{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T22:37:08Z","timestamp":1775083028070,"version":"3.50.1"},"reference-count":11,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T00:00:00Z","timestamp":1645488000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Adult\u2010onset Nieman\u2013Pick disease type C (NPC) is a rare progressive ataxia caused by lysosomal accumulation of unesterified cholesterol resulting in severe disability and death. The diagnosis of NPC can be challenging as clinical features overlap with other more common hereditary ataxias. This study pursued the molecular genetic basis of adult\u2010onset cerebellar ataxia manifesting in two siblings. A prior diagnosis of spinocerebellar ataxia type 2 (SCA2) based on an ataxia gene panel was questioned when the younger sibling developed similar symptoms but had discordant genetic results.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Neurologic examination, whole exome sequence (WES), targeted sequence to establish genome phasing, and cytochemical and biochemical studies of fibroblast cultures were employed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The pedigree and neurological examinations suggested a recessive or possibly dominant cerebellar ataxia. WES showed the siblings were both compound heterozygous for two rare variants in the <jats:italic>NPC1<\/jats:italic> gene\u2014one pathogenic, stop gain at p.Arg934Ter (NM_000271.4), and a missense change, p.Pro471Leu (NM_000271.4), of uncertain significance. Filipin staining of fibroblast cultures showed lysosomal cholesterol accumulation and biochemical assay demonstrated impaired cholesterol esterification.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The study established the correct molecular diagnosis of biallelic, adult\u2010onset NPC in a patient initially diagnosed with SCA. Additionally, the p.Pro471Leu variant was identified as likely pathogenic. Inaccurate molecular diagnosis will deprive NPC patients of treatment options. Investigation using WES is justified when a detected expansion size is in the borderline range for pathogenicity.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1906","type":"journal-article","created":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T13:58:56Z","timestamp":1645538336000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Adult\u2010onset <scp>Niemann\u2013Pick<\/scp> disease type C masquerading as spinocerebellar ataxia"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9497-1411","authenticated-orcid":false,"given":"Mary L.","family":"Vo","sequence":"first","affiliation":[{"name":"Department of Neurology Weill Cornell Medicine  New York New York USA"},{"name":"Center for Neurogenetics Feil Family Brain and Mind Research Institute, Weill Cornell Medicine  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tess","family":"Levy","sequence":"additional","affiliation":[{"name":"Center for Neurogenetics Feil Family Brain and Mind Research Institute, Weill Cornell Medicine  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shenela","family":"Lakhani","sequence":"additional","affiliation":[{"name":"Center for Neurogenetics Feil Family Brain and Mind Research Institute, Weill Cornell Medicine  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengbing","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Neurogenetics Feil Family Brain and Mind Research Institute, Weill Cornell Medicine  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Elizabeth","family":"Ross","sequence":"additional","affiliation":[{"name":"Department of Neurology Weill Cornell Medicine  New York New York USA"},{"name":"Center for Neurogenetics Feil Family Brain and Mind Research Institute, Weill Cornell Medicine  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,2,22]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9030679"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31735"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023\u2010018\u20100785\u20107"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/121.3.459"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1607795113"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023\u2010018\u20100844\u20100"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2017.00108"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awl260"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/tra.12727"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.mcb.2014.10.028"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.25"}],"container-title":["Molecular Genetics &amp; Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.1906","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mgg3.1906","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.1906","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T09:46:23Z","timestamp":1692956783000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.1906"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,22]]},"references-count":11,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2022,4]]}},"alternative-id":["10.1002\/mgg3.1906"],"URL":"https:\/\/doi.org\/10.1002\/mgg3.1906","archive":["Portico"],"relation":{},"ISSN":["2324-9269","2324-9269"],"issn-type":[{"value":"2324-9269","type":"print"},{"value":"2324-9269","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,22]]},"assertion":[{"value":"2021-11-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-02-02","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-02-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e1906"}}