Phenotypic and genetic heterogeneity in Niemann-Pick disease type C: current knowledge and practical implications.

The eponym "Niemann-Pick disease" includes two metabolically distinct entities. Niemann-Pick type C (NPC) is characterized by unique abnormalities of intracellular transport of exogenous cholesterol with sequestration of unesterified cholesterol in lysosomes, while Niemann-Pick types A and B are acid sphingomyelinase deficiencies resulting from mutations in the gene coding for lysosomal sphingomyelinase. Current knowledge regarding abnormalities of cholesterol processing in cultured cells from NPC patients is reviewed. The wide spectrum of expression of the disease is outlined. Based on experience with more than 350 patients, the problems encountered in the author's laboratory in the diagnosis of patients are discussed, as well as the relatively poor correlation between clinical and biochemical phenotypes. Recent major developments are, furthermore, reviewed. Cell hybridization studies have established an intergenic heterogeneity within NPC, consisting of one major (90% of patients) and one minor complementation group. Both groups show a wide phenotypic heterogeneity. The major gene has been mapped to 18q11-12, while the minor gene has been excluded from this region of chromosome 18. The function of both genes is yet unknown.