Acid sphingomyelinase deficiency: Prevalence and characterization of an intermediate phenotype of Niemann-Pick disease

Wasserstein, Melissa P.; Aron, Alan M.; Brodie, Scott E.; Simonaro, Calogera M.; Desnick, Robert J.; McGovern, Margaret M.

doi:10.1016/j.jpeds.2006.06.034

Cited by 111 publications

(94 citation statements)

References 28 publications

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“…However, clinical data on S-ASM activity in NPD patients remain limited because in most studies only cellular L-ASM activity is determined (Vanier et al, 1980;Pavlu-Pereira et al, 2005). Because lysosomal hypertrophy is a hallmark of lysosomal storage disorders, a parallel assessment of the acidic compartment volume combined with L-and S-ASM activities could provide a basis for genotype-phenotype correlations, particularly to explain the large heterogeneity of symptom severity observed in NPD patients with an intermediate phenotype (Pavlu-Pereira et al, 2005;Wasserstein et al, 2006). Interestingly, there is growing support for a genetic convergence of lysosomal storage disorders and Parkinson's disease (Deng et al, 2014).…”

Section: Genetic Impact On S-asm Activitymentioning

confidence: 99%

Secretory sphingomyelinase in health and disease

Kornhuber

Rhein

Müller

et al. 2015

Biological Chemistry

124

138

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Acid sphingomyelinase (ASM), a key enzyme in sphingolipid metabolism, hydrolyzes sphingomyelin to ceramide and phosphorylcholine. In mammals, the expression of a single gene, SMPD1, results in two forms of the enzyme that differ in several characteristics. Lysosomal ASM (L-ASM) is located within the lysosome, requires no additional Zn 2+ ions for activation and is glycosylated mainly with high-mannose oligosaccharides. By contrast, the secretory ASM (S-ASM) is located extracellularly, requires Zn 2+ ions for activation, has a complex glycosylation pattern and has a longer in vivo half-life. In this review, we summarize current knowledge regarding the physiology and pathophysiology of S-ASM, including its sources and distribution, molecular and cellular mechanisms of generation and regulation and relevant in vitro and in vivo studies. Polymorphisms or mutations of SMPD1 lead to decreased S-ASM activity, as detected in patients with Niemann-Pick disease B. Thus, lower serum/ plasma activities of S-ASM are trait markers. No genetic causes of increased S-ASM activity have been identified. Instead, elevated activity is the result of enhanced release (e.g., induced by lipopolysaccharide and cytokine stimulation) or increased enzyme activation (e.g., induced by oxidative stress). Increased S-ASM activity in serum or plasma is a state marker of a wide range of diseases. In particular, high S-ASM activity occurs in inflammation of the endothelium and liver. Several studies have demonstrated a correlation between S-ASM activity and mortality induced by severe inflammatory diseases. Serial measurements of S-ASM reveal prolonged activation and, therefore, the measurement of this enzyme may also provide information on past inflammatory processes. Thus, S-ASM may be both a promising clinical chemistry marker and a therapeutic target.

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Section: Genetic Impact On S-asm Activitymentioning

confidence: 99%

Secretory sphingomyelinase in health and disease

Kornhuber

Rhein

Müller

et al. 2015

Biological Chemistry

124

138

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“…[2][3][4][5][6][7] In addition, there is a subset of variant patients who survive early childhood but have progressive neurologic findings including ataxia, variable degrees of developmental delay, and peripheral neuropathy. 8,9 Accompanying this marked phenotypic variability among patients with NP-B is a broad range of disease severity. For example, age at clinical presentation can range from early childhood to the fourth or fifth decades of life.…”

Section: Original Research Article © American College Of Medical Genementioning

confidence: 99%

“…Pulmonary function testing typically shows a restrictive pattern of lung involvement with abnormal diffusing capacity, compatible with interstitial lung disease. 8 Chest radiographs in affected patients reveal interstitial infiltrates with reticulonodular changes and areas of ground-glass density that may be out of proportion to clinical findings. 16 Severely affected patients may exhibit cough, shortness of breath, and recurrent respiratory infections, 17 and some patients develop chronic oxygen dependence with progressive pulmonary failure.…”

Section: Genetics In Medicine | Volume 15 | Number 8 | August 2013mentioning

confidence: 99%

Morbidity and mortality in type B Niemann–Pick disease

McGovern

Lippa

Bagiella

et al. 2013

Genetics in Medicine

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114

168

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“…2,4,5 Patients with intermediate phenotypes between types A and B NPD have also been described. 6,7 These patients represent the expected continuum caused by inheriting different variants in the ASM gene. 2 More than 100 pathogenic variants in the SMPD1 gene have been identified throughout the gene, albeit most are located in exon 2.…”

Section: Introductionmentioning

confidence: 99%

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

Acuña

Martínez

Moraga³

et al. 2015

Eur J Hum Genet

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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.

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Acid sphingomyelinase deficiency: Prevalence and characterization of an intermediate phenotype of Niemann-Pick disease

Cited by 111 publications

References 28 publications

Secretory sphingomyelinase in health and disease

Secretory sphingomyelinase in health and disease

Morbidity and mortality in type B Niemann–Pick disease

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

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