surname><given-names>H</given-names></name><etal></etal></person-group><article-title>Dopa-responsive dystonia simulating spastic paraplegia due to tyrosine hydroxylase (TH) gene mutations</article-title><source>Neurology</source><year>2001</year><volume>56</volume><fpage>260</fpage><lpage>263</lpage><pub-id pub-id-type="pmid">11160968</pub-id></element-citation></ref><ref id="CR54"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ginsberg</surname><given-names>D</given-names></name><name><surname>Cruz</surname><given-names>F</given-names></name><name><surname>Herschorn</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>OnabotulinumtoxinA is effective in patients with urinary incontinence due to neurogenic detrusor overactivity [corrected] regardless of concomitant anticholinergic use or neurologic etiology</article-title><source>Adv Ther</source><year>2013</year><volume>30</volume><fpage>819</fpage><lpage>833</lpage><pub-id pub-id-type="pmid">24072665</pub-id></element-citation></ref><ref id="CR55"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Goizet</surname><given-names>C</given-names></name><name><surname>Boukhris</surname><given-names>A</given-names></name><name><surname>Maltete</surname><given-names>D</given-names></name><etal></etal></person-group><article-title>SPG15 is the second most common cause of hereditary spastic paraplegia with thin corpus callosum</article-title><source>Neurology</source><year>2009</year><volume>73</volume><fpage>1111</fpage><lpage>1119</lpage><pub-id pub-id-type="pmid">19805727</pub-id></element-citation></ref><ref id="CR56"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Goizet</surname><given-names>C</given-names></name><name><surname>Boukhris</surname><given-names>A</given-names></name><name><surname>Mundwiller</surname><given-names>E</given-names></name><etal></etal></person-group><article-title>Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10</article-title><source>Hum Mutat</source><year>2009</year><volume>30</volume><fpage>E376</fpage><lpage>E385</lpage><pub-id pub-id-type="pmid">18853458</pub-id></element-citation></ref><ref id="CR57"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Goizet</surname><given-names>C</given-names></name><name><surname>Depienne</surname><given-names>C</given-names></name><name><surname>Benard</surname><given-names>G</given-names></name><etal></etal></person-group><article-title>REEP1 mutations in SPG31: frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction</article-title><source>Hum Mutat</source><year>2011</year><volume>32</volume><fpage>1118</fpage><lpage>1127</lpage><pub-id pub-id-type="pmid">21618648</pub-id></element-citation></ref><ref id="CR58"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gonzalez</surname><given-names>M</given-names></name><name><surname>McLaughlin</surname><given-names>H</given-names></name><name><surname>Houlden</surname><given-names>H</given-names></name><etal></etal></person-group><article-title>Exome sequencing identifies a significant variant in methionyl-tRNA synthetase (MARS) in a family with late-onset CMT2</article-title><source>J Neurol Neurosurg Psychiatry</source><year>2013</year><volume>84</volume><fpage>1247</fpage><lpage>1249</lpage><pub-id pub-id-type="pmid">23729695</pub-id></element-citation></ref><ref id="CR59"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gonzalez-Carmona</surname><given-names>MA</given-names></name><name><surname>Sandhoff</surname><given-names>R</given-names></name><name><surname>Tacke</surname><given-names>F</given-names></name><etal></etal></person-group><article-title>Beta-glucosidase 2 knockout mice with increased glucosylceramide show impaired liver regeneration</article-title><source>Liver Int</source><year>2012</year><volume>32</volume><fpage>1354</fpage><lpage>1362</lpage><pub-id pub-id-type="pmid">22764777</pub-id></element-citation></ref><ref id="CR60"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Goyal</surname><given-names>U</given-names></name><name><surname>Blackstone</surname><given-names>C</given-names></name></person-group><article-title>Untangling the web: mechanisms underlying ER network formation</article-title><source>Biochim Biophys Acta</source><year>2013</year><volume>1833</volume><fpage>2492</fpage><lpage>2498</lpage><pub-id pub-id-type="pmid">23602970</pub-id></element-citation></ref><ref id="CR61"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hamdan</surname><given-names>FF</given-names></name><name><surname>Gauthier</surname><given-names>J</given-names></name><name><surname>Araki</surname><given-names>Y</given-names></name><etal></etal></person-group><article-title>Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability</article-title><source>Am J Hum Genet</source><year>2011</year><volume>88</volume><fpage>306</fpage><lpage>316</lpage><pub-id pub-id-type="pmid">21376300</pub-id></element-citation></ref><ref id="CR62"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hammer</surname><given-names>MB</given-names></name><name><surname>Eleuch-Fayache</surname><given-names>G</given-names></name><name><surname>Schottlaender</surname><given-names>LV</given-names></name><etal></etal></person-group><article-title>Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity</article-title><source>Am J Hum Genet</source><year>2013</year><volume>92</volume><fpage>245</fpage><lpage>251</lpage><pub-id pub-id-type="pmid">23332917</pub-id></element-citation></ref><ref id="CR63"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hansen</surname><given-names>JJ</given-names></name><name><surname>Dürr</surname><given-names>A</given-names></name><name><surname>Cournu-Rebeix</surname><given-names>I</given-names></name><etal></etal></person-group><article-title>Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60</article-title><source>Am J Hum Genet</source><year>2002</year><volume>70</volume><fpage>1328</fpage><lpage>1332</lpage><pub-id pub-id-type="pmid">11898127</pub-id></element-citation></ref><ref id="CR64"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Harding</surname><given-names>AE</given-names></name></person-group><article-title>Classification of the hereditary ataxias and paraplegias</article-title><source>Lancet</source><year>1983</year><volume>1</volume><fpage>1151</fpage><lpage>1155</lpage><pub-id pub-id-type="pmid">6133167</pub-id></element-citation></ref><ref id="CR65"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Harlalka</surname><given-names>GV</given-names></name><name><surname>Lehman</surname><given-names>A</given-names></name><name><surname>Chioza</surname><given-names>B</given-names></name><etal></etal></person-group><article-title>Mutations in B4GALNT1 (GM2 synthase) underlie a new disorder of ganglioside biosynthesis</article-title><source>Brain</source><year>2013</year><volume>136</volume><fpage>3618</fpage><lpage>3624</lpage><pub-id pub-id-type="pmid">24103911</pub-id></element-citation></ref><ref id="CR66"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hartig</surname><given-names>MB</given-names></name><name><surname>Iuso</surname><given-names>A</given-names></name><name><surname>Haack</surname><given-names>T</given-names></name><etal></etal></person-group><article-title>Absence of an orphan mitochondrial protein, C19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation</article-title><source>Am J Hum Genet</source><year>2011</year><volume>89</volume><fpage>543</fpage><lpage>550</lpage><pub-id pub-id-type="pmid">21981780</pub-id></element-citation></ref><ref id="CR210"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hanein</surname><given-names>S</given-names></name><name><surname>Durr</surname><given-names>A</given-names></name><name><surname>Ribai</surname><given-names>P</given-names></name><etal></etal></person-group><article-title>A novel locus for autosomal dominant “uncomplicated” hereditary spastic paraplegia maps to chromosome 8p21.1-q13.3</article-title><source>Hum Genet</source><year>2007</year><volume>122</volume><fpage>261</fpage><lpage>273</lpage><pub-id pub-id-type="pmid">17605047</pub-id></element-citation></ref><ref id="CR211"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hanein</surname><given-names>S</given-names></name><name><surname>Martin</surname><given-names>E</given-names></name><name><surname>Boukhris</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal recessive spastic paraplegia including Kjellin syndrome</article-title><source>Am J Hum Genet</source><year>2008</year><volume>82</volume><fpage>992</fpage><lpage>1002</lpage><pub-id pub-id-type="pmid">18394578</pub-id></element-citation></ref><ref id="CR67"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hazan</surname><given-names>J</given-names></name><name><surname>Fonknechten</surname><given-names>N</given-names></name><name><surname>Mavel</surname><given-names>D</given-names></name><etal></etal></person-group><article-title>Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia</article-title><source>Nat Genet</source><year>1999</year><volume>23</volume><fpage>296</fpage><lpage>303</lpage><pub-id pub-id-type="pmid">10610178</pub-id></element-citation></ref><ref id="CR68"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Heffernan</surname><given-names>LF</given-names></name><name><surname>Simpson</surname><given-names>JC</given-names></name></person-group><article-title>The trials and tubule-ations of Rab6 involvement in Golgi-to-ER retrograde transport</article-title><source>Biochem Soc Trans</source><year>2014</year><volume>42</volume><fpage>1453</fpage><lpage>1459</lpage><pub-id pub-id-type="pmid">25233431</pub-id></element-citation></ref><ref id="CR69"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hehr</surname><given-names>U</given-names></name><name><surname>Bauer</surname><given-names>P</given-names></name><name><surname>Winner</surname><given-names>B</given-names></name><etal></etal></person-group><article-title>Long-term course and mutational spectrum of spatacsin-linked spastic paraplegia</article-title><source>Ann Neurol</source><year>2007</year><volume>62</volume><fpage>656</fpage><lpage>665</lpage><pub-id pub-id-type="pmid">18067136</pub-id></element-citation></ref><ref id="CR70"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hewamadduma</surname><given-names>C</given-names></name><name><surname>McDermott</surname><given-names>C</given-names></name><name><surname>Kirby</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>New pedigrees and novel mutation expand the phenotype of REEP1-associated hereditary spastic paraplegia (HSP)</article-title><source>Neurogenetics</source><year>2009</year><volume>10</volume><fpage>105</fpage><lpage>110</lpage><pub-id pub-id-type="pmid">19034539</pub-id></element-citation></ref><ref id="CR71"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hiroko</surname><given-names>H</given-names></name></person-group><article-title>Fatty acid 2-Hydroxylation in mammalian sphingolipid biology</article-title><source>Biochim Biophys Acta</source><year>2010</year><volume>1801</volume><fpage>405</fpage><lpage>414</lpage><pub-id pub-id-type="pmid">20026285</pub-id></element-citation></ref><ref id="CR72"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hirst</surname><given-names>J</given-names></name><name><surname>Borner</surname><given-names>GHH</given-names></name><name><surname>Edgar</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Interaction between AP-5 and the hereditary spastic paraplegia proteins SPG11 and SPG15</article-title><source>Mol Biol Cell</source><year>2013</year><volume>24</volume><issue>16</issue><fpage>2558</fpage><lpage>2569</lpage><pub-id pub-id-type="pmid">23825025</pub-id></element-citation></ref><ref id="CR212"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hodgkinson</surname><given-names>CA</given-names></name><name><surname>Bohlega</surname><given-names>S</given-names></name><name><surname>Abu-Amero</surname><given-names>SN</given-names></name><etal></etal></person-group><article-title>A novel form of autosomal recessive pure hereditary spastic paraplegia maps to chromosome 13q14</article-title><source>Neurology</source><year>2002</year><volume>59</volume><fpage>1905</fpage><lpage>1909</lpage><pub-id pub-id-type="pmid">12499481</pub-id></element-citation></ref><ref id="CR213"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ilgaz-Aydinlar</surname><given-names>E</given-names></name><name><surname>Rolfs</surname><given-names>A</given-names></name><name><surname>Serteser</surname><given-names>M</given-names></name><name><surname>Parman</surname><given-names>Y</given-names></name></person-group><article-title>Mutation in FAM134B causing hereditary sensory neuropathy with spasticity in a Turkish family</article-title><source>Muscle Nerve</source><year>2014</year><volume>49</volume><fpage>774</fpage><lpage>775</lpage><pub-id pub-id-type="pmid">24327336</pub-id></element-citation></ref><ref id="CR73"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ishiura</surname><given-names>H</given-names></name><name><surname>Sako</surname><given-names>W</given-names></name><name><surname>Yoshida</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>The TRK-fused gene is mutated in hereditary motor and sensory neuropathy with proximal dominant involvement</article-title><source>Am J Hum Genet</source><year>2012</year><volume>91</volume><fpage>320</fpage><lpage>329</lpage><pub-id pub-id-type="pmid">22883144</pub-id></element-citation></ref><ref id="CR74"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ito</surname><given-names>D</given-names></name><name><surname>Suzuki</surname><given-names>N</given-names></name></person-group><article-title>Seipinopathy: a novel endoplasmic reticulum stress-associated disease</article-title><source>Brain</source><year>2009</year><volume>132</volume><fpage>8</fpage><lpage>15</lpage><pub-id pub-id-type="pmid">18790819</pub-id></element-citation></ref><ref id="CR214"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jouet</surname><given-names>M</given-names></name><name><surname>Rosenthal</surname><given-names>A</given-names></name><name><surname>Armstrong</surname><given-names>G</given-names></name><etal></etal></person-group><article-title>X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene</article-title><source>Nat Genet</source><year>1994</year><volume>7</volume><fpage>402</fpage><lpage>407</lpage><pub-id pub-id-type="pmid">7920659</pub-id></element-citation></ref><ref id="CR75"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Karle</surname><given-names>KN</given-names></name><name><surname>Möckel</surname><given-names>D</given-names></name><name><surname>Reid</surname><given-names>E</given-names></name><name><surname>Schöls</surname><given-names>L</given-names></name></person-group><article-title>Axonal transport deficit in a KIF5A(−/−) mouse model</article-title><source>Neurogenetics</source><year>2012</year><volume>13</volume><fpage>169</fpage><lpage>179</lpage><pub-id pub-id-type="pmid">22466687</pub-id></element-citation></ref><ref id="CR76"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kasher</surname><given-names>PR</given-names></name><name><surname>De Vos</surname><given-names>KJ</given-names></name><name><surname>Wharton</surname><given-names>SB</given-names></name><etal></etal></person-group><article-title>Direct evidence for axonal transport defects in a novel mouse model of mutant spastin-induced hereditary spastic paraplegia (HSP) and human HSP patients</article-title><source>J Neurochem</source><year>2009</year><volume>110</volume><fpage>34</fpage><lpage>44</lpage><pub-id pub-id-type="pmid">19453301</pub-id></element-citation></ref><ref id="CR77"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Khan</surname><given-names>TN</given-names></name><name><surname>Klar</surname><given-names>J</given-names></name><name><surname>Tariq</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation</article-title><source>Eur J Hum Genet</source><year>2014</year><volume>22</volume><issue>10</issue><fpage>1180</fpage><lpage>1184</lpage><pub-id pub-id-type="pmid">24473461</pub-id></element-citation></ref><ref id="CR78"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Klebe</surname><given-names>S</given-names></name><name><surname>Depienne</surname><given-names>C</given-names></name><name><surname>Gerber</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy</article-title><source>Brain</source><year>2012</year><volume>135</volume><fpage>2980</fpage><lpage>2993</lpage><pub-id pub-id-type="pmid">23065789</pub-id></element-citation></ref><ref id="CR79"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Klebe</surname><given-names>S</given-names></name><name><surname>Lossos</surname><given-names>A</given-names></name><name><surname>Azzedine</surname><given-names>H</given-names></name><etal></etal></person-group><article-title>KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations</article-title><source>Eur J Hum Genet</source><year>2012</year><volume>20</volume><fpage>645</fpage><lpage>649</lpage><pub-id pub-id-type="pmid">22258533</pub-id></element-citation></ref><ref id="CR80"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Klemm</surname><given-names>RW</given-names></name><name><surname>Norton</surname><given-names>JP</given-names></name><name><surname>Cole</surname><given-names>RA</given-names></name><etal></etal></person-group><article-title>A conserved role for atlastin GTPases in regulating lipid droplet size</article-title><source>Cell Rep</source><year>2013</year><volume>3</volume><fpage>1465</fpage><lpage>1475</lpage><pub-id pub-id-type="pmid">23684613</pub-id></element-citation></ref><ref id="CR81"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kruer</surname><given-names>MC</given-names></name><name><surname>Paisán-Ruiz</surname><given-names>C</given-names></name><name><surname>Boddaert</surname><given-names>N</given-names></name><etal></etal></person-group><article-title>Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA)</article-title><source>Ann Neurol</source><year>2010</year><volume>68</volume><fpage>611</fpage><lpage>618</lpage><pub-id pub-id-type="pmid">20853438</pub-id></element-citation></ref><ref id="CR215"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kurth</surname><given-names>I</given-names></name><name><surname>Pamminger</surname><given-names>T</given-names></name><name><surname>Hennings</surname><given-names>JC</given-names></name><etal></etal></person-group><article-title>Mutations in FAM134B, encoding a newly identified Golgi protein, cause severe sensory and autonomic neuropathy</article-title><source>Nat Genet</source><year>2009</year><volume>41</volume><fpage>1179</fpage><lpage>1181</lpage><pub-id pub-id-type="pmid">19838196</pub-id></element-citation></ref><ref id="CR82"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Landouré</surname><given-names>G</given-names></name><name><surname>Zhu</surname><given-names>P-P</given-names></name><name><surname>Lourenço</surname><given-names>CM</given-names></name><etal></etal></person-group><article-title>Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12</article-title><source>Hum Mutat</source><year>2013</year><volume>34</volume><fpage>1357</fpage><lpage>1360</lpage><pub-id pub-id-type="pmid">23857908</pub-id></element-citation></ref><ref id="CR83"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Leoni</surname><given-names>V</given-names></name><name><surname>Caccia</surname><given-names>C</given-names></name></person-group><article-title>Oxysterols as biomarkers in neurodegenerative diseases</article-title><source>Chem Phys Lipids</source><year>2011</year><volume>164</volume><fpage>515</fpage><lpage>524</lpage><pub-id pub-id-type="pmid">21515244</pub-id></element-citation></ref><ref id="CR216"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Liguori</surname><given-names>R</given-names></name><name><surname>Giannoccaro</surname><given-names>MP</given-names></name><name><surname>Arnoldi</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Impairment of brain and muscle energy metabolism detected by magnetic resonance spectroscopy in hereditary spastic paraparesis type 28 patients with DDHD1 mutations</article-title><source>J Neurol</source><year>2014</year><volume>261</volume><issue>9</issue><fpage>1789</fpage><lpage>1793</lpage><pub-id pub-id-type="pmid">24989667</pub-id></element-citation></ref><ref id="CR217"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lin</surname><given-names>P</given-names></name><name><surname>Li</surname><given-names>J</given-names></name><name><surname>Liu</surname><given-names>Q</given-names></name><etal></etal></person-group><article-title>A missense mutation in SLC33A1, which encodes the acetyl-CoA transporter, causes autosomal-dominant spastic paraplegia (SPG42)</article-title><source>Am J Hum Genet</source><year>2008</year><volume>83</volume><fpage>752</fpage><lpage>759</lpage><pub-id pub-id-type="pmid">19061983</pub-id></element-citation></ref><ref id="CR84"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lindsey</surname><given-names>JC</given-names></name><name><surname>Lusher</surname><given-names>ME</given-names></name><name><surname>McDermott</surname><given-names>CJ</given-names></name><etal></etal></person-group><article-title>Mutation analysis of the spastin gene (SPG4) in patients with hereditary spastic paraparesis</article-title><source>J Med Genet</source><year>2000</year><volume>37</volume><issue>10</issue><fpage>759</fpage><lpage>765</lpage><pub-id pub-id-type="pmid">11015453</pub-id></element-citation></ref><ref id="CR85"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Liu</surname><given-names>Y-T</given-names></name><name><surname>Laurá</surname><given-names>M</given-names></name><name><surname>Hersheson</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Extended phenotypic spectrum of KIF5A mutations: from spastic paraplegia to axonal neuropathy</article-title><source>Neurology</source><year>2014</year><volume>83</volume><fpage>612</fpage><lpage>619</lpage><pub-id pub-id-type="pmid">25008398</pub-id></element-citation></ref><ref id="CR86"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lossos</surname><given-names>A</given-names></name><name><surname>Stümpfig</surname><given-names>C</given-names></name><name><surname>Stevanin</surname><given-names>G</given-names></name><etal></etal></person-group><article-title>Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia</article-title><source>Neurology</source><year>2015</year><volume>84</volume><issue>7</issue><fpage>659</fpage><lpage>667</lpage><pub-id pub-id-type="pmid">25609768</pub-id></element-citation></ref><ref id="CR87"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Loureiro</surname><given-names>JL</given-names></name><name><surname>Brandão</surname><given-names>E</given-names></name><name><surname>Ruano</surname><given-names>L</given-names></name><etal></etal></person-group><article-title>Autosomal dominant spastic paraplegias: a review of 89 families resulting from a Portuguese survey</article-title><source>JAMA Neurol</source><year>2013</year><volume>70</volume><fpage>481</fpage><lpage>487</lpage><pub-id pub-id-type="pmid">23400676</pub-id></element-citation></ref><ref id="CR88"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Luo</surname><given-names>Y</given-names></name><name><surname>Chen</surname><given-names>C</given-names></name><name><surname>Zhan</surname><given-names>Z</given-names></name><etal></etal></person-group><article-title>Mutation and clinical characteristics of autosomal-dominant hereditary spastic paraplegias in china</article-title><source>Neurodegener Dis</source><year>2014</year><volume>14</volume><issue>4</issue><fpage>176</fpage><lpage>183</lpage><pub-id pub-id-type="pmid">25341883</pub-id></element-citation></ref><ref id="CR218"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Macedo-Souza</surname><given-names>LI</given-names></name><name><surname>Kok</surname><given-names>F</given-names></name><name><surname>Santos</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Reevaluation of a large family defines a new locus for X-linked recessive pure spastic paraplegia (SPG34) on chromosome Xq25</article-title><source>Neurogenetics</source><year>2008</year><volume>9</volume><fpage>225</fpage><lpage>226</lpage><pub-id pub-id-type="pmid">18463901</pub-id></element-citation></ref><ref id="CR89"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Magen</surname><given-names>D</given-names></name><name><surname>Georgopoulos</surname><given-names>C</given-names></name><name><surname>Bross</surname><given-names>P</given-names></name><etal></etal></person-group><article-title>Mitochondrial hsp60 chaperonopathy causes an autosomal-recessive neurodegenerative disorder linked to brain hypomyelination and leukodystrophy</article-title><source>Am J Hum Genet</source><year>2008</year><volume>83</volume><fpage>30</fpage><lpage>42</lpage><pub-id pub-id-type="pmid">18571143</pub-id></element-citation></ref><ref id="CR90"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Magré</surname><given-names>J</given-names></name><name><surname>Delépine</surname><given-names>M</given-names></name><name><surname>Khallouf</surname><given-names>E</given-names></name><etal></etal></person-group><article-title>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13</article-title><source>Nat Genet</source><year>2001</year><volume>28</volume><fpage>365</fpage><lpage>370</lpage><pub-id pub-id-type="pmid">11479539</pub-id></element-citation></ref><ref id="CR219"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mannan</surname><given-names>AU</given-names></name><name><surname>Krawen</surname><given-names>P</given-names></name><name><surname>Sauter</surname><given-names>SM</given-names></name><etal></etal></person-group><article-title>ZFYVE27 (SPG33), a novel spastin-binding protein, is mutated in hereditary spastic paraplegia</article-title><source>Am J Hum Genet</source><year>2006</year><volume>79</volume><fpage>351</fpage><lpage>357</lpage><pub-id pub-id-type="pmid">16826525</pub-id></element-citation></ref><ref id="CR91"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Martin</surname><given-names>E</given-names></name><name><surname>Schüle</surname><given-names>R</given-names></name><name><surname>Smets</surname><given-names>K</given-names></name><etal></etal></person-group><article-title>Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia</article-title><source>Am J Hum Genet</source><year>2013</year><volume>92</volume><fpage>238</fpage><lpage>244</lpage><pub-id pub-id-type="pmid">23332916</pub-id></element-citation></ref><ref id="CR92"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>McDermott</surname><given-names>CJ</given-names></name><name><surname>Dayaratne</surname><given-names>RK</given-names></name><name><surname>Tomkins</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Paraplegin gene analysis in hereditary spastic paraparesis (HSP) pedigrees in northeast England</article-title><source>Neurology</source><year>2001</year><volume>56</volume><issue>4</issue><fpage>467</fpage><lpage>471</lpage><pub-id pub-id-type="pmid">11222789</pub-id></element-citation></ref><ref id="CR93"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Meijer</surname><given-names>IA</given-names></name><name><surname>Hand</surname><given-names>CK</given-names></name><name><surname>Cossette</surname><given-names>P</given-names></name><etal></etal></person-group><article-title>Spectrum of SPG4 mutations in a large collection of North American families with hereditary spastic paraplegia</article-title><source>Arch Neurol</source><year>2002</year><volume>59</volume><fpage>281</fpage><lpage>286</lpage><pub-id pub-id-type="pmid">11843700</pub-id></element-citation></ref><ref id="CR220"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Meijer</surname><given-names>IA</given-names></name><name><surname>Cossette</surname><given-names>P</given-names></name><name><surname>Roussel</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>A novel locus for pure recessive hereditary spastic paraplegia maps to 10q22.1-10q24.1</article-title><source>Ann Neurol</source><year>2004</year><volume>56</volume><fpage>579</fpage><lpage>582</lpage><pub-id pub-id-type="pmid">15455396</pub-id></element-citation></ref><ref id="CR94"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mitne-Neto</surname><given-names>M</given-names></name><name><surname>Kok</surname><given-names>F</given-names></name><name><surname>Beetz</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>A multi-exonic SPG4 duplication underlies sex-dependent penetrance of hereditary spastic paraplegia in a large Brazilian pedigree</article-title><source>Eur J Hum Genet</source><year>2007</year><volume>15</volume><issue>12</issue><fpage>1276</fpage><lpage>1279</lpage><pub-id pub-id-type="pmid">17895902</pub-id></element-citation></ref><ref id="CR95"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Montenegro</surname><given-names>G</given-names></name><name><surname>Rebelo</surname><given-names>AP</given-names></name><name><surname>Connell</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12</article-title><source>J Clin Invest</source><year>2012</year><volume>122</volume><fpage>538</fpage><lpage>544</lpage><pub-id pub-id-type="pmid">22232211</pub-id></element-citation></ref><ref id="CR96"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Moreno-De-Luca</surname><given-names>A</given-names></name><name><surname>Helmers</surname><given-names>SL</given-names></name><name><surname>Mao</surname><given-names>H</given-names></name><etal></etal></person-group><article-title>Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability</article-title><source>J Med Genet</source><year>2011</year><volume>48</volume><fpage>141</fpage><lpage>144</lpage><pub-id pub-id-type="pmid">20972249</pub-id></element-citation></ref><ref id="CR97"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Murakami</surname><given-names>Y</given-names></name><name><surname>Tawamie</surname><given-names>H</given-names></name><name><surname>Maeda</surname><given-names>Y</given-names></name><etal></etal></person-group><article-title>Null mutation in PGAP1 impairing Gpi-anchor maturation in patients with intellectual disability and encephalopathy</article-title><source>PLoS Genet</source><year>2014</year><volume>10</volume><fpage>e1004320</fpage><pub-id pub-id-type="pmid">24784135</pub-id></element-citation></ref><ref id="CR98"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Musumeci</surname><given-names>O</given-names></name><name><surname>Bassi</surname><given-names>MT</given-names></name><name><surname>Mazzeo</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>A novel mutation in KIF5A gene causing hereditary spastic paraplegia with axonal neuropathy</article-title><source>Neurol Sci</source><year>2011</year><volume>32</volume><fpage>665</fpage><lpage>668</lpage><pub-id pub-id-type="pmid">21107874</pub-id></element-citation></ref><ref id="CR99"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Neveling</surname><given-names>K</given-names></name><name><surname>Martinez-Carrera</surname><given-names>LA</given-names></name><name><surname>Hölker</surname><given-names>I</given-names></name><etal></etal></person-group><article-title>Mutations in BICD2, which encodes a golgin and important motor adaptor, cause congenital autosomal-dominant spinal muscular atrophy</article-title><source>Am J Hum Genet</source><year>2013</year><volume>92</volume><fpage>946</fpage><lpage>954</lpage><pub-id pub-id-type="pmid">23664116</pub-id></element-citation></ref><ref id="CR100"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Novarino</surname><given-names>G</given-names></name><name><surname>Fenstermaker</surname><given-names>AG</given-names></name><name><surname>Zaki</surname><given-names>MS</given-names></name><etal></etal></person-group><article-title>Exome Sequencing links corticospinal motor neuron disease to common neurodegenerative disorders</article-title><source>Science</source><year>2014</year><volume>343</volume><fpage>506</fpage><lpage>511</lpage><pub-id pub-id-type="pmid">24482476</pub-id></element-citation></ref><ref id="CR101"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Oates</surname><given-names>EC</given-names></name><name><surname>Rossor</surname><given-names>AM</given-names></name><name><surname>Hafezparast</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Mutations in BICD2 cause dominant congenital spinal muscular atrophy and hereditary spastic paraplegia</article-title><source>Am J Hum Genet</source><year>2013</year><volume>92</volume><fpage>965</fpage><lpage>973</lpage><pub-id pub-id-type="pmid">23664120</pub-id></element-citation></ref><ref id="CR102"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ohmi</surname><given-names>Y</given-names></name><name><surname>Tajima</surname><given-names>O</given-names></name><name><surname>Ohkawa</surname><given-names>Y</given-names></name><etal></etal></person-group><article-title>Gangliosides are essential in the protection of inflammation and neurodegeneration via maintenance of lipid rafts: elucidation by a series of ganglioside-deficient mutant mice</article-title><source>J Neurochem</source><year>2011</year><volume>116</volume><fpage>926</fpage><lpage>935</lpage><pub-id pub-id-type="pmid">21214571</pub-id></element-citation></ref><ref id="CR221"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Orlacchio</surname><given-names>A</given-names></name><name><surname>Kawarai</surname><given-names>T</given-names></name><name><surname>Gaudiello</surname><given-names>F</given-names></name><etal></etal></person-group><article-title>New locus for hereditary spastic paraplegia maps to chromosome 1p31.1-1p21.1</article-title><source>Ann Neurol</source><year>2005</year><volume>58</volume><fpage>423</fpage><lpage>429</lpage><pub-id pub-id-type="pmid">16130112</pub-id></element-citation></ref><ref id="CR222"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Orlacchio</surname><given-names>A</given-names></name><name><surname>Patrono</surname><given-names>C</given-names></name><name><surname>Gaudiello</surname><given-names>F</given-names></name><etal></etal></person-group><article-title>Silver syndrome variant of hereditary spastic paraplegia: a locus to 4p and allelism with SPG4</article-title><source>Neurology</source><year>2008</year><volume>70</volume><fpage>1959</fpage><lpage>1966</lpage><pub-id pub-id-type="pmid">18401025</pub-id></element-citation></ref><ref id="CR223"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Orlacchio</surname><given-names>A</given-names></name><name><surname>Babalini</surname><given-names>C</given-names></name><name><surname>Borreca</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis</article-title><source>Brain</source><year>2010</year><volume>133</volume><issue>Pt 2</issue><fpage>591</fpage><lpage>598</lpage><pub-id pub-id-type="pmid">20110243</pub-id></element-citation></ref><ref id="CR103"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Orso</surname><given-names>G</given-names></name><name><surname>Pendin</surname><given-names>D</given-names></name><name><surname>Liu</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Homotypic fusion of ER membranes requires the dynamin-like GTPase atlastin</article-title><source>Nature</source><year>2009</year><volume>460</volume><fpage>978</fpage><lpage>983</lpage><pub-id pub-id-type="pmid">19633650</pub-id></element-citation></ref><ref id="CR104"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Orthmann-Murphy</surname><given-names>JL</given-names></name><name><surname>Salsano</surname><given-names>E</given-names></name><name><surname>Abrams</surname><given-names>CK</given-names></name><etal></etal></person-group><article-title>Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations</article-title><source>Brain</source><year>2009</year><volume>132</volume><fpage>426</fpage><lpage>438</lpage><pub-id pub-id-type="pmid">19056803</pub-id></element-citation></ref><ref id="CR105"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Oz-Levi</surname><given-names>D</given-names></name><name><surname>Ben-Zeev</surname><given-names>B</given-names></name><name><surname>Ruzzo</surname><given-names>EK</given-names></name><etal></etal></person-group><article-title>Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis</article-title><source>Am J Hum Genet</source><year>2012</year><volume>91</volume><fpage>1065</fpage><lpage>1072</lpage><pub-id pub-id-type="pmid">23176824</pub-id></element-citation></ref><ref id="CR106"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Paisan-Ruiz</surname><given-names>C</given-names></name><name><surname>Dogu</surname><given-names>O</given-names></name><name><surname>Yilmaz</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>SPG11 mutations are common in familial cases of complicated hereditary spastic paraplegia</article-title><source>Neurology</source><year>2008</year><volume>70</volume><fpage>1384</fpage><lpage>1389</lpage><pub-id pub-id-type="pmid">18337587</pub-id></element-citation></ref><ref id="CR107"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Park</surname><given-names>SH</given-names></name><name><surname>Zhu</surname><given-names>P-P</given-names></name><name><surname>Parker</surname><given-names>RL</given-names></name><name><surname>Blackstone</surname><given-names>C</given-names></name></person-group><article-title>Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network</article-title><source>J Clin Invest</source><year>2010</year><volume>120</volume><fpage>1097</fpage><lpage>1110</lpage><pub-id pub-id-type="pmid">20200447</pub-id></element-citation></ref><ref id="CR224"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Patel</surname><given-names>H</given-names></name><name><surname>Cross</surname><given-names>H</given-names></name><name><surname>Proukakis</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia</article-title><source>Nat Genet</source><year>2002</year><volume>31</volume><fpage>347</fpage><lpage>348</lpage><pub-id pub-id-type="pmid">12134148</pub-id></element-citation></ref><ref id="CR108"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pérez-Brangulí</surname><given-names>F</given-names></name><name><surname>Mishra</surname><given-names>HK</given-names></name><name><surname>Prots</surname><given-names>I</given-names></name><etal></etal></person-group><article-title>Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia</article-title><source>Hum Mol Genet</source><year>2014</year><volume>23</volume><fpage>4859</fpage><lpage>4874</lpage><pub-id pub-id-type="pmid">24794856</pub-id></element-citation></ref><ref id="CR109"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pfeffer</surname><given-names>G</given-names></name><name><surname>Gorman</surname><given-names>GS</given-names></name><name><surname>Griffin</surname><given-names>H</given-names></name><etal></etal></person-group><article-title>Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance</article-title><source>Brain</source><year>2014</year><volume>137</volume><fpage>1323</fpage><lpage>1336</lpage><pub-id pub-id-type="pmid">24727571</pub-id></element-citation></ref><ref id="CR110"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Potter</surname><given-names>KA</given-names></name><name><surname>Kern</surname><given-names>MJ</given-names></name><name><surname>Fullbright</surname><given-names>G</given-names></name><etal></etal></person-group><article-title>Central nervous system dysfunction in a mouse model of Fa2h deficiency</article-title><source>Glia</source><year>2011</year><volume>59</volume><fpage>1009</fpage><lpage>1021</lpage><pub-id pub-id-type="pmid">21491498</pub-id></element-citation></ref><ref id="CR111"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Proukakis</surname><given-names>C</given-names></name><name><surname>Moore</surname><given-names>D</given-names></name><name><surname>Labrum</surname><given-names>R</given-names></name><name><surname>Wood</surname><given-names>NW</given-names></name><name><surname>Houlden</surname><given-names>H</given-names></name></person-group><article-title>Detection of novel mutations and review of published data suggests that hereditary spastic paraplegia caused by spastin (SPAST) mutations is found more often in males</article-title><source>J Neurol Sci</source><year>2011</year><volume>306</volume><issue>1–2</issue><fpage>62</fpage><lpage>65</lpage><pub-id pub-id-type="pmid">21546041</pub-id></element-citation></ref><ref id="CR112"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rahman</surname><given-names>M</given-names></name><name><surname>Haberman</surname><given-names>A</given-names></name><name><surname>Tracy</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>Drosophila mauve mutants reveal a role of LYST homologs late in the maturation of phagosomes and autophagosomes</article-title><source>Traffic</source><year>2012</year><volume>13</volume><fpage>1680</fpage><lpage>1692</lpage><pub-id pub-id-type="pmid">22934826</pub-id></element-citation></ref><ref id="CR225"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rainier</surname><given-names>S</given-names></name><name><surname>Chai</surname><given-names>J-H</given-names></name><name><surname>Tokarz</surname><given-names>D</given-names></name><etal></etal></person-group><article-title>NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6)</article-title><source>Am J Hum Genet</source><year>2003</year><volume>73</volume><fpage>967</fpage><lpage>971</lpage><pub-id pub-id-type="pmid">14508710</pub-id></element-citation></ref><ref id="CR113"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rainier</surname><given-names>S</given-names></name><name><surname>Bui</surname><given-names>M</given-names></name><name><surname>Mark</surname><given-names>E</given-names></name><etal></etal></person-group><article-title>Neuropathy target esterase gene mutations cause motor neuron disease</article-title><source>Am J Hum Genet</source><year>2008</year><volume>82</volume><fpage>780</fpage><lpage>785</lpage><pub-id pub-id-type="pmid">18313024</pub-id></element-citation></ref><ref id="CR114"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Reid</surname><given-names>E</given-names></name><name><surname>Dearlove</surname><given-names>AM</given-names></name><name><surname>Osborn</surname><given-names>O</given-names></name><etal></etal></person-group><article-title>A locus for autosomal dominant “pure” hereditary spastic paraplegia maps to chromosome 19q13</article-title><source>Am J Hum Genet</source><year>2000</year><volume>66</volume><fpage>728</fpage><lpage>732</lpage><pub-id pub-id-type="pmid">10677333</pub-id></element-citation></ref><ref id="CR226"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Reid</surname><given-names>E</given-names></name><name><surname>Kloos</surname><given-names>M</given-names></name><name><surname>Ashley-Koch</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10)</article-title><source>Am J Hum Genet</source><year>2002</year><volume>71</volume><fpage>1189</fpage><lpage>1194</lpage><pub-id pub-id-type="pmid">12355402</pub-id></element-citation></ref><ref id="CR115"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Renvoisé</surname><given-names>B</given-names></name><name><surname>Stadler</surname><given-names>J</given-names></name><name><surname>Singh</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>Spg20−/− mice reveal multimodal functions for Troyer syndrome protein spartin in lipid droplet maintenance, cytokinesis and BMP signaling</article-title><source>Hum Mol Genet</source><year>2012</year><volume>21</volume><fpage>3604</fpage><lpage>3618</lpage><pub-id pub-id-type="pmid">22619377</pub-id></element-citation></ref><ref id="CR227"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ribai</surname><given-names>P</given-names></name><name><surname>Stevanin</surname><given-names>G</given-names></name><name><surname>Bouslam</surname><given-names>N</given-names></name><etal></etal></person-group><article-title>A new phenotype linked to SPG27 and refinement of the critical region on chromosome</article-title><source>J Neurol</source><year>2006</year><volume>253</volume><fpage>714</fpage><lpage>719</lpage><pub-id pub-id-type="pmid">16511635</pub-id></element-citation></ref><ref id="CR116"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rismanchi</surname><given-names>N</given-names></name><name><surname>Soderblom</surname><given-names>C</given-names></name><name><surname>Stadler</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Atlastin GTPases are required for Golgi apparatus and ER morphogenesis</article-title><source>Hum Mol Genet</source><year>2008</year><volume>17</volume><fpage>1591</fpage><lpage>1604</lpage><pub-id pub-id-type="pmid">18270207</pub-id></element-citation></ref><ref id="CR117"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rivière</surname><given-names>J-B</given-names></name><name><surname>Ramalingam</surname><given-names>S</given-names></name><name><surname>Lavastre</surname><given-names>V</given-names></name><etal></etal></person-group><article-title>KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2</article-title><source>Am J Hum Genet</source><year>2011</year><volume>89</volume><fpage>219</fpage><lpage>230</lpage><pub-id pub-id-type="pmid">21820098</pub-id></element-citation></ref><ref id="CR118"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Romagnolo</surname><given-names>A</given-names></name><name><surname>Masera</surname><given-names>S</given-names></name><name><surname>Mattioda</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Atypical hereditary spastic paraplegia mimicking multiple sclerosis associated with a novel SPG11 mutation</article-title><source>Eur J Neurol</source><year>2014</year><volume>21</volume><fpage>e14</fpage><lpage>e15</lpage><pub-id pub-id-type="pmid">24571105</pub-id></element-citation></ref><ref id="CR228"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rosenthal</surname><given-names>A</given-names></name><name><surname>Jouet</surname><given-names>M</given-names></name><name><surname>Kenwrick</surname><given-names>S</given-names></name></person-group><article-title>Aberrant splicing of neural cell adhesion molecule L1 mRNA in a family with X-linked hydrocephalus</article-title><source>Nat Genet</source><year>1992</year><volume>2</volume><fpage>107</fpage><lpage>112</lpage><pub-id pub-id-type="pmid">1303258</pub-id></element-citation></ref><ref id="CR119"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ruano</surname><given-names>L</given-names></name><name><surname>Melo</surname><given-names>C</given-names></name><name><surname>Silva</surname><given-names>MC</given-names></name><name><surname>Coutinho</surname><given-names>P</given-names></name></person-group><article-title>The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies</article-title><source>Neuroepidemiology</source><year>2014</year><volume>42</volume><fpage>174</fpage><lpage>183</lpage><pub-id pub-id-type="pmid">24603320</pub-id></element-citation></ref><ref id="CR120"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sánchez-Ferrero</surname><given-names>E</given-names></name><name><surname>Coto</surname><given-names>E</given-names></name><name><surname>Beetz</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>SPG7 mutational screening in spastic paraplegia patients supports a dominant effect for some mutations and a pathogenic role for p. A510V</article-title><source>Clin Genet</source><year>2013</year><volume>83</volume><issue>3</issue><fpage>257</fpage><lpage>262</lpage><pub-id pub-id-type="pmid">22571692</pub-id></element-citation></ref><ref id="CR229"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Saugier-Veber</surname><given-names>P</given-names></name><name><surname>Munnich</surname><given-names>A</given-names></name><name><surname>Bonneau</surname><given-names>D</given-names></name><etal></etal></person-group><article-title>X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus</article-title><source>Nat Genet</source><year>1994</year><volume>6</volume><fpage>257</fpage><lpage>262</lpage><pub-id pub-id-type="pmid">8012387</pub-id></element-citation></ref><ref id="CR121"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schneider</surname><given-names>SA</given-names></name><name><surname>Bhatia</surname><given-names>KP</given-names></name></person-group><article-title>Three faces of the same gene: FA2H links neurodegeneration with brain iron accumulation, leukodystrophies, and hereditary spastic paraplegias</article-title><source>Ann Neurol</source><year>2010</year><volume>68</volume><fpage>575</fpage><lpage>577</lpage><pub-id pub-id-type="pmid">21031573</pub-id></element-citation></ref><ref id="CR230"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schüle</surname><given-names>R</given-names></name><name><surname>Bonin</surname><given-names>M</given-names></name><name><surname>Dürr</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Autosomal dominant spastic paraplegia with peripheral neuropathy maps to chr12q23-24</article-title><source>Neurology</source><year>2009</year><volume>72</volume><fpage>1893</fpage><lpage>1898</lpage><pub-id pub-id-type="pmid">19357379</pub-id></element-citation></ref><ref id="CR122"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schüle</surname><given-names>R</given-names></name><name><surname>Schlipf</surname><given-names>N</given-names></name><name><surname>Synofzik</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Frequency and phenotype of SPG11 and SPG15 in complicated hereditary spastic paraplegia</article-title><source>J Neurol Neurosurg Psychiatry</source><year>2009</year><volume>80</volume><fpage>1402</fpage><lpage>1404</lpage><pub-id pub-id-type="pmid">19917823</pub-id></element-citation></ref><ref id="CR123"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schüle</surname><given-names>R</given-names></name><name><surname>Siddique</surname><given-names>T</given-names></name><name><surname>Deng</surname><given-names>H-X</given-names></name><etal></etal></person-group><article-title>Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis</article-title><source>J Lipid Res</source><year>2010</year><volume>51</volume><fpage>819</fpage><lpage>823</lpage><pub-id pub-id-type="pmid">19812052</pub-id></element-citation></ref><ref id="CR231"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schuurs-Hoeijmakers</surname><given-names>JHM</given-names></name><name><surname>Geraghty</surname><given-names>MT</given-names></name><name><surname>Kamsteeg</surname><given-names>E-J</given-names></name><etal></etal></person-group><article-title>Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia</article-title><source>Am J Hum Genet</source><year>2012</year><volume>91</volume><fpage>1073</fpage><lpage>1081</lpage><pub-id pub-id-type="pmid">23176823</pub-id></element-citation></ref><ref id="CR232"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schwartz</surname><given-names>CE</given-names></name><name><surname>May</surname><given-names>MM</given-names></name><name><surname>Carpenter</surname><given-names>NJ</given-names></name><etal></etal></person-group><article-title>Allan-Herndon-Dudley syndrome and the monocarboxylate transporter 8 (MCT8) gene</article-title><source>Am J Hum Genet</source><year>2005</year><volume>77</volume><fpage>41</fpage><lpage>53</lpage><pub-id pub-id-type="pmid">15889350</pub-id></element-citation></ref><ref id="CR124"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sedel</surname><given-names>F</given-names></name><name><surname>Fontaine</surname><given-names>B</given-names></name><name><surname>Saudubray</surname><given-names>JM</given-names></name><name><surname>Lyon-Caen</surname><given-names>O</given-names></name></person-group><article-title>Hereditary spastic paraparesis in adults associated with inborn errors of metabolism: a diagnostic approach</article-title><source>J Inherit Metab Dis</source><year>2007</year><volume>30</volume><fpage>855</fpage><lpage>864</lpage><pub-id pub-id-type="pmid">17957490</pub-id></element-citation></ref><ref id="CR233"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Seri</surname><given-names>M</given-names></name><name><surname>Cusano</surname><given-names>R</given-names></name><name><surname>Forabosco</surname><given-names>P</given-names></name><etal></etal></person-group><article-title>Genetic mapping to 10q23.3-q24.2, in a large Italian pedigree, of a new syndrome showing bilateral cataracts, gastroesophageal reflux, and spastic paraparesis with amyotrophy</article-title><source>Am J Hum Genet</source><year>1999</year><volume>64</volume><fpage>586</fpage><lpage>593</lpage><pub-id pub-id-type="pmid">9973297</pub-id></element-citation></ref><ref id="CR125"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Shimazaki</surname><given-names>H</given-names></name><name><surname>Takiyama</surname><given-names>Y</given-names></name><name><surname>Ishiura</surname><given-names>H</given-names></name><etal></etal></person-group><article-title>A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55)</article-title><source>J Med Genet</source><year>2012</year><volume>49</volume><fpage>777</fpage><lpage>784</lpage><pub-id pub-id-type="pmid">23188110</pub-id></element-citation></ref><ref id="CR126"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Shimazaki</surname><given-names>H</given-names></name><name><surname>Honda</surname><given-names>J</given-names></name><name><surname>Naoi</surname><given-names>T</given-names></name><etal></etal></person-group><article-title>Autosomal-recessive complicated spastic paraplegia with a novel lysosomal trafficking regulator gene mutation</article-title><source>J Neurol Neurosurg Psychiatry</source><year>2014</year><volume>85</volume><fpage>1024</fpage><lpage>1028</lpage><pub-id pub-id-type="pmid">24521565</pub-id></element-citation></ref><ref id="CR234"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Simpson</surname><given-names>MA</given-names></name><name><surname>Cross</surname><given-names>H</given-names></name><name><surname>Proukakis</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>Maspardin is mutated in mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia</article-title><source>Am J Hum Genet</source><year>2003</year><volume>73</volume><fpage>1147</fpage><lpage>1156</lpage><pub-id pub-id-type="pmid">14564668</pub-id></element-citation></ref><ref id="CR127"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sivakumar</surname><given-names>K</given-names></name><name><surname>Sambuughin</surname><given-names>N</given-names></name><name><surname>Selenge</surname><given-names>B</given-names></name><etal></etal></person-group><article-title>Novel exon 3B proteolipid protein gene mutation causing late-onset spastic paraplegia type 2 with variable penetrance in female family members</article-title><source>Ann Neurol</source><year>1999</year><volume>45</volume><fpage>680</fpage><lpage>683</lpage><pub-id pub-id-type="pmid">10319897</pub-id></element-citation></ref><ref id="CR235"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Słabicki</surname><given-names>M</given-names></name><name><surname>Theis</surname><given-names>M</given-names></name><name><surname>Krastev</surname><given-names>DB</given-names></name><etal></etal></person-group><article-title>A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia</article-title><source>PLoS Biol</source><year>2010</year><volume>8</volume><fpage>e1000408</fpage><pub-id pub-id-type="pmid">20613862</pub-id></element-citation></ref><ref id="CR128"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Spiegel</surname><given-names>R</given-names></name><name><surname>Mandel</surname><given-names>H</given-names></name><name><surname>Saada</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Delineation of C12orf65-related phenotypes: a genotype–phenotype relationship</article-title><source>Eur J Hum Genet</source><year>2014</year><volume>22</volume><fpage>1019</fpage><lpage>1025</lpage><pub-id pub-id-type="pmid">24424123</pub-id></element-citation></ref><ref id="CR129"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Starling</surname><given-names>A</given-names></name><name><surname>Rocco</surname><given-names>P</given-names></name><name><surname>Passos-Bueno</surname><given-names>MR</given-names></name><name><surname>Hazan</surname><given-names>J</given-names></name><name><surname>Marie</surname><given-names>SK</given-names></name><name><surname>Zatz</surname><given-names>M</given-names></name></person-group><article-title>Autosomal dominant (AD) pure spastic paraplegia (HSP) linked to locus SPG4 affects almost exclusively males in a large pedigree</article-title><source>J Med Genet</source><year>2002</year><volume>39</volume><issue>12</issue><fpage>e77</fpage><pub-id pub-id-type="pmid">12471215</pub-id></element-citation></ref><ref id="CR236"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Steinmüller</surname><given-names>R</given-names></name><name><surname>Lantigua-Cruz</surname><given-names>A</given-names></name><name><surname>Garcia-Garcia</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>Evidence of a third locus in X-linked recessive spastic paraplegia</article-title><source>Hum Genet</source><year>1997</year><volume>100</volume><fpage>287</fpage><lpage>289</lpage><pub-id pub-id-type="pmid">9254866</pub-id></element-citation></ref><ref id="CR237"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Stevanin</surname><given-names>G</given-names></name><name><surname>Paternotte</surname><given-names>C</given-names></name><name><surname>Coutinho</surname><given-names>P</given-names></name><etal></etal></person-group><article-title>A new locus for autosomal recessive spastic paraplegia (SPG32) on chromosome 14q12-q21</article-title><source>Neurology</source><year>2007</year><volume>68</volume><fpage>1837</fpage><lpage>1840</lpage><pub-id pub-id-type="pmid">17515546</pub-id></element-citation></ref><ref id="CR130"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Stevanin</surname><given-names>G</given-names></name><name><surname>Santorelli</surname><given-names>FM</given-names></name><name><surname>Azzedine</surname><given-names>H</given-names></name><etal></etal></person-group><article-title>Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum</article-title><source>Nat Genet</source><year>2007</year><volume>39</volume><fpage>366</fpage><lpage>372</lpage><pub-id pub-id-type="pmid">17322883</pub-id></element-citation></ref><ref id="CR131"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Stevanin</surname><given-names>G</given-names></name><name><surname>Azzedine</surname><given-names>H</given-names></name><name><surname>Denora</surname><given-names>P</given-names></name><etal></etal></person-group><article-title>Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration</article-title><source>Brain</source><year>2008</year><volume>131</volume><fpage>772</fpage><lpage>784</lpage><pub-id pub-id-type="pmid">18079167</pub-id></element-citation></ref><ref id="CR132"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Stevanin</surname><given-names>G</given-names></name><name><surname>Ruberg</surname><given-names>M</given-names></name><name><surname>Brice</surname><given-names>A</given-names></name></person-group><article-title>Recent advances in the genetics of spastic paraplegias</article-title><source>Curr Neurol Neurosci Rep</source><year>2008</year><volume>8</volume><fpage>198</fpage><lpage>210</lpage><pub-id pub-id-type="pmid">18541115</pub-id></element-citation></ref><ref id="CR133"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Svenson</surname><given-names>IK</given-names></name><name><surname>Kloos</surname><given-names>MT</given-names></name><name><surname>Gaskell</surname><given-names>PC</given-names></name><etal></etal></person-group><article-title>Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations</article-title><source>Neurogenetics</source><year>2004</year><volume>5</volume><fpage>157</fpage><lpage>164</lpage><pub-id pub-id-type="pmid">15248095</pub-id></element-citation></ref><ref id="CR134"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Synofzik</surname><given-names>M</given-names></name><name><surname>Gonzalez</surname><given-names>MA</given-names></name><name><surname>Lourenco</surname><given-names>CM</given-names></name><etal></etal></person-group><article-title>PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum</article-title><source>Brain</source><year>2014</year><volume>137</volume><fpage>69</fpage><lpage>77</lpage><pub-id pub-id-type="pmid">24355708</pub-id></element-citation></ref><ref id="CR135"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Takiyama</surname><given-names>Y</given-names></name></person-group><article-title>Japan Spastic Paraplegia Research Consortium (JASPAC)</article-title><source>Brain Nerve</source><year>2014</year><volume>66</volume><issue>10</issue><fpage>1210</fpage><lpage>1217</lpage><pub-id pub-id-type="pmid">25296875</pub-id></element-citation></ref><ref id="CR136"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tallaksen</surname><given-names>CM</given-names></name><name><surname>Dürr</surname><given-names>A</given-names></name><name><surname>Brice</surname><given-names>A</given-names></name></person-group><article-title>Recent advances in hereditary spastic paraplegia</article-title><source>Curr Opin Neurol</source><year>2001</year><volume>14</volume><fpage>457</fpage><lpage>463</lpage><pub-id pub-id-type="pmid">11470961</pub-id></element-citation></ref><ref id="CR238"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tamagaki</surname><given-names>A</given-names></name><name><surname>Shima</surname><given-names>M</given-names></name><name><surname>Tomita</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>Segregation of a pure form of spastic paraplegia and NOR insertion into Xq11.2</article-title><source>Am J Med Genet</source><year>2000</year><volume>94</volume><fpage>5</fpage><lpage>8</lpage><pub-id pub-id-type="pmid">10982474</pub-id></element-citation></ref><ref id="CR137"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tanyel</surname><given-names>MC</given-names></name><name><surname>Mancano</surname><given-names>LD</given-names></name></person-group><article-title>Neurologic findings in vitamin E deficiency</article-title><source>Am Fam Physician</source><year>1997</year><volume>55</volume><fpage>197</fpage><lpage>201</lpage><pub-id pub-id-type="pmid">9012278</pub-id></element-citation></ref><ref id="CR138"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tarrade</surname><given-names>A</given-names></name><name><surname>Fassier</surname><given-names>C</given-names></name><name><surname>Courageot</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>A mutation of spastin is responsible for swellings and impairment of transport in a region of axon characterized by changes in microtubule composition</article-title><source>Hum Mol Genet</source><year>2006</year><volume>15</volume><fpage>3544</fpage><lpage>3558</lpage><pub-id pub-id-type="pmid">17101632</pub-id></element-citation></ref><ref id="CR139"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tessa</surname><given-names>A</given-names></name><name><surname>Silvestri</surname><given-names>G</given-names></name><name><surname>de Leva</surname><given-names>MF</given-names></name><etal></etal></person-group><article-title>A novel KIF5A/SPG10 mutation in spastic paraplegia associated with axonal neuropathy</article-title><source>J Neurol</source><year>2008</year><volume>255</volume><fpage>1090</fpage><lpage>1092</lpage><pub-id pub-id-type="pmid">18500496</pub-id></element-citation></ref><ref id="CR239"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tesson</surname><given-names>C</given-names></name><name><surname>Nawara</surname><given-names>M</given-names></name><name><surname>Salih</surname><given-names>MAM</given-names></name><etal></etal></person-group><article-title>Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia</article-title><source>Am J Hum Genet</source><year>2012</year><volume>91</volume><fpage>1051</fpage><lpage>1064</lpage><pub-id pub-id-type="pmid">23176821</pub-id></element-citation></ref><ref id="CR140"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Theofilopoulos</surname><given-names>S</given-names></name><name><surname>Griffiths</surname><given-names>WJ</given-names></name><name><surname>Crick</surname><given-names>PJ</given-names></name><etal></etal></person-group><article-title>Cholestenoic acids regulate motor neuron survival via liver X receptors</article-title><source>J Clin Invest</source><year>2014</year><volume>124</volume><fpage>4829</fpage><lpage>4842</lpage><pub-id pub-id-type="pmid">25271621</pub-id></element-citation></ref><ref id="CR240"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tiranti</surname><given-names>V</given-names></name><name><surname>Corona</surname><given-names>P</given-names></name><name><surname>Greco</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>A novel frameshift mutation of the mtDNA COIII gene leads to impaired assembly of cytochrome c oxidase in a patient affected by Leigh-like syndrome</article-title><source>Hum Mol Genet</source><year>2000</year><volume>9</volume><fpage>2733</fpage><lpage>2742</lpage><pub-id pub-id-type="pmid">11063732</pub-id></element-citation></ref><ref id="CR141"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tsang</surname><given-names>HTH</given-names></name><name><surname>Edwards</surname><given-names>TL</given-names></name><name><surname>Wang</surname><given-names>X</given-names></name><etal></etal></person-group><article-title>The hereditary spastic paraplegia proteins NIPA1, spastin and spartin are inhibitors of mammalian BMP signalling</article-title><source>Hum Mol Genet</source><year>2009</year><volume>18</volume><fpage>3805</fpage><lpage>3821</lpage><pub-id pub-id-type="pmid">19620182</pub-id></element-citation></ref><ref id="CR241"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tsaousidou</surname><given-names>MK</given-names></name><name><surname>Ouahchi</surname><given-names>K</given-names></name><name><surname>Warner</surname><given-names>TT</given-names></name><etal></etal></person-group><article-title>Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration</article-title><source>Am J Hum Genet</source><year>2008</year><volume>82</volume><fpage>510</fpage><lpage>515</lpage><pub-id pub-id-type="pmid">18252231</pub-id></element-citation></ref><ref id="CR142"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tucci</surname><given-names>A</given-names></name><name><surname>Liu</surname><given-names>Y-T</given-names></name><name><surname>Preza</surname><given-names>E</given-names></name><etal></etal></person-group><article-title>Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy</article-title><source>J Neurol Neurosurg Psychiatry</source><year>2013</year><volume>85</volume><fpage>486</fpage><lpage>492</lpage><pub-id pub-id-type="pmid">24198383</pub-id></element-citation></ref><ref id="CR143"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Uhlenberg</surname><given-names>B</given-names></name><name><surname>Schuelke</surname><given-names>M</given-names></name><name><surname>Rüschendorf</surname><given-names>F</given-names></name><etal></etal></person-group><article-title>Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus–Merzbacher-like disease</article-title><source>Am J Hum Genet</source><year>2004</year><volume>75</volume><fpage>251</fpage><lpage>260</lpage><pub-id pub-id-type="pmid">15192806</pub-id></element-citation></ref><ref id="CR144"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Valdmanis</surname><given-names>PN</given-names></name><name><surname>Meijer</surname><given-names>IA</given-names></name><name><surname>Reynolds</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia</article-title><source>Am J Hum Genet</source><year>2007</year><volume>80</volume><fpage>152</fpage><lpage>161</lpage><pub-id pub-id-type="pmid">17160902</pub-id></element-citation></ref><ref id="CR242"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Valente</surname><given-names>EM</given-names></name><name><surname>Brancati</surname><given-names>F</given-names></name><name><surname>Caputo</surname><given-names>V</given-names></name><etal></etal></person-group><article-title>Novel locus for autosomal dominant pure hereditary spastic paraplegia (SPG19) maps to chromosome 9q33-q34</article-title><source>Ann Neurol</source><year>2002</year><volume>51</volume><fpage>681</fpage><lpage>685</lpage><pub-id pub-id-type="pmid">12112072</pub-id></element-citation></ref><ref id="CR145"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Varga</surname><given-names>R-E</given-names></name><name><surname>Schüle</surname><given-names>R</given-names></name><name><surname>Fadel</surname><given-names>H</given-names></name><etal></etal></person-group><article-title>Do not trust the pedigree: reduced and sex-dependent penetrance at a novel mutation hotspot in ATL1 blurs autosomal dominant inheritance of spastic paraplegia</article-title><source>Hum Mutat</source><year>2013</year><volume>34</volume><fpage>860</fpage><lpage>863</lpage><pub-id pub-id-type="pmid">23483706</pub-id></element-citation></ref><ref id="CR243"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Vazza</surname><given-names>G</given-names></name><name><surname>Zortea</surname><given-names>M</given-names></name><name><surname>Boaretto</surname><given-names>F</given-names></name><etal></etal></person-group><article-title>A new locus for autosomal recessive spastic paraplegia associated with mental retardation and distal motor neuropathy, SPG14, maps to chromosome 3q27-q28</article-title><source>Am J Hum Genet</source><year>2000</year><volume>67</volume><fpage>504</fpage><lpage>509</lpage><pub-id pub-id-type="pmid">10877981</pub-id></element-citation></ref><ref id="CR244"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Verkerk</surname><given-names>AJMH</given-names></name><name><surname>Schot</surname><given-names>R</given-names></name><name><surname>Dumee</surname><given-names>B</given-names></name><etal></etal></person-group><article-title>Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy</article-title><source>Am J Hum Genet</source><year>2009</year><volume>85</volume><fpage>40</fpage><lpage>52</lpage><pub-id pub-id-type="pmid">19559397</pub-id></element-citation></ref><ref id="CR245"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Verny</surname><given-names>C</given-names></name><name><surname>Guegen</surname><given-names>N</given-names></name><name><surname>Desquiret</surname><given-names>V</given-names></name><etal></etal></person-group><article-title>Hereditary spastic paraplegia-like disorder due to a mitochondrial ATP6 gene point mutation</article-title><source>Mitochondrion</source><year>2011</year><volume>11</volume><fpage>70</fpage><lpage>75</lpage><pub-id pub-id-type="pmid">20656066</pub-id></element-citation></ref><ref id="CR146"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Votsi</surname><given-names>C</given-names></name><name><surname>Zamba-Papanicolaou</surname><given-names>E</given-names></name><name><surname>Middleton</surname><given-names>LT</given-names></name><etal></etal></person-group><article-title>A novel GBA2 gene missense mutation in spastic ataxia</article-title><source>Ann Hum Genet</source><year>2014</year><volume>78</volume><fpage>13</fpage><lpage>22</lpage><pub-id pub-id-type="pmid">24252062</pub-id></element-citation></ref><ref id="CR147"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wakil</surname><given-names>SM</given-names></name><name><surname>Bohlega</surname><given-names>S</given-names></name><name><surname>Hagos</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>A novel splice site mutation in ERLIN2 causes hereditary spastic paraplegia in a Saudi family</article-title><source>Eur J Med Genet</source><year>2013</year><volume>56</volume><fpage>43</fpage><lpage>45</lpage><pub-id pub-id-type="pmid">23085305</pub-id></element-citation></ref><ref id="CR148"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wan</surname><given-names>J</given-names></name><name><surname>Yourshaw</surname><given-names>M</given-names></name><name><surname>Mamsa</surname><given-names>H</given-names></name><etal></etal></person-group><article-title>Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration</article-title><source>Nat Genet</source><year>2012</year><volume>44</volume><fpage>704</fpage><lpage>708</lpage><pub-id pub-id-type="pmid">22544365</pub-id></element-citation></ref><ref id="CR149"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>X</given-names></name><name><surname>Shaw</surname><given-names>WR</given-names></name><name><surname>Tsang</surname><given-names>HTH</given-names></name><etal></etal></person-group><article-title>Drosophila spichthyin inhibits BMP signaling and regulates synaptic growth and axonal microtubules</article-title><source>Nat Neurosci</source><year>2007</year><volume>10</volume><fpage>177</fpage><lpage>185</lpage><pub-id pub-id-type="pmid">17220882</pub-id></element-citation></ref><ref id="CR246"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>X</given-names></name><name><surname>Yang</surname><given-names>Y</given-names></name><name><surname>Wang</surname><given-names>X</given-names></name><name><surname>Li</surname><given-names>C</given-names></name><name><surname>Jia</surname><given-names>J</given-names></name></person-group><article-title>A novel KIAA0196 (SPG8) mutation in a Chinese family with spastic paraplegia</article-title><source>Chin Med J (Engl)</source><year>2014</year><volume>127</volume><issue>10</issue><fpage>1987</fpage><lpage>1989</lpage><pub-id pub-id-type="pmid">24824269</pub-id></element-citation></ref><ref id="CR247"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Watts</surname><given-names>GDJ</given-names></name><name><surname>Wymer</surname><given-names>J</given-names></name><name><surname>Kovach</surname><given-names>MJ</given-names></name><etal></etal></person-group><article-title>Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein</article-title><source>Nat Genet</source><year>2004</year><volume>36</volume><fpage>377</fpage><lpage>381</lpage><pub-id pub-id-type="pmid">15034582</pub-id></element-citation></ref><ref id="CR150"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wedding</surname><given-names>IM</given-names></name><name><surname>Koht</surname><given-names>J</given-names></name><name><surname>Tran</surname><given-names>GT</given-names></name><etal></etal></person-group><article-title>Spastic paraplegia type 7 is associated with multiple mitochondrial DNA deletions</article-title><source>PLoS One</source><year>2014</year><volume>9</volume><fpage>e86340</fpage><pub-id pub-id-type="pmid">24466038</pub-id></element-citation></ref><ref id="CR151"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Werner</surname><given-names>HB</given-names></name><name><surname>Krämer-Albers</surname><given-names>E-M</given-names></name><name><surname>Strenzke</surname><given-names>N</given-names></name><etal></etal></person-group><article-title>A critical role for the cholesterol-associated proteolipids PLP and M6B in myelination of the central nervous system</article-title><source>Glia</source><year>2013</year><volume>61</volume><fpage>567</fpage><lpage>586</lpage><pub-id pub-id-type="pmid">23322581</pub-id></element-citation></ref><ref id="CR152"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Windpassinger</surname><given-names>C</given-names></name><name><surname>Auer-Grumbach</surname><given-names>M</given-names></name><name><surname>Irobi</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome</article-title><source>Nat Genet</source><year>2004</year><volume>36</volume><fpage>271</fpage><lpage>276</lpage><pub-id pub-id-type="pmid">14981520</pub-id></element-citation></ref><ref id="CR153"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yao</surname><given-names>D</given-names></name><name><surname>McGonigal</surname><given-names>R</given-names></name><name><surname>Barrie</surname><given-names>JA</given-names></name><etal></etal></person-group><article-title>Neuronal expression of GalNAc transferase is sufficient to prevent the age-related neurodegenerative phenotype of complex ganglioside-deficient mice</article-title><source>J Neurosci</source><year>2014</year><volume>34</volume><fpage>880</fpage><lpage>891</lpage><pub-id pub-id-type="pmid">24431446</pub-id></element-citation></ref><ref id="CR154"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yıldırım</surname><given-names>Y</given-names></name><name><surname>Orhan</surname><given-names>EK</given-names></name><name><surname>Iseri</surname><given-names>SAU</given-names></name><etal></etal></person-group><article-title>A frameshift mutation of ERLIN2 in recessive intellectual disability, motor dysfunction and multiple joint contractures</article-title><source>Hum Mol Genet</source><year>2011</year><volume>20</volume><fpage>1886</fpage><lpage>1892</lpage><pub-id pub-id-type="pmid">21330303</pub-id></element-citation></ref><ref id="CR155"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zanni</surname><given-names>G</given-names></name><name><surname>Scotton</surname><given-names>C</given-names></name><name><surname>Passarelli</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>Exome sequencing in a family with intellectual disability, early onset spasticity, and cerebellar atrophy detects a novel mutation in EXOSC3</article-title><source>Neurogenetics</source><year>2013</year><volume>14</volume><fpage>247</fpage><lpage>250</lpage><pub-id pub-id-type="pmid">23975261</pub-id></element-citation></ref><ref id="CR249"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhao</surname><given-names>X</given-names></name><name><surname>Alvarado</surname><given-names>D</given-names></name><name><surname>Rainier</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia</article-title><source>Nat Genet</source><year>2001</year><volume>29</volume><fpage>326</fpage><lpage>331</lpage><pub-id pub-id-type="pmid">11685207</pub-id></element-citation></ref><ref id="CR248"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhao</surname><given-names>G</given-names></name><name><surname>Hu</surname><given-names>Z</given-names></name><name><surname>Shen</surname><given-names>L</given-names></name><etal></etal></person-group><article-title>A novel candidate locus on chromosome 11p14.1-p11.2 for autosomal dominant hereditary spastic paraplegia</article-title><source>Chin Med J (Engl)</source><year>2008</year><volume>121</volume><fpage>430</fpage><lpage>434</lpage><pub-id pub-id-type="pmid">18364116</pub-id></element-citation></ref><ref id="CR156"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhu</surname><given-names>P-P</given-names></name><name><surname>Denton</surname><given-names>KR</given-names></name><name><surname>Pierson</surname><given-names>TM</given-names></name><etal></etal></person-group><article-title>Pharmacologic rescue of axon growth defects in a human iPSC model of hereditary spastic paraplegia SPG3A</article-title><source>Hum Mol Genet</source><year>2014</year><volume>23</volume><fpage>5638</fpage><lpage>5648</lpage><pub-id pub-id-type="pmid">24908668</pub-id></element-citation></ref><ref id="CR250"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zivony-Elboum</surname><given-names>Y</given-names></name><name><surname>Westbroek</surname><given-names>W</given-names></name><name><surname>Kfir</surname><given-names>N</given-names></name><etal></etal></person-group><article-title>A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis</article-title><source>J Med Genet</source><year>2012</year><volume>49</volume><fpage>462</fpage><lpage>472</lpage><pub-id pub-id-type="pmid">22717650</pub-id></element-citation></ref><ref id="CR157"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zöller</surname><given-names>I</given-names></name><name><surname>Meixner</surname><given-names>M</given-names></name><name><surname>Hartmann</surname><given-names>D</given-names></name><etal></etal></person-group><article-title>Absence of 2-hydroxylated sphingolipids is compatible with normal neural development but causes late-onset axon and myelin sheath degeneration</article-title><source>J Neurosci</source><year>2008</year><volume>28</volume><fpage>9741</fpage><lpage>9754</lpage><pub-id pub-id-type="pmid">18815260</pub-id></element-citation></ref><ref id="CR251"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zortea</surname><given-names>M</given-names></name><name><surname>Vettori</surname><given-names>A</given-names></name><name><surname>Trevisan</surname><given-names>CP</given-names></name><etal></etal></person-group><article-title>Genetic mapping of a susceptibility locus for disc herniation and spastic paraplegia on 6q23.3-q24.1</article-title><source>J Med Genet</source><year>2002</year><volume>39</volume><fpage>387</fpage><lpage>390</lpage><pub-id pub-id-type="pmid">12070243</pub-id></element-citation></ref><ref id="CR158"><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Züchner</surname><given-names>S</given-names></name><name><surname>Wang</surname><given-names>G</given-names></name><name><surname>Tran-Viet</surname><given-names>K-N</given-names></name><etal></etal></person-group><article-title>Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31</article-title><source>Am J Hum Genet</source><year>2006</year><volume>79</volume><fpage>365</fpage><lpage>369</lpage><pub-id pub-id-type="pmid">16826527</pub-id></element-citation></ref></ref-list></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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