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Adult‐onset Niemann–Pick disease type C masquerading as spinocerebellar ataxia

BACKGROUND: Adult‐onset Nieman–Pick 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....

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Detalles Bibliográficos
Autores principales: Vo, Mary L., Levy, Tess, Lakhani, Shenela, Wang, Chengbing, Ross, M. Elizabeth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9000929/
https://www.ncbi.nlm.nih.gov/pubmed/35192242
http://dx.doi.org/10.1002/mgg3.1906
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author Vo, Mary L.
Levy, Tess
Lakhani, Shenela
Wang, Chengbing
Ross, M. Elizabeth
author_facet Vo, Mary L.
Levy, Tess
Lakhani, Shenela
Wang, Chengbing
Ross, M. Elizabeth
author_sort Vo, Mary L.
collection PubMed
description BACKGROUND: Adult‐onset Nieman–Pick 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‐onset 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. METHODS: Neurologic examination, whole exome sequence (WES), targeted sequence to establish genome phasing, and cytochemical and biochemical studies of fibroblast cultures were employed. RESULTS: 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 NPC1 gene—one 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. CONCLUSIONS: The study established the correct molecular diagnosis of biallelic, adult‐onset 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.
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spelling pubmed-90009292022-04-15 Adult‐onset Niemann–Pick disease type C masquerading as spinocerebellar ataxia Vo, Mary L. Levy, Tess Lakhani, Shenela Wang, Chengbing Ross, M. Elizabeth Mol Genet Genomic Med Original Articles BACKGROUND: Adult‐onset Nieman–Pick 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‐onset 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. METHODS: Neurologic examination, whole exome sequence (WES), targeted sequence to establish genome phasing, and cytochemical and biochemical studies of fibroblast cultures were employed. RESULTS: 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 NPC1 gene—one 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. CONCLUSIONS: The study established the correct molecular diagnosis of biallelic, adult‐onset 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. John Wiley and Sons Inc. 2022-02-22 /pmc/articles/PMC9000929/ /pubmed/35192242 http://dx.doi.org/10.1002/mgg3.1906 Text en © 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Vo, Mary L.
Levy, Tess
Lakhani, Shenela
Wang, Chengbing
Ross, M. Elizabeth
Adult‐onset Niemann–Pick disease type C masquerading as spinocerebellar ataxia
title Adult‐onset Niemann–Pick disease type C masquerading as spinocerebellar ataxia
title_full Adult‐onset Niemann–Pick disease type C masquerading as spinocerebellar ataxia
title_fullStr Adult‐onset Niemann–Pick disease type C masquerading as spinocerebellar ataxia
title_full_unstemmed Adult‐onset Niemann–Pick disease type C masquerading as spinocerebellar ataxia
title_short Adult‐onset Niemann–Pick disease type C masquerading as spinocerebellar ataxia
title_sort adult‐onset niemann–pick disease type c masquerading as spinocerebellar ataxia
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9000929/
https://www.ncbi.nlm.nih.gov/pubmed/35192242
http://dx.doi.org/10.1002/mgg3.1906
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