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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en"><italic>CNTNAP1</italic> mutations cause CNS hypomyelination and neuropathy with or without arthrogryposis</title><author><name sortKey="Hengel, Holger" sort="Hengel, Holger" uniqKey="Hengel H" first="Holger" last="Hengel">Holger Hengel</name></author><author><name sortKey="Magee, Alex" sort="Magee, Alex" uniqKey="Magee A" first="Alex" last="Magee">Alex Magee</name></author><author><name sortKey="Mahanjah, Muhammad" sort="Mahanjah, Muhammad" uniqKey="Mahanjah M" first="Muhammad" last="Mahanjah">Muhammad Mahanjah</name></author><author><name sortKey="Vallat, Jean Michel" sort="Vallat, Jean Michel" uniqKey="Vallat J" first="Jean-Michel" last="Vallat">Jean-Michel Vallat</name></author><author><name sortKey="Ouvrier, Robert" sort="Ouvrier, Robert" uniqKey="Ouvrier R" first="Robert" last="Ouvrier">Robert Ouvrier</name></author><author><name sortKey="Abu Rashid, Mohammad" sort="Abu Rashid, Mohammad" uniqKey="Abu Rashid M" first="Mohammad" last="Abu-Rashid">Mohammad Abu-Rashid</name></author><author><name sortKey="Mahamid, Jamal" sort="Mahamid, Jamal" uniqKey="Mahamid J" first="Jamal" last="Mahamid">Jamal Mahamid</name></author><author><name sortKey="Schule, Rebecca" sort="Schule, Rebecca" uniqKey="Schule R" first="Rebecca" last="Schüle">Rebecca Schüle</name></author><author><name sortKey="Schulze, Martin" sort="Schulze, Martin" uniqKey="Schulze M" first="Martin" last="Schulze">Martin Schulze</name></author><author><name sortKey="Kr Geloh Mann, Ingeborg" sort="Kr Geloh Mann, Ingeborg" uniqKey="Kr Geloh Mann I" first="Ingeborg" last="Kr Geloh-Mann">Ingeborg Kr Geloh-Mann</name></author><author><name sortKey="Bauer, Peter" sort="Bauer, Peter" uniqKey="Bauer P" first="Peter" last="Bauer">Peter Bauer</name></author><author><name sortKey="Zuchner, Stephan" sort="Zuchner, Stephan" uniqKey="Zuchner S" first="Stephan" last="Züchner">Stephan Züchner</name></author><author><name sortKey="Sharkia, Rajech" sort="Sharkia, Rajech" uniqKey="Sharkia R" first="Rajech" last="Sharkia">Rajech Sharkia</name></author><author><name sortKey="Schols, Ludger" sort="Schols, Ludger" uniqKey="Schols L" first="Ludger" last="Schöls">Ludger Schöls</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28374019</idno><idno type="pmc">5363873</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363873</idno><idno type="RBID">PMC:5363873</idno><idno type="doi">10.1212/NXG.0000000000000144</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">002796</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002796</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"><italic>CNTNAP1</italic> mutations cause CNS hypomyelination and neuropathy with or without arthrogryposis</title><author><name sortKey="Hengel, Holger" sort="Hengel, Holger" uniqKey="Hengel H" first="Holger" last="Hengel">Holger Hengel</name></author><author><name sortKey="Magee, Alex" sort="Magee, Alex" uniqKey="Magee A" first="Alex" last="Magee">Alex Magee</name></author><author><name sortKey="Mahanjah, Muhammad" sort="Mahanjah, Muhammad" uniqKey="Mahanjah M" first="Muhammad" last="Mahanjah">Muhammad Mahanjah</name></author><author><name sortKey="Vallat, Jean Michel" sort="Vallat, Jean Michel" uniqKey="Vallat J" first="Jean-Michel" last="Vallat">Jean-Michel Vallat</name></author><author><name sortKey="Ouvrier, Robert" sort="Ouvrier, Robert" uniqKey="Ouvrier R" first="Robert" last="Ouvrier">Robert Ouvrier</name></author><author><name sortKey="Abu Rashid, Mohammad" sort="Abu Rashid, Mohammad" uniqKey="Abu Rashid M" first="Mohammad" last="Abu-Rashid">Mohammad Abu-Rashid</name></author><author><name sortKey="Mahamid, Jamal" sort="Mahamid, Jamal" uniqKey="Mahamid J" first="Jamal" last="Mahamid">Jamal Mahamid</name></author><author><name sortKey="Schule, Rebecca" sort="Schule, Rebecca" uniqKey="Schule R" first="Rebecca" last="Schüle">Rebecca Schüle</name></author><author><name sortKey="Schulze, Martin" sort="Schulze, Martin" uniqKey="Schulze M" first="Martin" last="Schulze">Martin Schulze</name></author><author><name sortKey="Kr Geloh Mann, Ingeborg" sort="Kr Geloh Mann, Ingeborg" uniqKey="Kr Geloh Mann I" first="Ingeborg" last="Kr Geloh-Mann">Ingeborg Kr Geloh-Mann</name></author><author><name sortKey="Bauer, Peter" sort="Bauer, Peter" uniqKey="Bauer P" first="Peter" last="Bauer">Peter Bauer</name></author><author><name sortKey="Zuchner, Stephan" sort="Zuchner, Stephan" uniqKey="Zuchner S" first="Stephan" last="Züchner">Stephan Züchner</name></author><author><name sortKey="Sharkia, Rajech" sort="Sharkia, Rajech" uniqKey="Sharkia R" first="Rajech" last="Sharkia">Rajech Sharkia</name></author><author><name sortKey="Schols, Ludger" sort="Schols, Ludger" uniqKey="Schols L" first="Ludger" last="Schöls">Ludger Schöls</name></author></analytic><series><title level="j">Neurology: Genetics</title><idno type="eISSN">2376-7839</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Objective:</title><p>To explore the phenotypic spectrum and pathophysiology of human disease deriving from mutations in the <italic>CNTNAP1</italic> gene.</p></sec><sec><title>Methods:</title><p>In a field study on consanguineous Palestinian families, we identified 3 patients carrying homozygous mutations in the <italic>CNTNAP1</italic> gene using whole-exome sequencing. An unrelated Irish family was detected by screening the GENESIS database for further <italic>CNTNAP1</italic> mutations. Neurophysiology, MRI, and nerve biopsy including electron microscopy were performed for deep phenotyping.</p></sec><sec><title>Results:</title><p>We identified 3 novel <italic>CNTNAP1</italic> mutations in 5 patients from 2 families: c.2015G>A:p.(Trp672*) in a homozygous state in family 1 and c.2011C>T:p.(Gln671*) in a compound heterozygous state with c.2290C>T:p.(Arg764Cys) in family 2. Affected patients suffered from a severe CNS disorder with hypomyelinating leukodystrophy and peripheral neuropathy of sensory-motor type. Arthrogryposis was present in 2 patients but absent in 3 patients. Brain MRI demonstrated severe hypomyelination and secondary cerebral and cerebellar atrophy as well as a mega cisterna magna and corpus callosum hypoplasia. Nerve biopsy revealed very distinct features with lack of transverse bands at the paranodes and widened paranodal junctional gaps.</p></sec><sec><title>Conclusions:</title><p><italic>CNTNAP1</italic> mutations have recently been linked to patients with arthrogryposis multiplex congenita. However, we show that arthrogryposis is not an obligate feature. <italic>CNTNAP1</italic>-related disorders are foremost severe hypomyelinating disorders of the CNS and the peripheral nervous system. The pathology is partly explained by the involvement of CNTNAP1 in the proper formation and preservation of paranodal junctions and partly by the assumed role of CNTNAP1 as a key regulator in the development of the cerebral cortex.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Laquerriere, A" uniqKey="Laquerriere A">A Laquerriere</name></author><author><name sortKey="Maluenda, J" uniqKey="Maluenda J">J Maluenda</name></author><author><name sortKey="Camus, A" uniqKey="Camus A">A Camus</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bamshad, M" uniqKey="Bamshad M">M Bamshad</name></author><author><name sortKey="Van Heest, Ae" uniqKey="Van Heest A">AE Van Heest</name></author><author><name sortKey="Pleasure, D" uniqKey="Pleasure D">D Pleasure</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gordon, A" uniqKey="Gordon A">A Gordon</name></author><author><name sortKey="Adamsky, K" uniqKey="Adamsky K">K Adamsky</name></author><author><name sortKey="Vainshtein, A" uniqKey="Vainshtein A">A Vainshtein</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Buttermore, Ed" uniqKey="Buttermore E">ED Buttermore</name></author><author><name sortKey="Thaxton, Cl" uniqKey="Thaxton C">CL Thaxton</name></author><author><name sortKey="Bhat, Ma" uniqKey="Bhat M">MA Bhat</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bhat, Ma" uniqKey="Bhat M">MA Bhat</name></author><author><name sortKey="Rios, Jc" uniqKey="Rios J">JC Rios</name></author><author><name sortKey="Lu, Y" uniqKey="Lu Y">Y Lu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sun, Xy" uniqKey="Sun X">XY Sun</name></author><author><name sortKey="Takagishi, Y" uniqKey="Takagishi Y">Y Takagishi</name></author><author><name sortKey="Okabe, E" uniqKey="Okabe E">E Okabe</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gonzalez, M" uniqKey="Gonzalez M">M Gonzalez</name></author><author><name sortKey="Falk, Mj" uniqKey="Falk M">MJ Falk</name></author><author><name sortKey="Gai, X" uniqKey="Gai X">X Gai</name></author><author><name sortKey="Postrel, R" uniqKey="Postrel R">R Postrel</name></author><author><name sortKey="Schule, R" uniqKey="Schule R">R Schule</name></author><author><name sortKey="Zuchner, S" uniqKey="Zuchner S">S Zuchner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, H" uniqKey="Li H">H Li</name></author><author><name sortKey="Durbin, R" uniqKey="Durbin R">R Durbin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vallat, Jm" uniqKey="Vallat J">JM Vallat</name></author><author><name sortKey="Vital, A" uniqKey="Vital A">A Vital</name></author><author><name sortKey="Magy, L" uniqKey="Magy L">L Magy</name></author><author><name sortKey="Martin Negrier, Ml" uniqKey="Martin Negrier M">ML Martin-Negrier</name></author><author><name sortKey="Vital, C" uniqKey="Vital C">C Vital</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kumar, P" uniqKey="Kumar P">P Kumar</name></author><author><name sortKey="Henikoff, S" uniqKey="Henikoff S">S Henikoff</name></author><author><name sortKey="Ng, Pc" uniqKey="Ng P">PC Ng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schwarz, Jm" uniqKey="Schwarz J">JM Schwarz</name></author><author><name sortKey="Cooper, Dn" uniqKey="Cooper D">DN Cooper</name></author><author><name sortKey="Schuelke, M" uniqKey="Schuelke M">M Schuelke</name></author><author><name sortKey="Seelow, D" uniqKey="Seelow D">D Seelow</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Adzhubei, Ia" uniqKey="Adzhubei I">IA Adzhubei</name></author><author><name sortKey="Schmidt, S" uniqKey="Schmidt S">S Schmidt</name></author><author><name sortKey="Peshkin, L" uniqKey="Peshkin L">L Peshkin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Andres, Kh" uniqKey="Andres K">KH Andres</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Boyle, Me" uniqKey="Boyle M">ME Boyle</name></author><author><name sortKey="Berglund, Eo" uniqKey="Berglund E">EO Berglund</name></author><author><name sortKey="Murai, Kk" uniqKey="Murai K">KK Murai</name></author><author><name sortKey="Weber, L" uniqKey="Weber L">L Weber</name></author><author><name sortKey="Peles, E" uniqKey="Peles E">E Peles</name></author><author><name sortKey="Ranscht, B" uniqKey="Ranscht B">B Ranscht</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sherman, Dl" uniqKey="Sherman D">DL Sherman</name></author><author><name sortKey="Tait, S" uniqKey="Tait S">S Tait</name></author><author><name sortKey="Melrose, S" uniqKey="Melrose S">S Melrose</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pouwels, Pj" uniqKey="Pouwels P">PJ Pouwels</name></author><author><name sortKey="Vanderver, A" uniqKey="Vanderver A">A Vanderver</name></author><author><name sortKey="Bernard, G" uniqKey="Bernard G">G Bernard</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wu, Zq" uniqKey="Wu Z">ZQ Wu</name></author><author><name sortKey="Li, D" uniqKey="Li D">D Li</name></author><author><name sortKey="Huang, Y" uniqKey="Huang Y">Y Huang</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Neurol Genet</journal-id><journal-id journal-id-type="iso-abbrev">Neurol Genet</journal-id><journal-id journal-id-type="hwp">nng</journal-id><journal-id journal-id-type="publisher-id">NNG</journal-id><journal-title-group><journal-title>Neurology: Genetics</journal-title></journal-title-group><issn pub-type="epub">2376-7839</issn><publisher><publisher-name>Wolters Kluwer</publisher-name><publisher-loc>Baltimore</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28374019</article-id><article-id pub-id-type="pmc">5363873</article-id><article-id pub-id-type="publisher-id">NG2016003939</article-id><article-id pub-id-type="doi">10.1212/NXG.0000000000000144</article-id><article-categories><subj-group subj-group-type="hwp-journal-coll"><subject>91</subject><subject>155</subject><subject>181</subject><subject>228</subject></subj-group><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title><italic>CNTNAP1</italic> mutations cause CNS hypomyelination and neuropathy with or without arthrogryposis</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Hengel</surname><given-names>Holger</given-names></name><degrees>MD</degrees><xref ref-type="author-notes" rid="fn1">*</xref><author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Gifts:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Editorial Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Patents:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Publishing Royalties:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Employment, Commercial Entity:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Consultancies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Speakers' Bureaus:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Other Activities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Commercial Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Government Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Academic Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Foundations and Societies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Legal Proceedings:</title><list-item><p>NONE</p></list-item></list></p></author-comment></contrib><contrib contrib-type="author"><name><surname>Magee</surname><given-names>Alex</given-names></name><degrees>MD</degrees><xref ref-type="author-notes" rid="fn1">*</xref><author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Gifts:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Editorial Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Patents:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Publishing Royalties:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Employment, Commercial Entity:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Consultancies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Speakers' Bureaus:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Other Activities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Commercial Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Government Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Academic Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Foundations and Societies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Legal Proceedings:</title><list-item><p>NONE</p></list-item></list></p></author-comment></contrib><contrib contrib-type="author"><name><surname>Mahanjah</surname><given-names>Muhammad</given-names></name><degrees>MD</degrees><xref ref-type="author-notes" rid="fn1">*</xref><author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Gifts:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Editorial Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Patents:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Publishing Royalties:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Employment, Commercial Entity:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Consultancies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Speakers' Bureaus:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Other Activities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Commercial Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Government Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Academic Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Foundations and Societies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Legal Proceedings:</title><list-item><p>NONE</p></list-item></list></p></author-comment></contrib><contrib contrib-type="author"><name><surname>Vallat</surname><given-names>Jean-Michel</given-names></name><degrees>MD</degrees><author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Gifts:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Editorial Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Patents:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Publishing Royalties:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Employment, Commercial Entity:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Consultancies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Speakers' Bureaus:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Other Activities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Commercial Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Government Entities:</title><list-item><p>French Minister of Health as a reference center for rare peripheral neuropathies : 2006 to 2011</p></list-item></list></p><p><list list-type="order"><title>Research Support, Academic Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Foundations and Societies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Legal Proceedings:</title><list-item><p>NONE</p></list-item></list></p></author-comment></contrib><contrib contrib-type="author"><name><surname>Ouvrier</surname><given-names>Robert</given-names></name><degrees>MD</degrees><author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title><list-item><p>I am on the scientific Advisory Board of the Nerve Foundation of the University of Sydney and of the Institute for Neuromuscular Research at The Children's Hospital at Westmead, Sydney. Both are non-profit bodies from which I receive no recompense.</p></list-item></list></p><p><list list-type="order"><title>Gifts:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Editorial Boards:</title><list-item><p>(1) Editorial advisory board member: Brain and Development for approximately twenty years</p></list-item></list></p><p><list list-type="order"><title>Patents:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Publishing Royalties:</title><list-item><p>I receive royalties of less than US$100 annually from MacKeith Press, London UK for a book entitled</p></list-item></list></p><p><list list-type="order"><title>Employment, Commercial Entity:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Consultancies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Speakers' Bureaus:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Other Activities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Commercial Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Government Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Academic Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Foundations and Societies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Legal Proceedings:</title><list-item><p>NONE</p></list-item></list></p></author-comment></contrib><contrib contrib-type="author"><name><surname>Abu-Rashid</surname><given-names>Mohammad</given-names></name><degrees>MD</degrees><author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Gifts:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Editorial Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Patents:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Publishing Royalties:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Employment, Commercial Entity:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Consultancies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Speakers' Bureaus:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Other Activities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Commercial Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Government Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Academic Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Foundations and Societies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Legal Proceedings:</title><list-item><p>NONE</p></list-item></list></p></author-comment></contrib><contrib contrib-type="author"><name><surname>Mahamid</surname><given-names>Jamal</given-names></name><degrees>MD</degrees><author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Gifts:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Editorial Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Patents:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Publishing Royalties:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Employment, Commercial Entity:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Consultancies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Speakers' Bureaus:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Other Activities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Commercial Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Government Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Academic Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Foundations and Societies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Legal Proceedings:</title><list-item><p>NONE</p></list-item></list></p></author-comment></contrib><contrib contrib-type="author"><name><surname>Schüle</surname><given-names>Rebecca</given-names></name><degrees>MD</degrees><author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title><list-item><p>(2) Scientific advisory board for Viagenetics</p></list-item></list></p><p><list list-type="order"><title>Gifts:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Editorial Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Patents:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Publishing Royalties:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Employment, Commercial Entity:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Consultancies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Speakers' Bureaus:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Other Activities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Commercial Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Government Entities:</title><list-item><p>European Union, PIOF-GA-2012-326681European Union, 01GM1408BNIH, 2R01NS072248-06A1</p></list-item></list></p><p><list list-type="order"><title>Research Support, Academic Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Foundations and Societies:</title><list-item><p>HSP Selbsthilfegruppe e.V.Spastic Paraplegia FoundationEva Luise und Horst K?hler Stiftung</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Legal Proceedings:</title><list-item><p>NONE</p></list-item></list></p></author-comment></contrib><contrib contrib-type="author"><name><surname>Schulze</surname><given-names>Martin</given-names></name><degrees>PhD</degrees><author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Gifts:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Editorial Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Patents:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Publishing Royalties:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Employment, Commercial Entity:</title><list-item><p>(1)Praxis f?r Humangenetik T?bingen, scientist indiagnostic service, 0.5 years(2) CeGaT T?bingen, scientist in diagnostic service, 0.5 years</p></list-item></list></p><p><list list-type="order"><title>Consultancies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Speakers' Bureaus:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Other Activities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Commercial Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Government Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Academic Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Foundations and Societies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Legal Proceedings:</title><list-item><p>NONE</p></list-item></list></p></author-comment></contrib><contrib contrib-type="author"><name><surname>Krägeloh-Mann</surname><given-names>Ingeborg</given-names></name><degrees>MD</degrees><author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title><list-item><p>intrathecal enzyme replacement in metachromaticleukodystrophy - phase I/II study startingShire 2012</p></list-item></list></p><p><list list-type="order"><title>Gifts:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Editorial Boards:</title><list-item><p>Developmental medicine and child neurology since 2006Neuropediatrics since 2000European Journal of Paediatric Neurology since 2009</p></list-item></list></p><p><list list-type="order"><title>Patents:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Publishing Royalties:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Employment, Commercial Entity:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Consultancies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Speakers' Bureaus:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Other Activities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Commercial Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Government Entities:</title><list-item><p>German Research CouncilDFGSFB 833 B05KSyntax and Semantics of Reorganized Languageand its Neuronal Architecture7/2010-6/2013SCPE-Net DGXII-BIOMED2BMH4-983701-QLG5-CT-2001.30133Surveillance in CerebralPalsy in Europe4/2002-12/2011Leukonet 01 GM030901 GM0644Childhood leukodystrophies with known geneticdefect11/2003-12/2011Leukonet01 GM0835Netzwerk Leukodystrophien12/2008-12/2012Leukotreat FP7-HEALTH-F2 2010-241622</p></list-item></list></p><p><list list-type="order"><title>Research Support, Academic Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Foundations and Societies:</title><list-item><p>Brains for BrainDeveloping treatment options for Metachromatic Leukodystrophy2010-2012</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Legal Proceedings:</title><list-item><p>NONE</p></list-item></list></p></author-comment></contrib><contrib contrib-type="author"><name><surname>Bauer</surname><given-names>Peter</given-names></name><degrees>MD</degrees><author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title><list-item><p>(1) Scientific advisory board for ZOOM study, ActelionPharmaceuticals, Allschwil, CH</p></list-item></list></p><p><list list-type="order"><title>Gifts:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title><list-item><p>(1) Speaker honoraria from Actelion Pharmaceuticals,Allschwil, CH</p></list-item></list></p><p><list list-type="order"><title>Editorial Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Patents:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Publishing Royalties:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Employment, Commercial Entity:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Consultancies:</title><list-item><p>(1) Consultant for Actelion Pharmaceuticals, Allschwil, CH(2) Consultant for CENTOGENE AG, Rostock, GER</p></list-item></list></p><p><list list-type="order"><title>Speakers' Bureaus:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Other Activities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Commercial Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Government Entities:</title><list-item><p>(1) German Research Council (BMBF) to GeNeMove (01GM0603),EUROSPA (01GM0807) and RISCA (09GM0820)(2) EU for EUROSCA (LSHM-CT-2004-503304), MarkMD(FP7-People PIAP-2008-230596) and TECHGENE (FP7-Health2007-B 223143).</p></list-item></list></p><p><list list-type="order"><title>Research Support, Academic Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Foundations and Societies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title><list-item><p>(1) Centogene AG, Rostock, Germany</p></list-item></list></p><p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title><list-item><p>(1) Improved DNase treatment protocol, Roche, Mannheim, GER</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Legal Proceedings:</title><list-item><p>NONE</p></list-item></list></p></author-comment></contrib><contrib contrib-type="author"><name><surname>Züchner</surname><given-names>Stephan</given-names></name><degrees>MD</degrees><author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Gifts:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Editorial Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Patents:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Publishing Royalties:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Employment, Commercial Entity:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Consultancies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Speakers' Bureaus:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Other Activities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Commercial Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Government Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Academic Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Foundations and Societies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Legal Proceedings:</title><list-item><p>NONE</p></list-item></list></p></author-comment></contrib><contrib contrib-type="author"><name><surname>Sharkia</surname><given-names>Rajech</given-names></name><degrees>PhD</degrees><author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Gifts:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Editorial Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Patents:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Publishing Royalties:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Employment, Commercial Entity:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Consultancies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Speakers' Bureaus:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Other Activities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Commercial Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Government Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Academic Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Foundations and Societies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Legal Proceedings:</title><list-item><p>NONE</p></list-item></list></p></author-comment></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Schöls</surname><given-names>Ludger</given-names></name><degrees>MD</degrees><author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Gifts:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title><list-item><p>(1) Speaker honorar from Actelion</p></list-item></list></p><p><list list-type="order"><title>Editorial Boards:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Patents:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Publishing Royalties:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Employment, Commercial Entity:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Consultancies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Speakers' Bureaus:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Other Activities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Commercial Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Government Entities:</title><list-item><p>I received the following grants:PI: Genetic disorders in Arab Societies (grantSCHO754/5-2), DFG: 2014-2017PI: NEUROMICS (F5-2012-305121) EU: 2012-2017</p></list-item></list></p><p><list list-type="order"><title>Research Support, Academic Entities:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Research Support, Foundations and Societies:</title><list-item><p>I received additional funding from theHSP-Selbsthilfegruppe Deutschland eV and the F?rdervereinfuer HSP-Forschung</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title><list-item><p>NONE</p></list-item></list></p><p><list list-type="order"><title>Legal Proceedings:</title><list-item><p>NONE</p></list-item></list></p></author-comment></contrib><aff>From the Department of Neurology and Hertie-Institute for Clinical Brain Research (H.H., R. Schüle, L.S.), University of Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE) (H.H., R.S., L.S.), Tübingen, Germany; Northern Ireland Regional Genetics Service (A.M.), Belfast City Hospital, Belfast; Department of Neurology (J.-M.V.), National Reference Center for Rare Peripheral Neuropathies, University Hospital, Limoges, France; Institute for Neuroscience and Muscle Research (R.O.), The Children's Hospital at Westmead, Sydney, New South Wales, Australia; The Triangle Regional Research and Development Center (R. Sharkia), Kfar Qari' Israel; Beit-Berl Academic College (R. Sharkia), Israel; Child Neurology and Development Center (M.M.), Hillel-Yaffe Medical Center, Hadera, Israel; Rappaport Faculty of Medicine (M.M.), Technion, Haifa, Israel; Institute of Medical Genetics and Applied Genomics (M.S.), University of Tübingen, Germany; Department of Pediatric Neurology (I.K.-M.), University Medical Center Tübingen, Germany; Hussman Institute for Human Genomics (S.Z.), University of Miami Miller School of Medicine, FL; Clalit Health Services (M.A.-R.), Haifa, Israel; and Meuhedet Health Services (J.M.), North District, Israel.</aff></contrib-group><author-notes><corresp id="cor1">Correspondence to Dr. Schöls: <email>Ludger.Schoels@uni-tuebingen.de</email></corresp><fn fn-type="other" id="fn1"><label>*</label><p>These authors contributed equally to the manuscript.</p></fn><fn fn-type="financial-disclosure"><p>Funding information and disclosures are provided at the end of the article. Go to <ext-link ext-link-type="uri" xlink:href="10.1212/NXG.0000000000000144">Neurology.org/ng</ext-link> for full disclosure forms. The Article Processing Charge was paid by the authors.</p></fn></author-notes><pub-date pub-type="epub"><day>22</day><month>3</month><year>2017</year></pub-date><pub-date pub-type="collection"><month>4</month><year>2017</year></pub-date><pub-date pub-type="pmc-release"><day>22</day><month>3</month><year>2017</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>3</volume><issue>2</issue><elocation-id>e144</elocation-id><history><date date-type="received"><day>19</day><month>10</month><year>2016</year></date><date date-type="accepted"><day>06</day><month>2</month><year>2017</year></date></history><permissions><copyright-statement>Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology</copyright-statement><copyright-year>2017</copyright-year><copyright-holder>American Academy of Neurology</copyright-holder><license license-type="open-access"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0/">Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND)</ext-link>, which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.</license-p></license></permissions><self-uri xlink:title="pdf" xlink:href="NG2016003939.pdf"></self-uri><abstract><sec><title>Objective:</title><p>To explore the phenotypic spectrum and pathophysiology of human disease deriving from mutations in the <italic>CNTNAP1</italic> gene.</p></sec><sec><title>Methods:</title><p>In a field study on consanguineous Palestinian families, we identified 3 patients carrying homozygous mutations in the <italic>CNTNAP1</italic> gene using whole-exome sequencing. An unrelated Irish family was detected by screening the GENESIS database for further <italic>CNTNAP1</italic> mutations. Neurophysiology, MRI, and nerve biopsy including electron microscopy were performed for deep phenotyping.</p></sec><sec><title>Results:</title><p>We identified 3 novel <italic>CNTNAP1</italic> mutations in 5 patients from 2 families: c.2015G>A:p.(Trp672*) in a homozygous state in family 1 and c.2011C>T:p.(Gln671*) in a compound heterozygous state with c.2290C>T:p.(Arg764Cys) in family 2. Affected patients suffered from a severe CNS disorder with hypomyelinating leukodystrophy and peripheral neuropathy of sensory-motor type. Arthrogryposis was present in 2 patients but absent in 3 patients. Brain MRI demonstrated severe hypomyelination and secondary cerebral and cerebellar atrophy as well as a mega cisterna magna and corpus callosum hypoplasia. Nerve biopsy revealed very distinct features with lack of transverse bands at the paranodes and widened paranodal junctional gaps.</p></sec><sec><title>Conclusions:</title><p><italic>CNTNAP1</italic> mutations have recently been linked to patients with arthrogryposis multiplex congenita. However, we show that arthrogryposis is not an obligate feature. <italic>CNTNAP1</italic>-related disorders are foremost severe hypomyelinating disorders of the CNS and the peripheral nervous system. The pathology is partly explained by the involvement of CNTNAP1 in the proper formation and preservation of paranodal junctions and partly by the assumed role of CNTNAP1 as a key regulator in the development of the cerebral cortex.</p></sec></abstract><custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name><meta-value>TRUE</meta-value></custom-meta></custom-meta-group></article-meta></front><body><p>Recently, mutations in <italic>CNTNAP1</italic> have been linked to patients with arthrogryposis multiplex congenita (AMC).<sup><xref rid="R1" ref-type="bibr">1</xref></sup> Four families were described with 3 different homozygous frameshift mutations. All patients suffered from distal joint contractures and died within the first 2 months of life. Etiologically, AMC can be divided into (1) the primary manifestation of an orthopedic disorder or (2) neurologic disorders causing secondary AMC. The second group is the most common cause of severe manifestations and is considered to be a result of fetal hypokinesia due to the underlying neurologic disease.<sup><xref rid="R2" ref-type="bibr">2</xref></sup> Thus, AMC can be caused by different genes impairing skeletal muscles, encoding components of the neuromuscular junction or affecting axoglial development.<sup><xref rid="R1" ref-type="bibr">1</xref>,<xref rid="R2" ref-type="bibr">2</xref></sup></p><p><italic>CNTNAP1</italic> encodes the contactin-associated protein (CASPR), a cell adhesion protein involved in the proper formation of paranodal junctions in myelinated axons.<sup><xref rid="R3" ref-type="bibr">3</xref><xref ref-type="bibr" rid="R4">–</xref><xref rid="R5" ref-type="bibr">5</xref></sup> CASPR knockout mice exhibit generalized motor paresis and cerebellar signs.<sup><xref rid="R5" ref-type="bibr">5</xref></sup> A similar phenotype is present in the shambling mouse, caused by a frameshift mutation in <italic>CNTNAP1</italic>.<sup><xref rid="R6" ref-type="bibr">6</xref></sup> Both mutant mice exhibit abnormal paranodal junctions both in the peripheral nervous system (PNS) and in the CNS.<sup><xref rid="R5" ref-type="bibr">5</xref>,<xref rid="R6" ref-type="bibr">6</xref></sup> Comparable findings with abnormal paranodal junctions and abnormal myelination have been revealed by transmission electron microscopy of the sciatic nerve in <italic>CNTNAP1</italic> patients.<sup><xref rid="R1" ref-type="bibr">1</xref></sup> This suggests that AMC due to <italic>CNTNAP1</italic> mutations is caused by axoglial defects.</p><p>Here, we report 5 patients with <italic>CNTNAP1</italic> mutations expanding the <italic>CNTNAP1</italic>-related phenotypic spectrum to a severe CNS disorder with hypomyelinating leukodystrophy and peripheral neuropathy, with or without arthrogryposis.</p><sec sec-type="methods" id="s1"><title>METHODS</title><sec id="s1-1"><title>Standard protocol approvals, registrations, and patient consents.</title><p>Patients were enrolled in Israel (family 1) and Northern Ireland (family 2). Written informed consent was obtained from the parents for diagnostic procedures and next-generation sequencing as well as for the publication of this case report including the accompanying images. The study was approved by the local ethical review board (vote 180/2010BO1).</p></sec><sec id="s1-2"><title>Exome sequencing and analysis.</title><p>Patients were screened for exonic variants using a whole-exome enrichment approach (SureSelectXT Human All Exon V5; Agilent, Santa Clara CA). Sequencing was performed on a HiSeq2500 (200 cycle chemistry) or NextSeq500 (300 cycle chemistry) platform (Illumina, San Diego, CA) in paired-end mode according to the manufacturers' protocol. FASTQ files were imported into GENESIS (<ext-link ext-link-type="uri" xlink:href="http://thegenesisprojectfoundation.org/">http://thegenesisprojectfoundation.org/</ext-link>)<sup><xref rid="R7" ref-type="bibr">7</xref></sup> for further analysis using a pipeline build on BWA,<sup><xref rid="R8" ref-type="bibr">8</xref></sup> Picard, and FreeBayes. Variants were filtered for changes that segregated in an autosomal recessive fashion and met the “strict” criteria, which requires that variants are rare (NHLBI ESP6500 minor allele frequency <0.1), present in less than 3 families within GENESIS (∼4,300 exomes), conserved (Genomic Evolutionary Rate Profiling [GERP] score >2 or PhastCons score >0.6), and have sufficient quality scores (Genotype Quality >75). Sanger sequencing was performed using standard methods and chemicals. Primer sequences are available on request.</p></sec><sec id="s1-3"><title>Screening for <italic>CNTNAP1</italic> patients using GEM.app/Genesis.</title><p>Previous studies on <italic>CNTNAP1</italic>-associated disease have exclusively focused on cohorts with AMC. To capture the full phenotypic spectrum caused by <italic>CNTNAP1</italic> in an unbiased approach, we screened a total of 2,599 families with various neurologic phenotypes and a family history compatible with autosomal recessive inheritance available in the GEM.app/Genesis database at the time<sup><xref rid="R7" ref-type="bibr">7</xref></sup> for rare homozygous or compound heterozygous <italic>CNTNAP1</italic> mutations. Phenotypes included 492 families with neuromuscular phenotypes, 251 HSP families, 721 ALS families, and 168 families with hereditary ataxia.</p></sec><sec id="s1-4"><title>Electron microscopy.</title><p>As described elsewhere,<sup><xref rid="R9" ref-type="bibr">9</xref></sup> samples of sciatic nerves were fixed for 3 hours in 2.5% glutaraldehyde in Sorensen buffer and osmificated for 1 hour in 1% OsO4. Afterward, they were rinsed in Sorensen buffer, dehydrated in graded acetone, and embedded in Epon. Semithin sections (1 μm) were stained with toluidine blue. Ultrathin sections were stained with uranyl acetate and lead citrate. The sections were observed through a JEOL electron microscope.</p></sec></sec><sec sec-type="results" id="s2"><title>RESULTS</title><sec id="s2-1"><title>Identification of new <italic>CNTNAP1</italic> mutations.</title><p>In a large Israeli consanguineous family of Palestinian ancestry (family 1 branch A + B), we identified 2 children (<xref ref-type="fig" rid="F1">figure 1</xref>) with multiple congenital anomalies affecting the skeleton and brain as indicated by fetal sonography. Polyhydramnios occurred during both pregnancies, and children were born at 34- and 35-week gestation, respectively, with normal birth weight. Both children were diagnosed with AMC at birth, with clenched hands, contractures of the elbows, knees, and feet. They were noted to have microcephaly, hypotonia, absent swallow, facial diplegia, low-set ears, cleft palate, and micrognathia.</p><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label><caption><title>Pedigree of family 1 and mutations in <italic>CNTNAP1</italic></title><p>(A) Pedigree of family 1 branches A–C with multiple consanguineous loops and segregation of the <italic>CNTNAP1</italic> variant. The identified variant (position indicated by red arrow) segregated with the disease in all affected patients. (B) Schematic representation of known and new mutations in <italic>CNTNAP1</italic>: previously described mutations are depicted in black, and new disease-causing mutations are indicated in red. The missense variant p.(Arg764Cys) has been found in a compound heterozygous state together with p.(Gln671*). All other variants were homozygous in affected patients. Blue: extracellular domain; red: helical domain (transmembrane); green: cytoplasmic domain (intracellular) (information of domains from <ext-link ext-link-type="uri" xlink:href="http://www.uniprot.org">uniprot.org</ext-link>).</p></caption><graphic xlink:href="NG2016003939FF1"></graphic></fig><p>Because of profound hypoventilation, both infants required ventilatory support. Both had severe developmental disabilities and never learned to sit, walk, or talk. Later, both developed generalized epilepsy with tonic-clonic seizures.</p><p>On neurologic examination at age 9 and 12 years, severe intellectual disability of both children was noted. They had small unresponsive pupils, were unable to make eye contact, did not follow visual stimuli, and did not react to sound stimuli. Both had pronounced contractures of hands, elbows, knees, and feet and showed increased muscle tone of the extremities while the tone of axial muscles was decreased. Reflexes were increased with positive Babinski sign. Both were microcephalic and showed dysmorphic features, including micrognathia, cleft palate, and large, low-set ears (<xref ref-type="fig" rid="F2">figure 2</xref>). Both received nutrition by gastrostomy and underwent tracheostomy.</p><fig id="F2" orientation="portrait" position="float"><label>Figure 2</label><caption><title>Phenotypic features of <italic>CNTNAP1</italic> patients</title><p>(A–C) Patient 1 with arthrogryposis multiplex congenita (AMC). (A) Contractures of the feet, (B) features including microcephaly, micrognathia, low-set ears, and cachexia, and (C) contractures of the hand and fingers. (D, E) Patient 3 without AMC but with microcephaly, low-set ears, and hypotonia. (F–H) Patient 4 without AMC. (F) No signs of contractures of the fingers, (G) hypotonia, and (H) midline notch upper gum.</p></caption><graphic xlink:href="NG2016003939FF2"></graphic></fig><p>Metabolic screening including amino acids, very long chain fatty acids, lactate and ammonia in serum, and organic acids in urine was normal as were CSF findings. Genetic testing excluded SMN1 mutations. Brain MRI of patient 1, taken at the age of 5 years, showed severe hypomyelinating leukodystrophy. There were no signs of myelination even in parts of the brain normally myelinated early after birth such as the posterior limb of the inner capsule. Reduced cerebral, cerebellar, and pontine volume was obvious with pronounced lack of white matter. Furthermore, a thin corpus callosum and mega cisterna magna were noted (<xref ref-type="fig" rid="F3">figure 3</xref>). To determine the genetic basis, we performed whole-exome sequencing on both patients. Following the hypothesis that both patients suffer from the same genetic disorder, only overlapping variants from both exomes were considered and filtered using the strict criteria mentioned in the methods. This resulted in only 9 rare homozygous variants including only 1 truncating variant: a homozygous stop-gain mutation in exon 13 of <italic>CNTNAP1</italic>: NM_003632.2:c.2015G>A:p.(Trp672*). Sanger sequencing of all family members showed full segregation with the disease (<xref ref-type="fig" rid="F1">figure 1</xref>). The parents were heterozygous for the mutation, and the healthy siblings were either heterozygous or homozygous for the wildtype. The mutation was not found in the ESP6500, 1000 Genomes, or the Exome Aggregation Consortium (ExAC) database.</p><fig id="F3" orientation="portrait" position="float"><label>Figure 3</label><caption><title>MRIs of <italic>CNTNAP1</italic> patients and controls</title><p>(A) T2-weighted image of healthy 8-day-old child. Signs of beginning myelination within the posterior limb of the inner capsule (PLIC; hypointense signal within the white circle). (B) T2-weighted image of healthy 36-month-old child. Myelination is complete, resulting in hypointense signals of white matter, inner capsule, and corpus callosum. (C) T2-weighted image of patient 4 taken at 4 days of age. No signs of myelination in the PLIC (white circle). No signs of obvious cortex malformation. (E) Sagittal T1 image of patient 4 at 4 days of age indicates normal cerebral, cerebellar, and pontine volume. Small mega cisterna magna is depicted by a white arrow. (D, F, G) T2-weighted images of patient 1 at 5 years of age. (D, G) White matter is hyperintense without signs of myelination; even early myelinating structures are hyperintense without myelin deposits (circle). Cerebral atrophy (white arrow) with pronounced lack of white matter (white star). (F) Midsagittal images show thin corpus callosum (white arrow), mega cisterna magna (white arrow), reduced pontine volume, and cerebellar atrophy.</p></caption><graphic xlink:href="NG2016003939FF3"></graphic></fig><p>Further follow-up of the family revealed a 4-week-old child in a distantly related family branch (branch C in <xref ref-type="fig" rid="F1">figure 1A</xref>) who was born at term with a history of polyhydramnios, had similar dysmorphic features with low-set ears, micrognathia, and microcephaly and required controlled ventilation. However, there were no joint contractures or signs of AMC. Genetic testing revealed the identical homozygous <italic>CNTNAP1</italic> mutation c.2015G>A:p.(Trp672*).</p></sec><sec id="s2-2"><title>Screening for <italic>CNTNAP1</italic> mutations reveals further non-AMC cases.</title><p>An unbiased screening approach using the GEM.app/Genesis database led to the identification of a nonconsanguineous Northern Irish family (family 2) with 2 affected brothers (patients 4 and 5, <xref ref-type="table" rid="T1">table</xref>), who shared compound heterozygous mutations in <italic>CNTNAP1</italic>: 1 stop-gain and 1 missense mutation (NM_003632.2:c.2011C>T:p.(Gln671*) and c.2290C>T:p.(Arg764Cys)). The latter changes a highly conserved polar amino acid residue (arginine) to a nonpolar residue (cysteine) (GERP score: 5.84, PhastCons: 1). Different prediction programs (Scale Invariant Feature Transform: 0.03, MutationTaster: 0.999, and PolyPhen: 0.998)<sup><xref rid="R10" ref-type="bibr">10</xref><xref ref-type="bibr" rid="R11">–</xref><xref rid="R12" ref-type="bibr">12</xref></sup> estimate the variant to be pathogenic, and it has never been described in public databases (ExAC, ESP6500, and 1000 Genomes).</p><table-wrap id="T1" orientation="portrait" position="float"><label>Table</label><caption><p>Clinical features of new cases and previously described cases</p></caption><graphic xlink:href="NG2016003939TT1"></graphic></table-wrap><p>Clinical findings were similar as in family 1. Patient 4 was diagnosed with polyhydramnios and reduced fetal movements at 27-week gestation. At birth, he was profoundly hypotonic and required ventilatory support. He was noted to have absent swallow, facial diplegia, complete ptosis, dolichocephaly, epicanthic folds, thickened nares, thickened lips, narrow ridged palate, thickened gums with a notch in the upper midline, micrognathia, and partial bilateral 2–3 toe syndactyly. He was areflexic and preferred to lie in a hyperextended position. Some voluntary limb movements were observed. No arthrogryposis was noted. A full range of passive limb and joint movements was possible. He was able to open his eyes for up to 40 seconds, but this gradually decreased. Tracheostomy was performed at the age of 3 weeks; with this, he was able to breathe unaided. Brainstem evoked responses confirmed bilateral sensorineural hearing loss. At the age of 10 weeks, he developed generalized clonic, brief tonic, and myoclonic seizures. Resting posture was noted to be less hyperextended, elbows and fingers were held flexed, but the range of passive movements remained full. Palliative care was introduced and he died at age 4 months. On brain MRI at the age of 4 days, any signs of beginning myelination were missing (<xref ref-type="fig" rid="F3">figure 3</xref>). There were mega cisterna magna and thin corpus callosum, but clear cerebral hypoplasia or cortical malformations were not detected. Nerve conduction studies and EMG suggested sensory-motor neuropathy and denervation.</p><p>Patient 5 was the brother of patient 4. Polyhydramnios and reduced fetal movements were diagnosed at 31-week gestation. At birth, he was profoundly hypotonic with no respiratory effort. He did not swallow and muscle reflexes were absent. No invasive treatment was initiated and he died at 4 hours of age.</p></sec><sec id="s2-3"><title>Sural nerve biopsy reveals paranodal abnormalities.</title><p>Sural nerve biopsy of patient 4 revealed a significant axonal loss which was homogeneous between nerve fascicles. There was a significant decrease of large myelinated fibers and a great number of myelinated fibers with too thin myelin sheaths (<xref ref-type="fig" rid="F4">figure 4</xref>); myelin debris was found in the cytoplasm of some Schwann cells and in a few macrophages in the endoneurial space. Electron microscopic examination of longitudinal sections showed frequent and marked widenings of the nodes of Ranvier typical of a demyelinating neuropathy. Most of the paranodal regions were characterized by loss of attachment sites of the loops, which seemed to be induced by Schwann cell processes penetrating between the axon and the loops (<xref ref-type="fig" rid="F4">figure 4</xref>). Moreover, the typical transverse bands<sup><xref rid="R13" ref-type="bibr">13</xref></sup> that cross the paranodal junctional gap were absent.</p><fig id="F4" orientation="portrait" position="float"><label>Figure 4</label><caption><title>Electron microscopy of sural nerves comparing patient 4 and with a healthy control</title><p>(A, B) Electron microscopy of sural nerve of patient 4. (A) Transverse section. Severe rarefaction of myelinated fibers; many have a too thin myelin sheath (arrows). (B) Longitudinal section. Abnormal widening of the node of Ranvier. The myelin loops are dissociated by the fingers of Schwann cell cytoplasm (arrows), which penetrate between the loops and the axon. (C, D) Age-matched control images. (C) Transverse section. Normal axonal density. (D) Longitudinal section. Normal node of Ranvier; the loops are closely attached to the axon.</p></caption><graphic xlink:href="NG2016003939FF4"></graphic></fig></sec></sec><sec sec-type="discussion" id="s3"><title>DISCUSSION</title><p>We found 3 new <italic>CNTNAP1</italic> mutations causing a severe hypomyelinating CNS disorder and peripheral neuropathy in 2 independent families. The 2 new stop-gain mutations c.2011C>T:p.(Gln671*) and c.2015G>A:p.(Trp672*) occur earlier than the 2 previously described frameshift mutations with premature stop codon (c.2901_2902del and c.2994-2_2994del) and the frameshift mutation c.3009_3010insT, thus either resulting in a severely truncated protein or nonsense-mediated decay (<xref ref-type="fig" rid="F1">figure 1</xref>). The missense mutation in family 2 changes a highly conserved amino acid residue from a polar to a nonpolar residue. Taken together with huge overlap in clinical findings of all children, we have no doubt about the pathogenicity of the missense mutation.</p><p>The clinical findings of the 5 new <italic>CNTNAP1</italic> patients lead to a better and extended characterization of the phenotype. All patients described so far presented with hypotonia, respiratory distress, facial diplegia, micrognathia, and absent swallowing. A history of polyhydramnios was present in all cases, probably as a result of the swallowing deficit. Including our series, AMC was present in 6 of 9 patients with <italic>CNTNAP1</italic> mutations described so far (<xref ref-type="table" rid="T1">table</xref>). This illustrates that AMC is not an obligate feature of <italic>CNTNAP1</italic>-related disease but most likely a secondary phenomenon due to hypotonia and, therefore, reduced fetal movements. Another feature that had so far not been related to <italic>CNTNAP1</italic> is epilepsy. We found epilepsy in all cases that survived at least 120 days. As patients in the earlier series died only a few days after birth, it is tempting to speculate that these patients would likely have developed epilepsy, later on. The prolonged survival of more than 12 years in our patients stands in contrast to the short survival of the initially described patients with death occurring within 40 days of life. This is probably not explained by a milder phenotype, but by extensive medical care. The 12-year-old and 9-year-old patients underwent tracheostomy at the preterm intensive care unit and received nutrition via gastrostomy tube. Given the missense rather than truncating mutation, family 2 might be expected to present a milder phenotype due to a partially functioning protein. However, we did not observe a milder phenotype in family 2 compared to family 1.</p><p>MRIs of our patients were taken at different ages and allow some cautious statements about the course of myelination. MRI of patient 4 was taken at 4 days of age. At this time, the expected first signs of myelination within the posterior limb of the inner capsule were missing in our patient; however, signs of atrophy were not present at that time point. MRI of patient 1 was taken at 5 years of age and showed a clear picture of hypomyelinating leukodystrophy. Even after 5 years, there were no myelin deposits. At this age, there was a marked reduction of cerebral, cerebellar, and pontine volume with pronounced lack of white matter. This suggests that the volume reduction is atrophy, at least to some extent secondary to hypomyelination. Furthermore, mega cisterna magna and thin corpus callosum were present in both patients (<xref ref-type="fig" rid="F3">figure 3</xref>).</p><p>Findings in nerve biopsy of patient 4 are consistent with previous descriptions of <italic>CNTNAP1</italic> cases. They share common features of hypomyelinating neuropathies with widening of the nodes of Ranvier and a great number of myelinated fibers with too thin myelin sheaths, but they also have very distinct features with lack of transverse bands at the paranodes and widened paranodal junctional gaps. Similar findings have been described in CASPR knockout mice and the shambling mouse harboring a CASPR missense mutation as well as other mouse models with paranodal junctional defects like contactin mutant mice<sup><xref rid="R14" ref-type="bibr">14</xref></sup> or neurofascin-deficient mice.<sup><xref rid="R15" ref-type="bibr">15</xref></sup> To the best of our knowledge, these distinct bioptic findings have been only described in the animal models mentioned above and not in humans.</p><p>Most of these findings are consistent with primary hypomyelination of the CNS and PNS, which can be explained by the well-established function of CASPR, i.e., the formation and preservation of paranodal junctions in the PNS and CNS. However, the massive neonatal symptomatology with microcephaly and early-onset epilepsy and the severe overall disease course are not common in hypomyelinating disorders but suggest a strong neuronal pathology. Other hypomyelinating leukodystrophies show primary developmental delay and usually some developmental progress during the first years of life.<sup><xref rid="R16" ref-type="bibr">16</xref></sup> Furthermore, the severe supratentorial pronounced atrophy is another clue for additional neuronal/axonal pathology.</p><p>More recently, CASPR was shown to control the specification of neural progenitor cells in mice through notch signaling and is therefore regarded as a key regulator in the development of the cerebral cortex.<sup><xref rid="R17" ref-type="bibr">17</xref></sup> Although MRI in neither patient displayed overt cortical maldevelopment, this dysfunction of <italic>CNTNAP1</italic> is likely to interfere with cortical development and may contribute to early cerebral disease directly after birth when myelination is just beginning. Thus, both established functions of CASPR provide basic concepts of pathogenesis and explain the clinical findings. As shown in our case series, unique findings at neurologic examination as well as imaging and sural nerve biopsy can help to guide straightforward genetic diagnostics even in the absence of AMC.</p></sec></body><back><sec sec-type="contributions"><title>AUTHOR CONTRIBUTIONS</title><p content-type="contributions">H. Hengel and A. Magee: drafting and editing of the manuscript, analysis and interpretation of data, and acquisition of data. M. Mahanjah, R. Sharkia, and J.-M. Vallat: acquisition, analysis and interpretation of data, and contributing to and revising the manuscript. M. Abu-Rashid and J. Mahamid: acquisition of data and contributing to the manuscript. M. Schulze: analysis and interpretation of data and contributing to the manuscript. I. Krägeloh-Mann: interpretation of MRI data and contributing to and revising the manuscript. R. Ouvrier, R. Schüle, and S. Züchner: contributing to and revising the manuscript. P. Bauer and L. Schöls: conceptualization of this study, study supervision, analysis and interpretation of data, revising the manuscript, and obtaining funding.</p></sec><sec sec-type="funding"><title>STUDY FUNDING</title><p content-type="funding">This work has been funded by the DFG trilateral project (reference number SCHO 754/5-2).</p></sec><sec sec-type="disclosure"><title>DISCLOSURE</title><p content-type="disclosure">P. Bauer received speaker honoraria from Actelion and is a paid consultant for Centogene AG. L. Schöls received speaker honoraria from Actelion. H. Hengel, A. Magee, M. Mahanjah, J.-M. Vallat, R. Ouvrier, M. Abu-Rashid, J. Mahamid, R. Schüle, M. Schulze, I. Krägeloh-Mann, S. Züchner, and R. Sharkia report no disclosures. 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