Niemann-Pick disease type C: Spectrum of HE1 mutations and genotype/phenotype correlations in the NPC2 group

In Niemann-Pick disease type C (NPC), a genetic heterogeneity with two comp lementation groups-NPC1, comprising greater than or equal to 95% of the fam ilies, and NPC2-has been demonstrated. Mutations in the NPC1 gene have now been well characterized. HE1 was recently identified as the gene underlying the very rare NPC2. Here we report the first comprehensive study of eight unrelated families with NPC2, originating from France, Algeria, Italy, Germ any, the Czech Republic, and Turkey. These cases represent essentially all patients with NPC2 who have been reported in the literature, as well as tho se known to us. All 16 mutant alleles were identified, but only five differ ent mutations, all with a severe impact on the protein, were found; these f ive mutations were as follows: two nonsense mutations (E20X and E118X), a 1 -bp deletion (27delG), a splice mutation (IVS2+5G -->A), and a missense mut ation (S67P) resulting in reduced amounts of abnormal HE1 protein. E20X, wi th an overall allele frequency of 56%, was established as the common mutant allele. Prenatal diagnosis was achieved by mutation analysis of an uncultu red chorionic-villus sample. All mutations except 27delG were observed in a homozygous state, allowing genotype/phenotype correlations. In seven famil ies (with E20X, E118X, S67P, and E20X/27delG mutations), patients suffered a severe and rapid disease course, with age at death being 6 mo-4 years. A remarkable feature was the pronounced lung involvement, leading, in six pat ients, to early death caused by respiratory failure. Two patients also deve loped a severe neurological disease with onset during infancy. Conversely, the splice mutation corresponded to a very different clinical presentation, with juvenile onset of neurological symptoms and prolonged survival. This mutation generated multiple transcripts, including a minute proportion of n ormally spliced RNA, which may explain the milder phenotype.