Clinical and molecular characterization of Niemann–Pick types A/B patients

What is it about?

Niemann–Pick disease type A/B is a lysosomal storage disorder caused by mutations in the sphingomyelin phosphodiesterase-1 (SMPD1) gene which lead to a lysosomal acid sphingomyelinase (ASM) deficiency. Our aim was to analyze the molecular basis, clinical characteristics and genotype-phenotype relationships in 15 NPD type A/B patients. NPD diagnosis was established by the analysis of sphingomyelinase activity in leukocytes and/or cultured skin fibroblasts; biomarkers: chitotriosidase (CT) activity and CCL18-PARC concentration were also measured. SMPD1 genotypes were determined by sequencing the promoter region, each exon, most introns, and the 3′-UTR using overlapping fragments. As a result we found eight previously described mutations and seven novel mutations including four missense, two frameshift and one of splicing. The most prevalent mutations were p.Arg610del and p.Gly247Ser, which accounted for 33% of the total alleles. We have found seven patients homozygous for four different mutations providing insights into genotype-phenotype relationship and a large variety of clinical presentations in our cohort. In conclusion, we have found a huge heterogeneity of SMPD1 gene mutations and our results emphasize the difficulty of classifying patients into types A and B, supporting the idea of a continuum between these two classic phenotypes. No relationship between plasma CT activity and CCL18 and severity was observed.

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