Niemann-Pick Disease Type C: Spectrum of HE1 Mutations and Genotype/Phenotype Correlations in the NPC2 Group

Abstract

In Niemann-Pick disease type C (NPC), a genetic heterogeneity with two complementation groups--NPC1, comprising > or =95% of the families, 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, Germany, the Czech Republic, and Turkey. These cases represent essentially all patients with NPC2 who have been reported in the literature, as well as those known to us. All 16 mutant alleles were identified, but only five different mutations, all with a severe impact on the protein, were found; these five mutations were as follows: two nonsense mutations (E20X and E118X), a 1-bp deletion (27delG), a splice mutation (IVS2+5G-->A), and a missense mutation (S67P) resulting in reduced amounts of abnormal HE1 protein. E20X, with an overall allele frequency of 56%, was established as the common mutant allele. Prenatal diagnosis was achieved by mutation analysis of an uncultured chorionic-villus sample. All mutations except 27delG were observed in a homozygous state, allowing genotype/phenotype correlations. In seven families (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 patients, to early death caused by respiratory failure. Two patients also developed 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 normally spliced RNA, which may explain the milder phenotype.

Niemann-Pick Type C-2 Disease: Identification by Analysis of Plasma Cholestane-3β,5α,6β-Triol and Further Insight into the Clinical Phenotype

“…Since systemic symptoms precede neurological signs, it is likely that these patients did not live long enough to develop characteristic neurological symptoms. These findings were also mentioned by Millat et al (2001), who described six NPC2 patients having a short lifespan, 4 of those did not show any neurological symptoms and died of respiratory failure in the first year of life. Two other patients were described who survived until 19 month and 4 years, respectively.…”

“…One patient carrying the homozygous p.E118X mutation also came from Germany and showed a similar clinical phenotype (Schofer et al 1998;Millat et al 2001). An Algerian patient described by Verot et al (2007) with the same mutation as patient 2 did not show a pronounced pulmonary involvement.…”

“…Usually, NPC2 patients present with a broad spectrum of clinical severity including progressive neurological dysfunction (Millat et al 2001;Verot et al 2007;Alavi et al 2013;Kl€ unemann 2002). However, in these cases, initial neurological symptoms were unspecific and did not lead to NPC diagnosis.…”

“…The diagnosis of Niemann-Pick type C-2 was confirmed by a genetic analysis of the NPC2 gene revealing the homozygous mutation c.352G>T (p.E118X). This mutation leads to a premature stop codon and has been associated with a severe phenotype of Niemann-Pick type C-2 before (Millat et al 2001;Schofer et al 1998).…”

“…To date, more than 300 mutations have been described in the NPC1 gene; about 20 mutations have been reported in the NPC2 gene. Most NPC2 mutations lead to a severe phenotype, frequently presenting with pronounced pulmonary involvement (Millat et al 2001;Verot et al 2007).…”