NPC1 is enriched in unexplained early onset ataxia: a targeted high-throughput screening

Journal of Neurology
Matthis SynofzikPeter Bauer

Abstract

Niemann-Pick disease type C (NP-C) is a rare autosomal-recessive neurodegenerative disease featuring pleiotropic neurological, psychiatric and visceral manifestations. Since many of the adult manifestations can be non-specific or missed, NP-C often goes undetected in adult-onset patients. Here we hypothesized that targeted high-throughput sequencing allows identifying NP-C patients among subjects with unexplained early-onset ataxia (EOA) and, moreover, that this population is enriched for NPC1 mutations. From 204 consecutive EOA patients, all 108 subjects with an established diagnosis were removed (including 4 NPC1 patients), yielding a target cohort of 96 subjects with unexplained EOA, but without primary suspicion of NP-C. This cohort was investigated for NPC1/NPC2 mutations using a high-coverage HaloPlex gene panel including 122 ataxia genes. Among 96 samples, we identified 4 known NPC1 mutations, 3 novel NPC1 missense variants of uncertain significance (VUS) and 1 novel NPC2 missense VUS. The total mutant allele frequency (8/192 = 4.17 %) was significantly enriched compared with control population data (1.57 %; p = 0.011). Two NPC1-positive patients were identified (both with non-specific incipient clinical features), givin...Continue Reading

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Citations

Dec 8, 2015·Cerebellum & Ataxias·David BargielaMarios Hadjivassiliou
Mar 22, 2016·The International Journal of Neuroscience·Vincenzo Di LazzaroStefano De Santis
Feb 15, 2017·Movement Disorders : Official Journal of the Movement Disorder Society·Matthis Synofzik, Rebecca Schüle
Mar 10, 2017·Current Medical Research and Opinion·Christian J HendrikszStefan A Kolb
Feb 20, 2018·The World Journal of Biological Psychiatry : the Official Journal of the World Federation of Societies of Biological Psychiatry·Olivier BonnotMark Walterfang
Sep 16, 2017·The World Journal of Biological Psychiatry : the Official Journal of the World Federation of Societies of Biological Psychiatry·Olivier BonnotMarc C Patterson
Dec 18, 2018·Movement Disorders : Official Journal of the Movement Disorder Society·Darius Ebrahimi-FakhariAlexander Münchau
Jan 28, 2018·Journal of Medical Case Reports·Dominick Amato, Mary Anne Patterson
Feb 13, 2018·Neurology. Clinical Practice·Marc C PattersonThorsten Marquardt
Jan 21, 2017·Journal of Medical Case Reports·Ferdinando CeravoloDaniela Concolino
Jun 18, 2016·Journal of Neurology·Matthis SynofzikStefan Kolb
Oct 23, 2019·International Journal of Molecular Sciences·Xiao FengJan Lukas

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