Do heterozygous mutations of Niemann–Pick type C predispose to late-onset neurodegeneration: a review of the literature
Monogenic diseases are important models for the study of neurodegenerative diseases, such as Parkinson’s disease (PD) and dementia. Notably, for some disorders, homozygosity is associated with a complex metabolic disease, while heterozygosity predisposes to late-onset neurodegeneration. For instance, biallelic glucocerebrosidase gene mutations cause Gaucher’s disease, while heterozygous mutations are a common genetic risk factor for late-onset PD. Little is known about similar risks of related diseases, such as Niemann–Pick type C (NPC). Given that both conditions map into related, i.e., lysosomal, pathways, we hypothesize a similar risk of single-NPC gene mutations. Indeed, there is increasing evidence based on clinical observations in humans and animal studies. Here we review the current knowledge of NPC heterozygosity.
Family history studies suggest a high proportion of late-onset neurodegenerative diseases in NPC families. We identified 19 cases with heterozygous NPC mutations in the literature who presented with a neurodegenerative disease, including levodopa-responsive PD, atypical parkinsonism (PSP, CBD), dystonia or dementia with a mean age at onset of about 57 years (range 8–87). Consistent splenomegaly and mildly abnormal filipin staining results have also been reported in heterozygous gene mutation carriers. Imaging and pathological data support this notion.
This finding has wider implications in so far as NPC-related forms of Parkinsonian syndromes, dementia, motor neuron disease and other neurodegenerative disorders may benefit from NPC-mechanistic therapies, in particular related to lysosomal dysfunction. Further research is warranted to generate systematic data of heterozygous mutation carriers, including longitudinal data.
KeywordsNiemann–Pick type C Heterozygosity Late-onset neurodegeneration Biomarker Risk factor Lysosomal storage disease Gaucher’s disease
We thank Baccara Hizli and Dr. Eva Schulte for useful discussion.
SAS and ST wrote the first draft; JH, MS and TBE review and critique.
SAS is supported by the Verum-Stiftung, the Ara Parseghian Medical Research Foundation and the LMU Clinician Scientist Programme. She received consultation fees from Actelion Pharma. ST is supported by the Neuronal Ceroid Lipofuscinosis (NCL) foundation and a bilateral project between the Deutsche Akademische Austauschdienst (DAAD) and the Ministry of Science and Education, Republic of Croatia. MS is Joint Chief Editor of the Journal of Neurology, Editor in Chief of Frontiers of Neuro-otology and Section Editor of F1000. He has received speaker’s honoraria from Abbott, Actelion, Auris Medical, Biogen, Eisai, Grünenthal, GSK, Henning Pharma, Interacoustics, MSD, Otometrics, Pierre-Fabre, TEVA, UCB. He is a shareholder of IntraBio. He acts as a consultant for Abbott, Actelion, AurisMedical, Heel, IntraBio and Sensorion. TBE received honoraria for lecturing from Actelion and Sanofi-Genzyme.
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Conflicts of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
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