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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Phenotypic and molecular analyses of primary lateral sclerosis</title><author><name sortKey="Mitsumoto, Hiroshi" sort="Mitsumoto, Hiroshi" uniqKey="Mitsumoto H" first="Hiroshi" last="Mitsumoto">Hiroshi Mitsumoto</name></author><author><name sortKey="Nagy, Peter L" sort="Nagy, Peter L" uniqKey="Nagy P" first="Peter L." last="Nagy">Peter L. Nagy</name></author><author><name sortKey="Gennings, Chris" sort="Gennings, Chris" uniqKey="Gennings C" first="Chris" last="Gennings">Chris Gennings</name></author><author><name sortKey="Murphy, Jennifer" sort="Murphy, Jennifer" uniqKey="Murphy J" first="Jennifer" last="Murphy">Jennifer Murphy</name></author><author><name sortKey="Andrews, Howard" sort="Andrews, Howard" uniqKey="Andrews H" first="Howard" last="Andrews">Howard Andrews</name></author><author><name sortKey="Goetz, Raymond" sort="Goetz, Raymond" uniqKey="Goetz R" first="Raymond" last="Goetz">Raymond Goetz</name></author><author><name sortKey="Floeter, Mary Kay" sort="Floeter, Mary Kay" uniqKey="Floeter M" first="Mary Kay" last="Floeter">Mary Kay Floeter</name></author><author><name sortKey="Hupf, Jonathan" sort="Hupf, Jonathan" uniqKey="Hupf J" first="Jonathan" last="Hupf">Jonathan Hupf</name></author><author><name sortKey="Singleton, Jessica" sort="Singleton, Jessica" uniqKey="Singleton J" first="Jessica" last="Singleton">Jessica Singleton</name></author><author><name sortKey="Barohn, Richard J" sort="Barohn, Richard J" uniqKey="Barohn R" first="Richard J." last="Barohn">Richard J. Barohn</name></author><author><name sortKey="Nations, Sharon" sort="Nations, Sharon" uniqKey="Nations S" first="Sharon" last="Nations">Sharon Nations</name></author><author><name sortKey="Shoesmith, Christen" sort="Shoesmith, Christen" uniqKey="Shoesmith C" first="Christen" last="Shoesmith">Christen Shoesmith</name></author><author><name sortKey="Kasarskis, Edward" sort="Kasarskis, Edward" uniqKey="Kasarskis E" first="Edward" last="Kasarskis">Edward Kasarskis</name></author><author><name sortKey="Factor Litvak, Pam" sort="Factor Litvak, Pam" uniqKey="Factor Litvak P" first="Pam" last="Factor-Litvak">Pam Factor-Litvak</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27066542</idno><idno type="pmc">4821084</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821084</idno><idno type="RBID">PMC:4821084</idno><idno type="doi">10.1212/01.NXG.0000464294.88607.dd</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000A48</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A48</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Phenotypic and molecular analyses of primary lateral sclerosis</title><author><name sortKey="Mitsumoto, Hiroshi" sort="Mitsumoto, Hiroshi" uniqKey="Mitsumoto H" first="Hiroshi" last="Mitsumoto">Hiroshi Mitsumoto</name></author><author><name sortKey="Nagy, Peter L" sort="Nagy, Peter L" uniqKey="Nagy P" first="Peter L." last="Nagy">Peter L. Nagy</name></author><author><name sortKey="Gennings, Chris" sort="Gennings, Chris" uniqKey="Gennings C" first="Chris" last="Gennings">Chris Gennings</name></author><author><name sortKey="Murphy, Jennifer" sort="Murphy, Jennifer" uniqKey="Murphy J" first="Jennifer" last="Murphy">Jennifer Murphy</name></author><author><name sortKey="Andrews, Howard" sort="Andrews, Howard" uniqKey="Andrews H" first="Howard" last="Andrews">Howard Andrews</name></author><author><name sortKey="Goetz, Raymond" sort="Goetz, Raymond" uniqKey="Goetz R" first="Raymond" last="Goetz">Raymond Goetz</name></author><author><name sortKey="Floeter, Mary Kay" sort="Floeter, Mary Kay" uniqKey="Floeter M" first="Mary Kay" last="Floeter">Mary Kay Floeter</name></author><author><name sortKey="Hupf, Jonathan" sort="Hupf, Jonathan" uniqKey="Hupf J" first="Jonathan" last="Hupf">Jonathan Hupf</name></author><author><name sortKey="Singleton, Jessica" sort="Singleton, Jessica" uniqKey="Singleton J" first="Jessica" last="Singleton">Jessica Singleton</name></author><author><name sortKey="Barohn, Richard J" sort="Barohn, Richard J" uniqKey="Barohn R" first="Richard J." last="Barohn">Richard J. Barohn</name></author><author><name sortKey="Nations, Sharon" sort="Nations, Sharon" uniqKey="Nations S" first="Sharon" last="Nations">Sharon Nations</name></author><author><name sortKey="Shoesmith, Christen" sort="Shoesmith, Christen" uniqKey="Shoesmith C" first="Christen" last="Shoesmith">Christen Shoesmith</name></author><author><name sortKey="Kasarskis, Edward" sort="Kasarskis, Edward" uniqKey="Kasarskis E" first="Edward" last="Kasarskis">Edward Kasarskis</name></author><author><name sortKey="Factor Litvak, Pam" sort="Factor Litvak, Pam" uniqKey="Factor Litvak P" first="Pam" last="Factor-Litvak">Pam Factor-Litvak</name></author></analytic><series><title level="j">Neurology: Genetics</title><idno type="eISSN">2376-7839</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Objective:</title><p>To understand phenotypic and molecular characteristics of patients with clinically “definite” primary lateral sclerosis (PLS) in a prospective study.</p></sec><sec><title>Methods:</title><p>Six sites enrolled 41 patients who had pure upper motor neuron dysfunction, bulbar symptoms, a normal EMG done within 12 months of enrollment, and onset of symptoms ≥5 years before enrollment. For phenotypic analyses, 27 demographic, clinical, and cognitive variables were analyzed using the k-means clustering method. For molecular studies, 34 available DNA samples were tested for the <italic>C9ORF72</italic> mutation, and exome sequencing was performed to exclude other neurologic diseases with known genetic cause.</p></sec><sec><title>Results:</title><p>K-means clustering using the 25 patients with complete datasets suggested that patients with PLS can be classified into 2 groups based on clinical variables, namely dysphagia, objective bulbar signs, and urinary urgency. Secondary analyses performed in all 41 patients and including only variables with complete data corroborated the results from the primary analysis. We found no evidence that neurocognitive variables are important in classifying patients with PLS. Molecular studies identified <italic>C9ORF72</italic> expansion in one patient. Well-characterized pathogenic mutations were identified in <italic>SPG7, DCTN1</italic>, and <italic>PARK2</italic>. Most cases showed no known relevant mutations.</p></sec><sec><title>Conclusions:</title><p>Cluster analyses based on clinical variables indicated at least 2 subgroups of clinically definite PLS. Molecular analyses further identified 4 cases with mutations associated with amyotrophic lateral sclerosis, Parkinson disease, and possibly hereditary spastic paraplegia. Phenotypic and molecular characterization is the first step in investigating biological clues toward the definition of PLS. Further studies with larger numbers of patients are essential.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Le Forestier, N" uniqKey="Le Forestier N">N Le Forestier</name></author><author><name sortKey="Maisonobe, T" uniqKey="Maisonobe T">T Maisonobe</name></author><author><name sortKey="Spelle, L" uniqKey="Spelle L">L Spelle</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="D Amico, E" uniqKey="D Amico E">E D'Amico</name></author><author><name sortKey="Pasmantier, M" uniqKey="Pasmantier M">M Pasmantier</name></author><author><name sortKey="Lee, Yw" uniqKey="Lee Y">YW Lee</name></author><author><name sortKey="Weimer, L" uniqKey="Weimer L">L Weimer</name></author><author><name sortKey="Mitsumoto, H" uniqKey="Mitsumoto H">H Mitsumoto</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gordon, Ph" uniqKey="Gordon P">PH Gordon</name></author><author><name 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<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">27066542</article-id><article-id pub-id-type="pmc">4821084</article-id><article-id pub-id-type="publisher-id">NNG-D-15-00003</article-id><article-id pub-id-type="doi">10.1212/01.NXG.0000464294.88607.dd</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Phenotypic and molecular analyses of primary lateral sclerosis</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Mitsumoto</surname><given-names>Hiroshi</given-names></name><degrees>MD, DSc</degrees><author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title><list-item><p>Avanir, 2007-2011 on Advisory Board Knopp 2007-2011 on Advisory Board NeuralStem, 2008, on Advisory board and on DSMB Sanofi-Aventis, 2009-2010 for giving a talk in Japan (invited by the janaese Society of Neurology. They made arrangements Biogen, 2011, Advisory Board</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>Avanir, 2008, on Advisory Board, honorarium $2000, Conference call 2011, $500 Knopp 2007, on Advisory Board, honorarium $2000 NeuralStem, 2008, on Advisory board, honorarium $1000, In 2010 $1,500. Otsuka, 2007, on Advisory Board, honorarium $2000 2011 Asubio 2012, Advisory Meeting, $3500 Shinogi 2011,Advisory Meeting, $2000 Biogren 2011, Educational Advisory, $300 Advance Medical, 2011-present, Case Consultation, $1500- $2000 yearly</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>Avanir, clinical trial research fund Teva, clinical trial research fund Knopp, clinical trial research fund and funds for ALS Conference at Columbia 2011 Sanofi-Aventis support for ALS Conference at Columbia Biogen support for ALS Conference at Columbia</p></list-item></list></p><p><list list-type="order"><title>Research Support, Government Entities:</title><list-item><p>NINDS, DNA repository 2008 as a supplement. NIEHS Center grant. 2007, 2009 ATSDR grant. 2013-2017</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>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>Nagy</surname><given-names>Peter L.</given-names></name><degrees>MD, 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"><name><surname>Gennings</surname><given-names>Chris</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"><name><surname>Murphy</surname><given-names>Jennifer</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>I have a position with a CRO, (INC Research), for which I receive compensation. My CRO position is unconnected to the research represented in this submitted paper.</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>I have a position with a CRO, (INC Research), for which I receive compensation. My CRO position is unconnected to the research represented in this submitted paper.</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>Andrews</surname><given-names>Howard</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>(1) Research Triangle Institute: consultation with respect to data preparation for federally sponsored data sharing website (FITBIR) (2) Michael J Fox Foundation: consultation with respect to data analysis and data quality</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>Research Foundation for Mental Hygiene (New York)</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>Goetz</surname><given-names>Raymond</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"><name><surname>Floeter</surname><given-names>Mary Kay</given-names></name><degrees>MD, 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>Muscle and Nerve editorial board</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. Federal employee salary, National Institute of Neurological Disorders and Stroke, NIH</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>Hupf</surname><given-names>Jonathan</given-names></name><degrees>BA</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>(1) NIEHS, R01ES016348, Research Assistant, 2012-2015</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>(1) Spastic Paraplegia Foundation (2) Muscular Dystrophy Association Wings Over Wall Street</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>Singleton</surname><given-names>Jessica</given-names></name><degrees>BA</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>Barohn</surname><given-names>Richard J.</given-names></name><degrees>MD</degrees><author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title><list-item><p>Diaphraghm stem study</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>Grifols, NuFactor, KU CME courses, Walgreens</p></list-item></list></p><p><list list-type="order"><title>Editorial Boards:</title><list-item><p>Journal of Clinical Neuromuscular Disease</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>Grifols, Baxter, Sanofi/Genzyme</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>(1) Cytokinetics (2) GSK (3) CSL-Behring (4) Alexion (5) Sanofi/Genzyme (6) Biomarin (7) PTC (8) Eli Lilly</p></list-item></list></p><p><list list-type="order"><title>Research Support, Government Entities:</title><list-item><p>TL1 TR000120 Barohn (PI) 06/01/2011 – 02/28/2016 KL2 TR000119 Aaronson (PI) UL1 TR0000001 NIH/NCATS Heartland Institute for Clinical and Translational Research. These linked Clinical and Translational Science Awards (CTSA) provide infrastructure facilities and support and educational and training. RO1FD003739 Barohn (PI) 09/14/2012-08/31/2016 FDAOPD Phase 2 Study of Rasagiline for Treatment of Amyotrophic Lateral Sclerosis. A multicenter study to evaluate the benefit of rasagiline in the treatment of amyotrophic lateral sclerosis. R01 FD003538 Barohn (PI) 04/15/2009 – 08/31/2013 FDA OPD Phase 2 Trial of Methotrexate in Myasthenia Gravis. A multicenter study to evaluate the benefit of oral methotrexate in the treatment of corticosterioid dependent Myasthenia Gravis. CER-1306-02496 Barohn (PI) 02/01/2014 – 01/31/2017 PCORI Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations (PAIN-CONTRoLS). CER-1306-04631 Waitman (PI) 02/01/2014 – 06/30/2017 PCORI Greater Plains Collaborative Clinical Data Research Network. 1U01NS084495 Nowack (PI) 09/05/2013 – 07/31/2017 NIH/NINDS A Phase II Trial of Rituximab in Myasthenia Gravis. R01 NS42685 Wolfe (PI) 03/01/2005 – 07/31/2013 NIH/NINDS Thymectomy trial in non-thymomatous myasthenia gravis patients receiving prednisone therapy. Randomized trial to study the effect of thymectomy in subjects with MG. Role: Co-I RO1 ES016348 Mitsumoto (PI) 07/22/2009 – 04/30/2014 NIH Multicenter ALS Study Cohort Study of Oxidative Stress and Disease Progression The goal of this study is to look at oxidative stress factors on subjects with ALS and determine what stress factors may be significant in the course of the disease. Role: Co-I R01FD003710 Benatar (PI) 07/14/2010 - 06/30/2014 FDA Effectiveness of Prednisone in the Treatment of Ocular MyasthEnia (EPITOMÉ). The goal of this randomized controlled trial is to examine the effectiveness and safety of oral prednisone in patients with ocular myasthenia. Role: Co-I</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>Nations</surname><given-names>Sharon</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>novartis - research support alexion - research support</p></list-item></list></p><p><list list-type="order"><title>Research Support, Government Entities:</title><list-item><p>FDA R01 FD003739 - sub-I, site investigator 2013,2014,2015 NIH-NINDS NS07732301 - site investigator 2014,2015</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>Shoesmith</surname><given-names>Christen</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>Husband is employed by Roche Canada.</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>Kasarskis</surname><given-names>Edward</given-names></name><degrees>MD, 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>(1) Associate editor, Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2012-present</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) Asubio Pharmaceuticals (2) Cytokinetics Pharmaceuticals (3) Neuraltus Pharmaceuticals</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>(1) Neuraltus Pharmaceuticals (2) Cytokinetics</p></list-item></list></p><p><list list-type="order"><title>Research Support, Government Entities:</title><list-item><p>(1) NINDS, U01 NS-049640-02, site PI, 2009-13 (2) NIEHS, R01 ES-016348, site PI, 2010-present</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>Factor-Litvak</surname><given-names>Pam</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>1. Non-profit entity: Environment and Health Fund, Israel, travel funds</p></list-item></list></p><p><list list-type="order"><title>Editorial Boards:</title><list-item><p>1. Journal of Environmental and Public Health, Editorial board, 2010-present 2. Neurotoxicology, Editoral board, 2014-presents</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>Columbia Global Center/FAPERJ Grant: Association Between Biomarkers and Gestational, Maternal and Infant Outcomes: Evidence from a Prospective Cohort from Pregnancy to 2 Years of Age. PI: Pam Factor-Litvak, PhD; Gilberto Kac, PhD Agency: FAPERJ/Columbia University Period: 09/01/2014-08/31/2016 Role: Co-Principal Investigator Synergistic Immunosuppression by Polycyclic Aromatic Hydrocarbon (PAHs) and Arsenite (As). PI: Faroque Parvez, PhD Agency: National Institute of Environmental Health Sciences Period: 11/1/2013-10/31/2016 Role: Co-Investigator A Prospective Comprehensive Epidemiologic Study in a Large Cohort in the National ALS Registry: Identifying ALS Risk Factors (ARREST-ALS) PI: Pam Factor-Litvak, PhD; Hiroshi Mitsumoto, MD, PhD Agency: Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry Contract Number: 200-2013-56886 Period: 9/1/2013 – 8/31/2017 Role: Co-PI Total Direct Costs: $ Effects of a Major Climatic Event -Superstorm Sandy- on Pregnancy Outcomes and Telomere Length PI: Pam Factor-Litvak, PhD Agency: National Institute of Environmental Health Sciences Period: 05/15/2013-04/14/2015 Role: PI Total Costs: $438,000 Prenatal Pyrethroid Exposure and Child Mental, Motor and Behavioral Development PI: Pam Factor-Litvak, PhD; Robin Whyatt, DrPH Agency: National Institute of Environmental Health Sciences (No number yet) Period: 04/01/2013 – 03/31/2018 Role: Multiple PI Total Costs: $2,049,168 Fetal Exposure to Maternal Stress and Inflammation: Effects on Neurodevelopment PI: Lauren Ellman (Temple University) Agency: National Institute of Mental Health Period: 04/01/2012-03/31/2017 Role: PI Columbia Subcontract Total Costs (subcontract): $100,000 Prenatal Determinants of Telomere Length PIs: Susser, Factor-Litvak, Aviv Agency: National Institute of Child Health and Development Period: 04/01/2012-03/30/2017 Role: Multiple PI Total Costs: $3,263,327 Impact of Exposure to Brominated Flame Retardants (BFRs) and Phthalates on Birth Outcomes in an Israeli Cohort PI: Matathias Berkovitch (Assaf Medical Center, Israel) Agency: Environmental Health Fund (Israel) Period: 09/01/2012-08/31/2015 Role: Co-investigator Interdisciplinary Training in Nutritional and Population Health Sciences PIs: Debra Wolgemuth, PhD; Ezra Susser, MD DrPH Co-PIS: Pam Factor-Litvak, PhD; Richard Decklebaum, MD Agency: National Institute of Diabetes, Digestive Disorders and Kidney Disorders Period: 08/01/2011-07/31/2016 Role: Co-PI, Co-chair Steering Committee Total Costs: $672,289 Early-life phthalate exposure, thyroid function and child cognitive development PI: Whyatt, Factor-Litvak (co-PIs) Agency: National Institute of Environmental Health Sciences Period: 04/01/10-03/31/15 Role: Multiple PI Total Costs: $3,250,000 Oxidative Stress in ALS: Relation to Symptom Onset and Disease Progression. PI: Hiroshi Mitsumoto, MD, PhD Agency: National Institute of Environmental Health Sciences Total Budget: $2,500,000 1R01ES016348 Period: 07/01/09-06/30/14 Role: Co-Principal Investigator Total Costs: $3,472,545 Folic Acid and Creatine as Therapeutic Approaches for Lowering Blood Arsenic PI: Mary Gamble, PhD Agency: National Cancer Institute/National Institute of Environmental Health Sciences Total Budget: $1,502,153 R01CA133595 Period: 09/01/09-08/30/14 Role: Co-Investigator A Lifecourse Perspective on Health Disparities PI: Bruce Link, PhD Agency: National Institute of Child Health and Development R01 HD058515 Period: 10/01/08-09/30/14 (NCE) Role: Co-Investigator Health Effects and Geochemistry of Arsenic and Lead PI: Joseph Graziano, PhD Agency: National Institute of Environmental Health Science/Environmental Protection Agency Total Budget (per year): $1,102,132 Superfund Award Period: 01/01/00-12/31/16 Roles: Principal Investigator, Training and Education Core Co-investigator (maternal and child health) The NIEHS Center for Environmental Health in Northern Manhattan Center Director: Regina Santella, PhD Agency: National Institute of Environmental Health Science P30 ES09089 Period: 03/31/03-02/28/18 Role: Epidemiologist Environmental Risk Factors for Essential Tremor PI: Elan Louis, MD, MPH Agency: National Institute of Environmental Health Science R01 NS39422 Period: 07/01/05-06/30/14 Total Budget per year: $ 461,000 Role: Co-Investigator</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>Impact of Exposure to Brominated Flame Retardants (BFRs) and Phthalates on Birth Outcomes in an Israeli Cohort PI: Matathias Berkovitch (Assaf Medical Center, Israel) Agency: Environmental Health Fund (Israel) Period: 09/01/2012-08/31/2015 Role: Co-investigator</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><on-behalf-of>For the PLS COSMOS Study Group</on-behalf-of><aff>From the Department of Neurology (H.M., J.H., J.S.), Eleanor and Lou Gehrig MDA/ALS Research Center, Columbia University Medical Center (CUMC), New York, NY; Department of Pathology and Cell Biology (P.L.N.), Personalized Genomic Medicine Laboratory, CUMC, New York, NY; Department of Biostatistics (C.G.), Virginia Commonwealth University, Richmond, VA; Department of Neurology (J.M.), University of California, San Francisco, CA; Departments of Biostatistics and Psychiatry (H.A., R.G.), Mailman School of Medicine, CUMC, New York, NY; Clinical Neuroscience Program (M.K.F.), NINDS, NIH, Bethesda, MD; Department of Neurology (R.J.B.), University of Kansas, Lawrence, KS; Department of Neurology (S.N.), University of Texas Southwestern Medical Center, Dallas, TX; Department of Neurology (C.S.), Western University, London, Ontario, Canada; Department of Neurology (E.K.), University of Kentucky, Lexington, KY; and Department of Epidemiology (P.F.-L), Mailman School of Public Health, CUMC, New York, NY.</aff></contrib-group><author-notes><corresp>Correspondence to Dr. Mitsumoto: <email>hm264@cumc.columbia.edu</email></corresp><fn fn-type="other"><p>PLS Study COSMOS Group coinvestigators are listed at <ext-link ext-link-type="uri" xlink:href="http://Neurology.org/ng">Neurology.org/ng</ext-link></p></fn><fn fn-type="other"><p>Funding information and disclosures are provided at the end of the article. Go to <ext-link ext-link-type="doi" xlink:href="10.1212/01.NXG.0000464246.83296.85">Neurology.org/ng</ext-link> for full disclosure forms. The Article Processing Charge was paid by Columbia University.</p></fn></author-notes><pub-date pub-type="epub"><day>14</day><month>4</month><year>2015</year></pub-date><pub-date pub-type="collection"><month>6</month><year>2015</year></pub-date><pub-date pub-type="pmc-release"><day>14</day><month>4</month><year>2015</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>1</volume><issue>1</issue><elocation-id>e3</elocation-id><history><date date-type="received"><day>09</day><month>2</month><year>2015</year></date><date date-type="accepted"><day>17</day><month>3</month><year>2015</year></date></history><permissions><copyright-statement>© 2015 American Academy of Neurology</copyright-statement><copyright-year>2015</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 Creative Commons Attribution-Noncommercial No Derivative 3.0 License, which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.</license-p></license></permissions><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="NNG-D-15-00003.pdf"></self-uri><abstract><sec><title>Objective:</title><p>To understand phenotypic and molecular characteristics of patients with clinically “definite” primary lateral sclerosis (PLS) in a prospective study.</p></sec><sec><title>Methods:</title><p>Six sites enrolled 41 patients who had pure upper motor neuron dysfunction, bulbar symptoms, a normal EMG done within 12 months of enrollment, and onset of symptoms ≥5 years before enrollment. For phenotypic analyses, 27 demographic, clinical, and cognitive variables were analyzed using the k-means clustering method. For molecular studies, 34 available DNA samples were tested for the <italic>C9ORF72</italic> mutation, and exome sequencing was performed to exclude other neurologic diseases with known genetic cause.</p></sec><sec><title>Results:</title><p>K-means clustering using the 25 patients with complete datasets suggested that patients with PLS can be classified into 2 groups based on clinical variables, namely dysphagia, objective bulbar signs, and urinary urgency. Secondary analyses performed in all 41 patients and including only variables with complete data corroborated the results from the primary analysis. We found no evidence that neurocognitive variables are important in classifying patients with PLS. Molecular studies identified <italic>C9ORF72</italic> expansion in one patient. Well-characterized pathogenic mutations were identified in <italic>SPG7, DCTN1</italic>, and <italic>PARK2</italic>. Most cases showed no known relevant mutations.</p></sec><sec><title>Conclusions:</title><p>Cluster analyses based on clinical variables indicated at least 2 subgroups of clinically definite PLS. Molecular analyses further identified 4 cases with mutations associated with amyotrophic lateral sclerosis, Parkinson disease, and possibly hereditary spastic paraplegia. Phenotypic and molecular characterization is the first step in investigating biological clues toward the definition of PLS. Further studies with larger numbers of patients are essential.</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>Primary lateral sclerosis (PLS) is considered the rarest motor neuron disease (MND). It is clinically characterized by isolated pure upper motor neuron (UMN) dysfunction. Thus, the absence of lower motor neuron (LMN) involvement distinguishes PLS from amyotrophic lateral sclerosis (ALS).<sup><xref rid="R1" ref-type="bibr">1</xref></sup> The diagnosis of PLS is also based on excluding all definable diseases, such as multiple sclerosis, myelopathy, metabolic diseases, and hereditary spastic paraplegia (HSP). In addition, after a few years of observation, some patients with suspected PLS develop features of LMN dysfunction.<sup><xref rid="R2" ref-type="bibr">2</xref></sup> Consequently, the diagnostic criteria for PLS have been extended from the originally recommended 3 years without LMN involvement to 4 years.<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> Although patients with PLS have markedly impaired motor function, PLS, unlike ALS, is not life-threatening. PLS is suspected to be a heterogeneous disease.<sup><xref rid="R6" ref-type="bibr">6</xref>,<xref rid="R7" ref-type="bibr">7</xref></sup> Because of its rarity, no prospective studies have analyzed the clinical and molecular characteristics of PLS. However, such investigations are an essential first step to clearly defining PLS and understanding the mechanisms underlying the disease. Here, we report novel analyses of the clinical phenotype and genetic markers of PLS.</p><sec sec-type="methods" id="s1"><title>METHODS</title><sec id="s1-1"><title>Standard protocol approvals, registrations, and patient consents.</title><p>The study protocol was approved by the Institutional Review Board (IRB) of Columbia University (Protocol Numbers: AAAE1115 and AAAE4850) and the individual IRBs of all participating sites.</p><p>Eligible patients were prospectively enrolled in this study, which is a parallel study to ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS) (NIEHS, R01ES016348). These 2 studies are nearly identical in structure and methodology,<sup><xref rid="R6" ref-type="bibr">6</xref></sup> except for eligibility criteria, follow-up visit frequency, and number of participating sites.<sup><xref rid="R8" ref-type="bibr">8</xref></sup></p><p>We defined clinically “definite” PLS when patients had (1) pure UMN dysfunction for at least 5 years following symptom onset based on subjective functional impairment<sup><xref rid="R2" ref-type="bibr">2</xref>,<xref rid="R3" ref-type="bibr">3</xref></sup>; (2) a normal EMG done within 12 months of enrollment (minimum changes in only one muscle were permitted)<sup><xref rid="R2" ref-type="bibr">2</xref>,<xref rid="R4" ref-type="bibr">4</xref></sup>; and (3) normal brain and spinal cord neuroimaging with allowance for increased signal intensity in the pyramidal tracts at the posterior internal capsules.<sup><xref rid="R9" ref-type="bibr">9</xref></sup> Exclusion criteria included patients in whom only the legs were affected, patients with known HSP, patients with a history of MND in immediate family, or those with other active neurologic and unstable medical diseases. The absence of bulbar symptoms, such as dysarthria, dysphagia, or pseudobulbar affect, although preferred, was not exclusionary.<sup><xref rid="R10" ref-type="bibr">10</xref></sup></p><p>Biospecimens (blood, DNA, urine, and skin biopsies) were collected, processed, and stored using appropriate methods. The patients had extensive clinical examinations and cognitive testing and had well-validated structured interviews as fully described in ALS COSMOS.<sup><xref rid="R8" ref-type="bibr">8</xref></sup></p></sec><sec id="s1-2"><title>Phenotype cluster analyses.</title><p>We collected data on 27 demographic and clinical variables for all 41 enrolled patients (table e-1 at <ext-link ext-link-type="doi" xlink:href="10.1212/01.NXG.0000464246.83296.85">Neurology.org/ng</ext-link>). Primary analyses were conducted on the 25 patients with complete data; secondary analyses were conducted on all 41 (<xref ref-type="table" rid="T1">table 1</xref>). Of the 27 potential clinical indicators, 5 (memory impairment, car sickness, stuttering, difficulty spelling, and predominantly unilateral symptoms) were present in no more than 1 patient and therefore excluded from the analysis. Verbal fluency was measured with the Written Verbal Fluency Test or the Controlled Oral Word Association Test (COWAT) with F, A, and S, which consisted of a combination of scores from the 3 subscales. Clinical verbal impairment was defined as either a Fluency Test index score of at least 19 or a COWAT score at least 2 SDs below the mean, adjusted for sex, age, and education level.<sup><xref rid="R11" ref-type="bibr">11</xref></sup> Finally, before conducting the cluster analysis, we standardized all variables, continuous and binary, to a mean of 0 and an SD of 1 to ensure that they had equal weight in the analysis.<sup><xref rid="R12" ref-type="bibr">12</xref></sup> A sensitivity analysis in which we scaled only the continuous variables and left the binary variables as 0 or 1 showed no meaningful difference.</p><table-wrap id="T1" position="float"><label>Table 1</label><caption><p>Sociodemographic, clinical, and cognitive data for patients with PLS</p></caption><graphic xlink:href="NNG-D-15-00003TT1"></graphic></table-wrap><p>In a secondary analysis, we restricted the variables to those with data available from all 41 patients, i.e., age, sex, disease duration, and the 15 binary clinical variables. A cluster analysis was performed following the method described above. Data analyses were conducted using SAS version 9.2 and R version 3.0.1.</p></sec><sec id="s1-3"><title>K-means clustering.</title><p>In preliminary analyses, we examined the plot of the within-groups sum of squares over a range of 2–15 possible clusters. Because we did not observe a “bend” in the plot (indicating the optimal number of clusters) and this was an exploratory analysis, we opted for 2 clusters in order to be conservative and for ease of interpretation (<xref ref-type="fig" rid="F1">figure 1</xref>).</p><fig id="F1" position="float"><label>Figure 1</label><caption><title>Within-groups sum of squares vs number of clusters</title><p>Within-groups sum of squares vs number of clusters to determine the number needed for k-means cluster analysis. The cluster algorithm assumes a given number of clusters to determine the grouping of patients. <xref ref-type="fig" rid="F1">Figure 1</xref> shows 15 separate cluster algorithms with 1–15 clusters assumed and the within-groups sum of squares calculated for each. Optimally, one would like to select a small number of clusters for ease of interpretation but with a small within-groups sum of squares. When there is a bend (like an elbow), it provides evidence that the gain is large (i.e., reducing the sum of squares) in identifying a fixed number of clusters with decreased evidence to increase the number of clusters. Our analysis showed no evidence of a bend, so we chose 2 clusters for convenience of interpretation.</p></caption><graphic xlink:href="NNG-D-15-00003FF1"></graphic></fig><p>We identified the 2 clusters using k-means with Euclidean distance. Variables associated with the clustering were identified in 2 steps. First, a model-building strategy using least absolute shrinkage and selection operator (Lasso) identified potentially important variables.<sup><xref rid="R13" ref-type="bibr">13</xref></sup> These were included in a logistic regression model. A Wald test for significance of parameters in the logistic model was used to identify important clustering variables.</p></sec><sec id="s1-4"><title>Genetic analysis.</title><p>All testing on the available 34 patient samples was performed in the Laboratory of Personalized Genomic Medicine (LPGM) at Columbia University.</p></sec><sec id="s1-5"><title><italic>C9ORF72</italic> expansion testing.</title><p>The presence of expanded repeats was determined using the method of Renton et al.<sup><xref rid="R14" ref-type="bibr">14</xref></sup></p></sec><sec id="s1-6"><title>Sequencing and bioinformatics.</title><p>Sequence capture for high-throughput sequencing was performed using Illumina TruSeq exome capture reagents, and 100-bp paired-end sequencing was performed on an Illumina HiSeq 2500 sequencer. Next-generation sequencing data were mapped and variants were called using NextGENe (SoftGenetics, State College, PA).<sup><xref rid="R15" ref-type="bibr">15</xref></sup> Variant filtering and comparative analysis were performed using the single nucleotide polymorphism (SNP) catcher software developed by the LPGM. This software relies on allele frequency and functional prediction data from multiple publicly available databases, including ClinVar,<sup><xref rid="R16" ref-type="bibr">16</xref></sup> 1000 Genomes Project,<sup><xref rid="R17" ref-type="bibr">17</xref></sup> Exome Variant Server,<sup><xref rid="R18" ref-type="bibr">18</xref></sup> and MSV3D.<sup><xref rid="R19" ref-type="bibr">19</xref>,<xref rid="R20" ref-type="bibr">20</xref></sup> Pathogenic mutations were confirmed by Sanger sequencing.</p></sec></sec><sec sec-type="results" id="s2"><title>RESULTS</title><p>All 41 patients had clinically typical PLS. Six patients had no dysarthria or dysphagia, and another 6 had the minimum EMG changes that were permitted for enrollment (table e-1). All patients were alive at the time of report, except 3 who died unexpectedly (patient 7 had a sudden death during sleep; patient 11 had a fall resulting in death; and patient 12 had sepsis, resulting in respiratory and cardiac failure). patient 4 had abnormal CSF (protein of 118 mg/dL and 8 cells) due to a traumatic spinal tap.</p><p><xref ref-type="table" rid="T1">Table 1</xref> compares sociodemographic, clinical, and cognitive variables between all patients (n = 41) and those patients with complete data (n = 25). Generally, the data were similar across the 2 datasets, with a slightly lower percentage of women and patients with dysarthria, dysphagia, and objective bulbar signs in patients with complete data.</p><p>Using Euclidean distance measures, we constructed a dendrogram to visualize the similarities in patients with complete data (<xref ref-type="fig" rid="F2">figure 2</xref>). The first branch separated 1 patient (case ID 7), leaving 24. The second branch separated 6 patients, with 18 remaining. The resulting 2 clusters differentiated the 6 patients separated in the second step from the remaining patients (i.e., case ID 7 was grouped with the 18 for a total of 19 patients in that cluster).</p><fig id="F2" position="float"><label>Figure 2</label><caption><title>Cluster dendrogram</title><p>Cluster dendrogram for similarity between patients with primary lateral sclerosis (PLS) with complete datasets (N = 25). Each patient is denoted by a corresponding code number.</p></caption><graphic xlink:href="NNG-D-15-00003FF2"></graphic></fig><p>The Lasso model selected 6 of the 19 variables associated with the cluster groupings: dysarthria, dysphagia, objective bulbar signs, urinary urgency, weight loss, and sensory impairment, the presence of which characterized the smaller cluster of 6 patients. Some of these clinical features were also present in other patients. None of these 6 variables was statistically significant in a joint logistic regression model, which predicted cluster membership. However, in individual logistic regression models, dysphagia (<italic>p</italic> = 0.01), objective bulbar signs (<italic>p</italic> = 0.01), and urinary urgency (<italic>p</italic> = 0.002) were associated with cluster membership. The modeling step was not based on an a priori specification of clustering variables and was exploratory in nature; therefore, the <italic>p</italic> values should be interpreted cautiously.</p><sec id="s2-1"><title>Secondary analyses.</title><p>Using all 41 patients, the plot of the within-groups sum of squares by number of clusters was similar to the curve found in the primary analysis, without an obvious bend. We again proceeded with the assumption of 2 clusters for ease of interpretation. Similar to the primary analysis, the Lasso model selected 7 of the 18 variables associated with the grouping: dysarthria, dysphagia, objective bulbar signs, minimum EMG changes, urinary urgency, weight loss, and female sex. Of these 7 variables, none were associated with cluster membership in a joint logistic regression model. However, in individual logistic regression models, dysphagia (<italic>p</italic> = 0.004), objective bulbar signs (<italic>p</italic> < 0.001), urinary urgency (<italic>p</italic> < 0.001), and female sex (<italic>p</italic> = 0.02) were associated with cluster membership. With the exception of sex, the results confirmed the primary analysis. Finally, we tested for cluster differences in all the cognitive variables that were not included in the k-means clustering and none differed across the 2 groups.</p><p>We repeated the analyses for the 37 patients with complete data for the Amyotrophic Lateral Sclerosis-Cognitive Behavioral Screen (ALS-CBS) variables. The plot of the within-groups sum of squares by number of clusters was similar to that shown in <xref ref-type="fig" rid="F1">figure 1</xref>. We proceeded assuming 2 clusters. The Lasso model selected 9 of the 18 variables associated with the grouping: age, disease duration at baseline, dysarthria, dysphagia, objective bulbar signs, minimum EMG changes, urinary urgency, sensory impairment, and female sex. Of these 9 variables, none were associated with cluster membership in a joint logistic model. However, in individual logistic regression models, dysphagia (<italic>p</italic> = 0.009), objective bulbar signs (<italic>p</italic> < 0.001), urinary urgency (<italic>p</italic> = 0.004), and female sex (<italic>p</italic> = 0.009) were associated with cluster membership. The final analysis used patients with no missing values on the ALS-CBS cognitive and behavior scales. Results (not shown) were similar to those in the primary analysis.</p></sec><sec id="s2-2"><title>Exome sequencing.</title><p>Table e-1 lists the mutations detected by <italic>C9ORF72</italic> expansion testing and exome sequencing in genes associated with HSP, familial ALS, and other known neurologic diseases. We identified one previously described pathogenic mutation in the <italic>SPG7</italic> gene in heterozygous form (A510V) in patient 1<sup><xref rid="R21" ref-type="bibr">21</xref></sup> and one <italic>C9ORF72</italic> expansion in patient 8.<sup><xref rid="R14" ref-type="bibr">14</xref></sup> Patient 1 and patient 8 belong to the larger cluster (<xref ref-type="fig" rid="F2">figure 2</xref>). Patient 11 had a predicted pathogenic heterozygous mutation in <italic>PARK2</italic>,<sup><xref rid="R22" ref-type="bibr">22</xref></sup> and patient 41 had a predicted risk allele in <italic>DCTN1</italic>.<sup><xref rid="R23" ref-type="bibr">23</xref></sup></p><p>Patient 11 also belonged to the larger cluster; patient 41 was not clustered because cognitive testing data were incomplete. A predicted pathogenic mutation in the <italic>SYNE2</italic> gene was identified in patient 6.<sup><xref rid="R24" ref-type="bibr">24</xref></sup> However, there was no evidence of myopathy. Several other patients showed SNPs of unknown significance in the <italic>PARK2</italic> (patient 23), <italic>VEGFA</italic> (patient 26), <italic>CLN6</italic> (patient 29), <italic>BTD</italic> (patient 29), and <italic>LRKK2</italic> (patient 32) genes.</p><p>From our exome sequencing performed on all patients with PLS, we have identified a combined 4,500 rare (population frequency less than 1%) missense or nonsense variants that occurred in at least 2 patients with PLS. Among these 4,500 variants, one-third mapped to genes with some disease-related annotation in the Online Mendelian Inheritance in Man database, and about one-third were predicted to disrupt protein function based on functional prediction algorithms (SIFT, Provean). We are currently refining our analysis and classification of these variants.</p></sec></sec><sec sec-type="discussion" id="s3"><title>DISCUSSION</title><p>Our overall goal was to take the first step toward determining, through analyzing phenotypes and genotypes, whether PLS is a single entity or a syndrome including multiple neurodegenerative variants. The expanding knowledge of genotypic expression has made it clear that the traditional view of the relationship between phenotypes and genotypes is simplistic. Detailed phenotypic information is now considered essential to understanding new or poorly defined diseases, such as PLS. We accomplished our goal in 2 ways: first, by using k-means clustering of phenotypic characteristics to identify groups of similar patients, and second, by using exome sequencing to identify possible genes associated with these phenotypes.</p><p>Our study has several strengths. We prospectively enrolled only those patients with clinically definite PLS to narrow clinical diversity and sought to identify any further possible subsets using phenotype cluster analyses. Subsequent k-means clustering, combined with a final model-building step, suggests that patients with PLS may be classified into 2 groups based on the presence or absence of the following clinical variables: dysarthria, dysphagia, objective bulbar signs, urinary urgency, weight loss, and sensory impairment. One limitation of this approach, however, is that the Lasso method chooses variables randomly from sets of highly correlated variables; thus, the selected variables may represent a subset of the entire group of variables.<sup><xref rid="R25" ref-type="bibr">25</xref></sup> However, the results of sensitivity analyses were essentially similar, and these put fewer restrictions on the number of variables with complete data. Therefore, our results suggest that the diagnosis of PLS may represent at least 2 different groups of patients.</p><p>Another important strength is genetic analysis of all patients to test for the presence of known disease-causing mutations associated with other neurodegenerative disorders. Mutations in <italic>SPG7</italic> (A510V) result in autosomal recessive spastic paraplegia. The mutation found in patient 1 is a heterozygous SPG variant, which is reported to predispose individuals to late-onset, complex neurodegenerative disorders.<sup><xref rid="R26" ref-type="bibr">26</xref></sup> A more recent study indicates that this particular heterozygosity can be pathogenic for HSP<sup><xref rid="R27" ref-type="bibr">27</xref></sup> (personal communication with Dr. John Fink, University of Michigan). Patient 8 presented with clinically typical PLS but was found to have <italic>C9ORF72</italic> hexonucleotide repeat expansion. A Dutch group previously described a single patient with <italic>C9ORF72</italic> expansion in a PLS cohort of 110 patients.<sup><xref rid="R28" ref-type="bibr">28</xref></sup> Although <italic>C9ORF72</italic> expansion is predominantly found in patients with ALS or ALS plus frontotemporal dementia, it has been described in other neurodegenerative diseases.<sup><xref rid="R28" ref-type="bibr">28</xref></sup> Variable clinical phenotypes may be the result of complex environmental interactions and genetic modifiers.<sup><xref rid="R29" ref-type="bibr">29</xref></sup> Our study and the Dutch study indicate that <italic>C9ORF72</italic> expansion can be expressed phenotypically as typical PLS.</p><p>Features of atypical Parkinson disease (PD) have been reported in patients with a diagnosis of PLS.<sup><xref rid="R30" ref-type="bibr">30</xref>,<xref rid="R31" ref-type="bibr">31</xref></sup> Although none of our patients had clinical features of PD, we found mutations in the <italic>PARK2</italic> gene (Arg275Trp) previously described as a cause of familial PD. This <italic>PARK2</italic> gene mutation is pathogenic when homozygous, but the heterozygous variants are reported to affect PD onset<sup><xref rid="R32" ref-type="bibr">32</xref></sup> and phenotype.<sup><xref rid="R33" ref-type="bibr">33</xref>,<xref rid="R34" ref-type="bibr">34</xref></sup> The <italic>LRRK2</italic> mutation is known to cause autosomal dominant familial PD, although in one study of large families the R1514Q mutation in our patient (patient 32) had not segregated with PD.<sup><xref rid="R35" ref-type="bibr">35</xref></sup> Yet other <italic>LRRK2</italic> mutations are found in sporadic PD cases,<sup><xref rid="R36" ref-type="bibr">36</xref></sup> and typical MND is reported in patients with familial PD resulting from a different <italic>LRRK2</italic> mutation.<sup><xref rid="R37" ref-type="bibr">37</xref></sup> Although the <italic>LRRK2</italic> mutation is interesting, its pathogenic significance in our patient with PLS is at best uncertain, and thus we consider it to be an SNP at this time. Our exome sequencing also identified another important mutation that is a known pathogenic mutation of the <italic>DCTN1</italic> gene<sup><xref rid="R38" ref-type="bibr">38</xref></sup>; although this mutation is rare, it has been reported in an apparent sporadic case of ALS.<sup><xref rid="R22" ref-type="bibr">22</xref></sup></p><p>Therefore, exome sequencing identified 4 potentially pathogenic mutations occurring in 34 patients with PLS (nearly 12%), all associated with neurodegenerative diseases such as ALS, HSP, and PD. With increasing knowledge in the near future, we may need to consider genetic counseling for patients who are found to have known gene mutations. Patients with 2 of these mutations belong to the cluster having the larger number of patients. Five other SNPs of unknown clinical significance were also detected (<italic>PARK2, VEGFA, CNL6, BTD</italic>, and <italic>LRRK2</italic>) as well as a predicted pathogenic mutation in <italic>SYNE2</italic>. Based on our experience, we recommend that patients with a diagnosis of PLS, especially those participating in research studies, be screened for pathogenic mutations using partial or complete exome sequencing to determine the prevalence of known pathogenic mutations and the pathogenic significance of variants of unknown significance. Further studies are needed to clarify the significance of these SNPs and the <italic>SYNE2</italic> mutation.</p><p>The diagnosis of PLS is still problematic because of the time required to wait before making a diagnosis and how strictly pure UMN involvement is defined. We decided to use very strict criteria (5 years after symptom onset before enrollment) so we could investigate clinically well-defined PLS cases. Yet waiting for such an extended time to make the diagnosis is neither practical nor helpful because physicians need to make a diagnosis at the earliest opportunity. Investigators also want to start PLS research at earlier stages of the disease, when active biological changes can be more readily found. We made every effort to select patients who had a definite diagnosis of PLS, short of autopsy proof. Therefore, disease diagnosed using our clinical criteria as described above (pure UMN dysfunction with normal EMG along with bulbar symptom(s), normal neuroimaging, and all definable diseases excluded) with negative exome sequencing and a negative <italic>C9ORF72</italic> expansion test can be considered clinically definite PLS for research purposes currently. PLS with a shorter disease duration (3–4 years) could be considered clinically “probable” or clinically “possible.” These clinically probable or possible cases could be elevated to definite PLS if the exome sequence and <italic>C9ORF72</italic> expansion tests detect no known molecular abnormalities. Until we have improved biological or genetic markers, such criteria may be suitable for research investigation of PLS. We need an updated international consensus for PLS diagnosis.</p><sec id="s3-1"><title>Study limitations.</title><p>Although the number of patients we studied is not small in comparison to other studies in PLS, a larger number of patients is required to achieve definitive results for both clinical clustering and exome sequencing analyses. We need to include more centers, preferably with long-term funding to allow adequate time for recruitment and to overcome the limitations involved with studying such a rare disease. Another limitation is the selection of patients with clinically “definite” PLS, which included patients who are in more advanced stages of the disease. Waiting a long period of time to diagnose PLS is a major drawback. Ideally, we should study PLS much earlier in the disease course, when biomarkers that can identify early PLS are most essential. To find such biomarkers, studying patients with clinically “definite” PLS is a necessary step.</p><p>We identified 2 phenotypic groups and a small number of patients with gene mutations known to be pathogenic for various neurodegenerative diseases. Further studies are needed. Our study is only the beginning of such investigations in PLS, providing a foundation that will hopefully stimulate other investigators to examine and expand our phenotypic and genetic studies in order to more fully understand PLS.</p></sec></sec><sec sec-type="supplementary-material"><title>Supplementary Material</title><supplementary-material id="PMC_1" content-type="local-data"><caption><title>Data Supplement</title></caption><media mimetype="text" mime-subtype="html" xlink:href="supp_1_1_e3__index.html"></media><media xlink:role="associated-file" mimetype="application" mime-subtype="msword" xlink:href="supp_1.1.e3_Table_e-1.docx"></media></supplementary-material><supplementary-material id="PMC_2" content-type="local-data"><caption><title>Coinvestigators</title></caption><media mimetype="text" mime-subtype="html" xlink:href="supp_1_1_e3_v2_index.html"></media><media xlink:role="associated-file" mimetype="application" mime-subtype="msword" xlink:href="supp_1.1.e3_COINVESTIGATORS.doc"></media></supplementary-material></sec></body><back><fn-group><fn fn-type="supplementary-material"><p>Supplemental data at <ext-link ext-link-type="doi" xlink:href="10.1212/01.NXG.0000464246.83296.85">Neurology.org/ng</ext-link></p></fn></fn-group><ack><title>ACKNOWLEDGMENT</title><p>The authors appreciate and thank the patients and families who participated in this study. John Fink, MD, Department of Neurology, University of Michigan, kindly gave suggestions and provided unpublished information. Jennifer Langsdorf, MD, Peripheral Neuropathy Center, Weill-Cornell University, gave a follow-up examination and performed EMG test for our study. Cassandra Talerico, PhD, provided substantive editing and comments. Georgia Christodoulou, MA, assisted with the preparation of the manuscript, including some copyediting and preparing materials for submission (neither met the criteria for authorship).</p></ack><sec sec-type="contributions"><title>AUTHOR CONTRIBUTIONS</title><p content-type="contributions">Dr. Mitsumoto served as the primary investigator for this study. He was involved in all stages of this project, including data collection, analyses, and preparing the draft of the manuscript. Dr. Nagy assisted in analyses of biomarkers in addition to reviewing the manuscript. Dr. Gennings assisted in statistical analyses, specifically cluster analyses, in addition to reviewing the manuscript. Dr. Murphy assisted in cognitive analyses in addition to reviewing the manuscript. Dr. Andrews assisted in data management for the entire study in addition to reviewing the manuscript. Dr. Goetz assisted in general statistical analyses in addition to reviewing the manuscript. Dr. Floeter served as a site investigator for National Institute of Neurological Diseases and Stroke and was involved in planning the study, data collection, and reviewing the manuscript. Mr. Hupf assisted in planning and coordination of the study, data collection, and reviewing the manuscript. Ms. Singleton assisted in coordination of the study, data collection, and reviewing the manuscript. Dr. Barohn served as site investigator for the University of Kansas and was involved with planning of the study, data collection, and reviewing the manuscript. Dr. Nations served as site investigator for University of Texas Southwestern Medical Center and was involved with planning of the study, data collection, and reviewing the manuscript. Dr. Shoesmith served as site investigator for Western University, London, Ontario, Canada, and was involved with planning of the study, data collection, and reviewing the manuscript. Dr. Kasarskis served as site investigator for University of Kentucky and was involved with planning the study, data collection, and reviewing the manuscript. Dr. Factor-Litvak assisted as the co-PI and was involved with the planning and statistical analyses as well as analyses of biomarkers, exposures, and cognition. She also reviewed the manuscript. All PLS COSMOS Study Group members assisted in data collection and reviewing the manuscript.</p></sec><sec sec-type="funding"><title>STUDY FUNDING</title><p content-type="funding">The study was funded by Spastic Paraplegia Foundation (SPF), MDA Wings Over Wall Street, NIEHS (R01ES016348) for the ALS COSMOS study, and private donations from Mr. and Mrs. David Marren.</p></sec><sec sec-type="disclosure"><title>DISCLOSURE</title><p content-type="disclosure">Dr. Mitsumoto has served on scientific advisory boards for Avanir, Knopp, Sanofi-Aventis, the Japanese Society of Neurology, and Biogen and received research support from SPF, MDA Wings Over Wall Street, NIEHS (R01ES016348), Avanir, Teva, Knopp, Columbia, Sanofi-Aventis, Biogen, <funding-source>National Institute of Neurological Disorders and Stroke</funding-source>, NIEHS, ATSDR, and private donations from Mr. and Mrs. David Marren. Dr. Nagy and Dr. Gennings report no disclosures. Dr. Murphy is employed by and has received travel funding and/or speaker honoraria from INC Research. Dr. Andrews has consulted for the Research Triangle Institute and Michael J. Fox Foundation and has received research support from Columbia University and the Research Foundation for Mental Hygiene. Dr. Goetz reports no disclosures. Dr. Floeter has served on the editorial board of <italic>Muscle and Nerve</italic> and is employed by <funding-source>National Institute of Neurological Disorders and Stroke</funding-source>/<funding-source>NIH</funding-source>. Mr. Hupf has received research support from NIEHS, Spastic Paraplegia Foundation, and Muscular Dystrophy Association Wings Over Wall Street. Ms. Singleton reports no disclosures. Dr. Barohn has served on a scientific advisory board for Diaphragm Stem Study; has received funding for travel and/or speaker honoraria from Grifols, NuFactor, KU, and Walgreens; has served on the editorial board of the <italic>Journal of Clinical Neuromuscular Disease</italic>; has served on speakers' bureaus for Grifols, Baxter, and Sanofi/Genzyme; and has received research support from Cytokinetics, GSK, CSL-Berhring, Alexion, Sanofi/Genzyme, Biomarin, PTC, Eli Lilly, <funding-source>NIH</funding-source>/<funding-source>National Institute of Neurological Disorders and Stroke</funding-source>, and FDA. Dr. Nations has served on Grifols speakers' bureau; has received research funding for travel and/or speaker honoraria from Grifols; and has received research support from Novartis, Alexion, FDA, and NIH-National Institute of Neurological Disorders and Stroke. Dr. Shoesmith reports no disclosures. Dr. Kasarskis serves as Associate Editor of <italic>Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration</italic>; has consulted for ASubio Pharmaceuticals, Cytokinetics Pharmaceuticals, and Neuraltus Pharmaceuticals; and has received research support from Neuraltus Pharmaceuticals, Cytokinetics, National Institute of Neurological Disorders and Stroke, NIEHS, and the ALS Association. Dr. Factor-Litvak has received funding for travel and/or speaker honoraria from the Environment and Health Fund; serves on the editorial boards of the <italic>Journal of Environmental and Public Health</italic> and <italic>Neurotoxicology</italic>; and has received research support from the Columbia Global Center/FABERJ, NIEHS, CDC, <funding-source>National Institute of Mental Health</funding-source>, Institute of Child Health and Development, Environmental Health Fund, National Institute of Diabetes, Digestive Disorders and Kidney Disorders, National Cancer Institute/National Institute of Environmental Health Sciences, and National Institute of Environmental Health Science/Environmental Protection Agency. Go to <ext-link ext-link-type="doi" xlink:href="10.1212/01.NXG.0000464246.83296.85">Neurology.org/ng</ext-link> for full disclosure forms.</p></sec><glossary><title>GLOSSARY</title><def-list><def-item><term id="G1">ALS</term><def><p>amyotrophic lateral sclerosis</p></def></def-item><def-item><term id="G2">ALS-CBS</term><def><p>Amyotrophic Lateral Sclerosis-Cognitive Behavioral Screen</p></def></def-item><def-item><term id="G3">COWAT</term><def><p>Controlled Oral Word Association Test</p></def></def-item><def-item><term id="G4">HSP</term><def><p>hereditary spastic paraplegia</p></def></def-item><def-item><term id="G5">IRB</term><def><p>Institutional Review Board</p></def></def-item><def-item><term id="G6">LMN</term><def><p>lower motor neuron</p></def></def-item><def-item><term id="G7">LPGM</term><def><p>Laboratory of Personalized Genomic Medicine</p></def></def-item><def-item><term id="G8">MND</term><def><p>motor neuron disease</p></def></def-item><def-item><term 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