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Do heterozygous mutations of Niemann–Pick type C predispose to late-onset neurodegeneration: a review of the literature

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Abstract

Background/methods

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.

Results

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.

Discussion/conclusion

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.

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Acknowledgements

We thank Baccara Hizli and Dr. Eva Schulte for useful discussion.

Funding

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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Authors and Affiliations

  1. Department of Neurology, Ludwig-Maximilians-University, Marchioninistr 15, 81377, Munich, Germany

    Susanne A. Schneider, Michael Strupp & Tatiana Bremova-Ertl

  2. German Center for Neurodegenerative Diseases (DZNE) Within the Helmholtz Association, Feodor-Lynen-Strasse 17, Munich, Germany

    Sabina Tahirovic

  3. Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK

    John Hardy

  4. Department of Neurology, Inselspital, University Hospital Bern, Bern, Switzerland

    Tatiana Bremova-Ertl

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  1. Susanne A. Schneider
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  2. Sabina Tahirovic
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SAS and ST wrote the first draft; JH, MS and TBE review and critique.

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Correspondence to Susanne A. Schneider.

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Schneider, S.A., Tahirovic, S., Hardy, J. et al. Do heterozygous mutations of Niemann–Pick type C predispose to late-onset neurodegeneration: a review of the literature. J Neurol 268, 2055–2064 (2021). https://doi.org/10.1007/s00415-019-09621-5

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  • DOI: https://doi.org/10.1007/s00415-019-09621-5

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