NPC1 is enriched in unexplained early onset ataxia: a targeted high-throughput screening.
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.
Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany. matthis.synofzik@uni-tuebingen.de.|German Research Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany. matthis.synofzik@uni-tuebingen.de.
Matthis
M
Synofzik
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Florian
F
Harmuth
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Miriam
M
Stampfer
Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.|German Research Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany.
Jennifer
J
Müller Vom Hagen
Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.|German Research Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany.
Ludger
L
Schöls
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Peter
P
Bauer
D000328:Adult; D017668:Age of Onset; D001259:Ataxia / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D005060:Europe; D005820:Genetic Testing; D006023:Glycoproteins / Q000235:genetics; D057166:High-Throughput Screening Assays; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000235:genetics*; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics*; D033921:Vesicular Transport Proteins
D002352:Carrier Proteins; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; C104585:NPC2 protein, human; D000077296:Niemann-Pick C1 Protein; D033921:Vesicular Transport Proteins
Ataxia; Early onset ataxia; Genetics; Lysosomal storage diseases; Prevalence; Recessive ataxia