Niemann-Pick disease: mutation update, genotype/phenotype correlations, and prospects for genetic testing

Niemann-Pick Disease (NPD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of acid sphingomyelinase (ASM). NPD occurs in two forms, neuronopathic Type A and nonneuronopathic Type B. The incidence of Type A NPD is highest among Ashkenazi Jews. Type B NPD is more common in non-Jews but has been reported in Ashkenazi Jews. Different mutations in ASM are presumed to be responsible for the different NPD phenotypes. Three mutations are predicted to account for > 95% of all Type A NPD chromosomes among Ashkenazi Jews (L302P, R496L, fsP330). Based on limited screens for these mutations among Ashkenazi Jews, a carrier frequency for Type A NPD of 1:90 is reported for this population. Less is known about mutations responsible for Type B NPD, although one mutation (delta R608) has been identified in both Ashkenazi Jews and non-Jews. Screening of the Ashkenazi Jewish population to detect > 95% of NPD carriers can be accomplished with a four-mutation panel that includes L302P, R496L, fsP330, and delta R608, the three predominant Type A mutations and one recurrent Type B mutation.