Niemann-Pick Disease Types A and B via the SMPD1 Gene

Niemann-Pick Disease (NPD) is one of several disorders of sphingolipid metabolism known as sphingolipidoses. NPD Types A and B (NPD-A and NPD-B) both result from deficient activity of acid-sphingomyelinase (ASM) and subsequent accumulation of sphingomyelin and other lipids in tissues. NPD-A and B are differentiated based on the age of onset, progression and clinical features. NPD-A is a uniformly fatal neurodegenerative disease with onset before the age of 6 months and death by the age of 3 years. The clinical hallmarks of NPD-A are hepatosplenomegaly, cherry-red maculae, failure to thrive, hypotonia, and severe psychomotor retardation. NPD-B is heterogeneous. Symptoms may begin in early childhood or adulthood and progression rate varies among affected individuals, with survival into adulthood. Clinical features of NPD-B may include hepatosplenomegaly, hematological findings, frequent respiratory infections and growth retardation. There is little or no central nervous involvement in NPD-B (Schuchman et al. In: Scriver et al. eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed.:3589–3610, 2001). ASM deficiency affects ~ 1:250,000 individuals (Meikle et al. JAMA 281(3):249-254, 1999). Both forms of the disease arise worldwide with high incidence in individuals of Turkish, Saudi and North African origins; however, the incidence of NPD-A is highest in Ashkenazi Jewish populations (Simonaro et al. Am J Hum Genet 71(6):1413-1419, 2002).

NPD-A and B are inherited in an autosomal recessive manner and result from mutations in the SMPD1 gene (Levran et al. Proc Natl Acad Sci USA 88(9):3748-3752, 1991). SMPD1 encodes the ASM, which catalyzes the hydrolysis of sphingomyelin to phosphorylcholine and ceramide. Although over 160 mutations distributed along the gene have been detected in patients with NPD-A and B, four common mutations have been reported. Three of these mutations (Leu304Pro, Arg498Leu and Phe333Serfs*52) account for ~ 95% of patients with NPD-A, and one recurrent mutation, Arg608del, is responsible for most cases of NPD-B of Ashkenazi Jewish origin (Schuchman and Miranda. Genet Test 1(1):13-19, 1997). The majority of mutations are missense. However, nonsense, splicing, small insertions or deletions have been reported. To date, no pathogenic regulatory variants or large deletions have been reported.

Paternal imprinting at the SMPD1 gene has been reported; and heterozygous carrier individuals may therefore develop NPD-B (Simonaro et.al. Am J Hum Genet 78(5): 865-870, 2006).

This test detects ~99% of SMPD1 mutations (McGovern, M.M. and Schuchman, E. H. GeneReviews, 2009).

Thus far, no gross deletions or duplications have been reported in SMPD1 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the SMPD1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.