Epidemiological, clinical and biochemical characterization of the p.(Ala359Asp) SMPD1 variant causing Niemann–Pick disease type B

Abstract

Niemann-Pick disease type B (NPDB) is a rare, inherited lysosomal storage disorder that occurs due to variants in the sphingomyelin phosphodiesterase 1 (SMPD1) gene and the resultant deficiency of acid sphingomyelinase (ASM) activity. While numerous variants causing NPDB have been described, only a small number have been studied in any detail. Herein, we describe the frequency of the p.(Ala359Asp) variant in the healthy Chilean population, and determine the haplotype background of homozygous patients to establish if this variant originated from a common founder. Genomic DNA samples from 1691 healthy individuals were analyzed for the p.(Ala359Asp) variant. The frequency of p.(Ala359Asp) was found to be 1/105.7, predicting a disease incidence of 1/44 960 in Chile, higher than the incidence estimated by the number of confirmed NPDB cases. We also describe the clinical characteristics of 13 patients homozygous for p.(Ala359Asp) and all of them had moderate to severe NPDB disease. In addition, a conserved haplotype and shared 280 Kb region around the SMPD1 gene was observed in the patients analyzed, indicating that the variant originated from a common ancestor. The haplotype frequency and mitochondrial DNA analysis suggest an Amerindian origin for the variant. To assess the effect of the p.(Ala359Asp) variant, we transfected cells with the ASM-p.(Ala359Asp) cDNA and the activity was only 4.2% compared with the wild-type cDNA, definitively demonstrating the causative effect of the variant on ASM function. Information on common variants such as p. (Ala359Asp) is essential to guide the successful implementation for future therapies and benefit to patients.

Types A and B Niemann-Pick disease

“…These and other findings have assisted physicians, genetic counselors and families in predicting the phenotypic outcome in individual NPD patients, and in the future may lead to large-scale screening for this disorder in specific populations. For example, one particularly interesting recent study examined a single mutation (A359D) that occurs in >90% of type B patients in Chile [61]. Screening for this mutation among healthy individuals living in Santiago indicated that the carrier frequency for type B NPD within Chile was ~1/106, predicting a disease incidence of ~1/45,000.…”

Lysosomal and Mitochondrial Liaisons in Niemann-Pick Disease

“…Although NPA and NPB are pan-ethnic, NPA is more frequent in individuals with Ashkenazi Jewish ancestry than in the general population, with an estimated carrier frequency close to 1:80 and a disease incidence of 1/40,000 (Schuchman and Desnick, 2014 ). In other populations, such as in Chile, the carrier frequency for the type B mutation A359D occurs in 90% of patients close to a 1:106 rate, predicting a disease incidence of 1/45,000 (Acuña et al, 2016a , b ).…”

“…More than 180 pathogenic mutations in the SMPD1 gene in patients with NPA and NPB have been identified, which are concentrated in exon two (Schuchman and Desnick, 2017 ). Recently, the ASMase crystal structure has been determined in humans (Xiong et al, 2016 ) and mouse (Gorelik et al, 2016 ), which may facilitate genotype-phenotype mutation analysis (Acuña et al, 2016b ; Zampieri et al, 2016 ).…”

SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants

“…Particularly, both p.L304P and p.R498L are frequent Ashkenazi Jewish mutations and have been clearly associated to the severe NPA phenotype in this population [Levran et al., , 1992]. However, 12 mutations (p.R230C, p.W246C, p.D253H, p.D253E, p.A283T, p.Q294K, p.L343P, p.A359D, p.M384I, p.H423Y, p.H577R, and p.R602P) cause a severe impairment of ASM activity and were found in homozygosity or in association with another severe mutation in NPB patients [Simonaro et al, , Pittis et al., ; Pavlů‐Pereira et al., ; Desnick et al., , Hollak et al., , Acuna et al., ]. It is worth noting that eight of them (p.R230C, p.D253H, p.D253E, p.Q294K, p.L343P, p.M384I, p.H423Y, and p.H577R) were found in NPB patients with an intermediate clinical phenotype [Simonaro et al, , Pittis et al., ; Pavlů‐Pereira et al., ; Desnick et al., , Hollak et al., ].…”