Journal of Neurology

, Volume 262, Issue 11, pp 2557–2563 | Cite as

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

  • Matthis Synofzik
  • Florian Harmuth
  • Miriam Stampfer
  • Jennifer Müller vom Hagen
  • Ludger Schöls
  • Peter Bauer
Original Communication


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), giving a NPC1 patient frequency of 2/96 = 2.1 % in unexplained EOA and of 6/204 = 2.9 % in the total EOA series. NPC1 mutations are substantially enriched in unexplained EOA, demonstrating EOA as a risk-group for NP-C disease. Targeted high-throughput sequencing allows to identify also those NP-C patients with non-specific conditions where the diagnosis has initially been missed. This method does not require having considered NP-C during differential diagnosis, but allows identification of NP-C as part of the default analysis.


Ataxia Recessive ataxia Early onset ataxia Genetics Lysosomal storage diseases Prevalence 



Chronic external ophthalmoplegia


Exome sequencing project


Exome variant server


Frontotemporal lobar degeneration


Minor allele frequency


Niemann pick type C


Parkinson’s disease


Progressive supranuclear gaze palsy


Vertical supranuclear gaze palsy


Variant of uncertain significance



This study was supported by the Interdisciplinary Center for Clinical Research IZKF Tübingen (Grant 2191-0-0 to MS), the European Union (Grant F5-2012-305121 “NEUROMICS” to LS), and E-RARE grants of the German Ministry for Education and Research (BMBF) to the EUROSCAR project (grant 01GM1206) (to LS and PB). We are thankful to Professor Dr. Heiko Runz for his support on the updated Niemann–Pick type C disease variation database.

Compliance with ethical standards

Conflicts of interest

M. Sy, M. St, J. MvH and P. B. have each received travel expenses and presentation honoraria from Actelion Pharmaceuticals Ltd. The preparation of this manuscript (but not the initiation and the performance of the study) was sponsored by Actelion Pharmaceuticals Ltd. Matthew Reilly Ph.D. at InTouch Medical Ltd provided medical writing support in the preparation of this manuscript, paid for by Actelion Pharmaceuticals.

Supplementary material

415_2015_7889_MOESM1_ESM.docx (56 kb)
Supplementary material 1–3 (DOCX 56 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Matthis Synofzik
    • 1
    • 2
  • Florian Harmuth
    • 3
  • Miriam Stampfer
    • 3
  • Jennifer Müller vom Hagen
    • 1
    • 2
  • Ludger Schöls
    • 1
    • 2
  • Peter Bauer
    • 3
  1. 1.Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain ResearchUniversity of TübingenTübingenGermany
  2. 2.German Research Center for Neurodegenerative Diseases (DZNE)University of TübingenTübingenGermany
  3. 3.Institute of Medical Genetics and Applied GenomicsUniversity of TübingenTübingenGermany

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