High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets

Abstract

PurposeNiemann-Pick disease, type C (NPC) is a recessive, neurodegenerative, lysosomal storage disease caused by mutations in either NPC1 or NPC2. The diagnosis is difficult and frequently delayed. Ascertainment is likely incomplete due to both these factors and that the full phenotypic spectrum may not have been fully delineated. Given the recent development of a blood-based diagnostic test and development of potential therapies, it is important to understand the incidence of NPC and to define at risk patient populations.MethodWe evaluated data from four large massively parallel exome sequencing data sets. Variant sequences were identified and classified as pathogenic or non-pathogenic based on a combination of literature review and bioinformatic analysis. This methodology provided an unbiased approach to determining the allele frequency.ResultsOur data suggests an incidence rate for NPC1 and NPC2 of 1/92,104 and 1/2,858,998, respectively. However, evaluation of common NPC1 variants, suggests that there may be a late-onset NPC1phenotype with a markedly higher incidence on the order of 1/20,000-39,000.ConclusionsWe determined a combined incidence of classical NPC of 1/89,229 or 1.12 affected patients per 100,000 conceptions, but predict incomplete ascertainment of a late-onset phenotype of NPC1. This finding strongly supports the need for increased screening of potential patients.

The Spectrum of Niemann-Pick Type C Disease in Greece

“…Also, only two siblings presented with an adult neurological onset, making the contribution of this disease form much lower than described in recent large cohorts from three countries (Jahnova et al 2014;Stampfer et al 2013;Imrie et al 2015). This strongly suggests decreased awareness regarding NPC among adult neurologists, which is in good agreement with probable underdiagnosis of mild and late-onset forms (Wassif et al 2016).…”

“…However, the extensive phenotypic heterogeneity of NPC that shows a broad clinical spectrum ranging from a neonatal rapidly fatal form to an adult onset chronic neurodegenerative disease, along with the relative difficulty of laboratory testing, makes the estimation of true prevalence difficult. While recent data from massive parallel sequencing are in fairly good agreement with these estimations for "classical" clinical forms of the disease, they also suggest a high incidence of unrecognized, mild adult onset forms (Wassif et al 2016). In Greece, the Institute of Child Health is the only center offering laboratory diagnosis for lysosomal storage diseases, including NPC.…”

Preliminary Results on Long-Term Potentiation-Like Cortical Plasticity and Cholinergic Dysfunction After Miglustat Treatment in Niemann-Pick Disease Type C

“…This autosomal recessive lysosomal storage disorder (LSD) is caused by mutations of either the NPC1 gene (in 95% of families) (Carstea et al 1997) or the NPC2 gene (Naureckiene et al 2000). The incidence of NPC is estimated to be one in every 100,000 live births, although the late-onset phenotypes or variant forms may have a much higher incidence, ranging from 1:19,000 to 1:36,000 (Wassif et al 2015).…”

Differential response of the liver to bile acid treatment in a mouse model of Niemann-Pick disease type C

“…Niemann-Pick disease type C (NPC) is a rare progressive neurodegenerative lysosomal disorder, which affects 1:100,000 live births 1, 2 . In addition to the central nervous system, the liver also plays a role in this disease, either presenting in infancy as cholestatic jaundice or if these patients survive as elevated levels of liver enzymes suggestive of chronic liver dysfunction 1 .…”