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

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.