Study on Niemann-Pick Disease Yields New Insights, Novel Variants

A total of 92 gene variants were sequenced, 41 of which were novel.

A new report offers novel insights into links between the clinical, biochemical, and genetic characteristics of Niemann-Pick disease.

The study, which focused on more than 100 Chinese patients with type A or B Niemann-Pick disease (NPA/B), was published in the journal Human Mutation. It described apparent markers of disease onset and severity, as well as newly identified variants of the main gene involved in the disorder, sphingomyelin phosphodiesterase‐1 (SMPD1).

In NPA/B, the SMPD1 mutation leads to a decrease in acid sphingomyelinase (ASM) activity, and the accumulation of sphingomyelin and other sphingolipids, which eventually become toxic, explained corresponding author Huiwen Zhang, PhD, of the Shanghai Jiao Tong University School of Medicine in China, and colleagues. Niemann-Pick type A is a neuronopathic form of the disease. It is the most severe type, and typically results in death by age 2 or 3. Niemann-Pick type B is typically centered around the liver, has a slower onset, and later involves respiratory insufficiency and/or neurological degeneration, the authors said.

Although the basic outlines of the disease have been explicated, a number of important questions remain, including the connection between ASM activity and disease severity, as well as apparent genetic variations in the disease.

“Given the broad range of SMPD1 variants and their different prevalence in distinct ethnic groups, it is essential to delineate the potential genotype‐phenotype correlations in Chinese NPA/B patients,” Zhang and colleagues wrote.

The investigators launched a study of 118 patients who had been diagnosed with NPA/B between 2007 and 2019, and for whom periodic clinical assessments were available. The patients were analyzed by peripheral leukocyte ASM activity levels, plasma 7‐ketocholesterol (7-KC) measurements, and SMPD1 gene sequencing.

The investigators found patients with peripheral leukocyte ASM activity had an inverse correlation with NPA/B disease severity, including lower ASM activity among the patients with NPA compared with those with NPB.

Increased plasma 7-KC levels were also found to be significantly correlated with disease phenotype. Overall, patients with NPA/B had 7-KC levels 43-fold higher than a reference group. Patients with NPB had significantly lower plasma 7-KC levels than patients with NPA or an intermediate clinical form of Niemann-Pick.

In their genetic analysis, the authors sequenced 92 different SMPD1 variants, 41 of which were novel.

“The most prevalent mutation was p.Arg602His, which accounted for 9.3% of the alleles,” the authors said. “Patients homozygous for p.Arg602His or p.Asn522Ser showed a late-onset form of the NPB phenotype. The homozygous SMPD1 variant p.Tyr500His correlated with the early‐onset NPB clinical form.”

The authors said the homozygous variants p.His284SerfsX18, p.Phe465Ser, and p.Ser486Arg were associated with the neuronopathic NPA clinical form, and the homozygous variant p.Arg3AlafsX74 was associated with the intermediate clinical form.

Zhang and colleagues concluded that their study can help investigators better understand the various phenotypes and genotypes of Niemann-Pick, and enable more personalized therapies in the future.

“This study contributes to the knowledge of NPA/B and will further assist in the development of more effective and individualized treatments for patients afflicted with this devastating lysosomal storage disorder,” they concluded.


Hu J, Maegawa GHB, Zhan X, et al. Clinical, biochemical, and genotype-phenotype correlations of 118 patients with Niemann-Pick disease Types A/B. Hum Mutat. 2021;42(5):614-625. doi:10.1002/humu.24192

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