Sphingolipid Disorders and the Neuronal Ceroid Lipofuscinoses or Batten Disease (Wolman Disease, Cholesteryl Ester Storage Disease, and Cerebrotendinous Xanthomatosis)

Boustany, Rose-Mary; Al-Shareef, Ibraheem; El-Haddad, Sariah

doi:10.1016/b978-0-12-383834-6.00109-9

Cited by 2 publications

(1 citation statement)

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“…The residual ASM activity has been regarded as one of the clinical features to distinguish NPA from NPB in Chinese people (13), while some bibliographic data that supports ASM residual activity threshold is not de nitive for discriminating between type A and B (23)(24)(25). Normally, < 5% of effective residual ASM activity in situ is observed in NPA, whereas 5-20% is detected in NPB (8, 26-28).…”

Section: Discussionmentioning

confidence: 99%

SMPD1 Expression Profile and Mutation Landscape Help Decipher Genotype–Phenotype Association and Precision Diagnosis for Acid Sphingomyelinase Deficiency

Wang

Qin

Huang

et al. 2022

Preprint

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Background Acid sphingomyelinase deficiency (ASMD) disorder, also known as Niemann–Pick disease (NPD) is a rare genetic disease caused by mutations in SMPD1 gene, which encodes sphingomyelin phosphodiesterase (ASM). Except for liver and spleen enlargement and lung disease, two subtypes (Type A and B) of NDP have different onset times, survival times, ASM activities, and neurological abnormalities. To comprehensively explore the genotype-phenotype association and pathophysiological characteristics of NPD, we collected 144 NPD cases with strict quality control through literature mining. Results The difference in ASM activity can differentiate NPD type A from other subtypes, with the ratio of ASM activity to the reference values being lower in type A (threshold 0.045 (4.45%)). Severe variations, such as deletion and insertion, can cause complete loss of ASM function, leading to type A, whereas relatively mild missense mutations generally result in type B. Among reported mutations, p.Arg3AlafsX76 mutation is highly prevalent in the Chinese population, and p.R608del mutation is common in Mediterranean countries. The expression profiles of SMPD1 from GTEx and single-cell RNA sequencing data of multiple fetal tissues showed that high expressions of SMPD1 can be observed in the liver, spleen, and brain tissues of adults and in hepatoblasts, hematopoietic stem cells, STC2_TLX1-positive cells, mesothelial cells of the spleen, vascular endothelial cells of the cerebellum and the cerebrum of fetuses, indicating that SMPD1 dysfunction is highly likely to have a significant effect on the function of those cell types during development and the clinicians need pay attention to these organs or tissues as well during diagnosis. In addition, we also predicted 21 new pathogenic mutations in the SMPD1 gene that potentially cause the NPD, signifying that more rare cases will be detected with those mutations in SMPD1. Conclusions Our study is the first one to elucidate the effects of SMPD1 mutation on cell types and at the tissue level, which provides new insights into the genotype-phenotype association and can help in the precise diagnosis of NPD.

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