Clinical, biochemical, and genotype-phenotype correlations of 118 patients with Niemann-Pick disease Types A/B
2021-05-05Clinical, biochemical, and genotype-phenotype correlations of 118 patients with Niemann-Pick disease Types A/B
Hum Mutat 2021 May;42(5):614-625. doi: 10.1002/humu.24192. Epub 2021 Mar 19.
PMID: 33675270
Jiayue Hu 1, Gustavo H B Maegawa 2, Xia Zhan
Highlights: This study contributes to the understanding of the natural history of NPA/B and assists in the development of efficacious treatments for patients afflicted with this devastating lysosomal storage disorder.
Abstract
Objective: The variants in the sphingomyelin phosphodiesterase-1 (SMPD1) gene cause autosomal recessive disorders called Niemann-Pick disease Type A ve B (NPA/B). The goal of this study was to describe and characterize a group of 118 individuals diagnosed with NPA/B based on clinical, biochemical, and molecular findings, as well as to discover solid links between laboratory findings and clinical manifestations.
Results: Increased plasma 7-ketocholesterol levels and decreased peripheral leukocyte acid sphingomyelinase activity were strongly associated with disease onset and severity of the clinical course. In 118 NPA/B patients, we found 92 distinct sequence SMPD1 variants, including 41 novel variants (19 NPA, 24 intermediate type, 75 NPB). The most common mutation was p.Arg602His, which was found in 9.3% of all alleles. A late-onset variant of the NPB phenotype was seen in patients homozygous for p.Arg602His or p.Asn522Ser. The early-onset NPB clinical form was linked to the homozygous SMPD1 mutation p.Tyr500His. The neuronopathic NPA clinical form was also linked to homozygous mutations p.His284SerfsX18, p.Phe465Ser, and p.Ser486Arg. The intermediate clinical form was linked to the homozygous variant p.Arg3AlafsX74.
Conclusion: Our research adds to our knowledge of NPA/B's natural history and aids in the development of effective therapies for individuals suffering from this life-threatening lysosomal storage disorder.
Keywords: Niemann-Pick disease Types A/B, SMPD1 variants, acid sphingomyelinase deficiency, biomarkers, genotype-phenotype correlation.