Autopsy pathology of infantile neurovisceral ASMD (Niemann-Pick Disease type A): Clinicopathologic correlations of a case report

Thurberg, Beth L.

doi:10.1016/j.ymgmr.2020.100626

Cited by 14 publications

(12 citation statements)

References 22 publications

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“…Functional ASM is crucial to prevent not only fatal lysosomal SM storage but also a secondary accumulation of cholesterol, lyso-SM, and glycolipids such as glucosylceramide and gangliosides GM2 and GM3 as observed in ASMD [53,65]. An extensive report on clinical course and autopsy findings of a three year old male patient with neurovisceral pathology was published recently [66]. For the diagnosis of ASMD, the plasma level lyso-SM, a biomarker for ASMD, is used [65].…”

Section: Emerging Functions Of Asm a Promiscuous Phospholipase C Cleaving Membrane Lipids Including Cer1p And Bmpmentioning

confidence: 99%

Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism

Breiden¹,

Sandhoff

2021

IJMS

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Here, we present the main features of human acid sphingomyelinase (ASM), its biosynthesis, processing and intracellular trafficking, its structure, its broad substrate specificity, and the proposed mode of action at the surface of the phospholipid substrate carrying intraendolysosomal luminal vesicles. In addition, we discuss the complex regulation of its phospholipid cleaving activity by membrane lipids and lipid-binding proteins. The majority of the literature implies that ASM hydrolyses solely sphingomyelin to generate ceramide and ignores its ability to degrade further substrates. Indeed, more than twenty different phospholipids are cleaved by ASM in vitro, including some minor but functionally important phospholipids such as the growth factor ceramide-1-phosphate and the unique lysosomal lysolipid bis(monoacylglycero)phosphate. The inherited ASM deficiency, Niemann-Pick disease type A and B, impairs mainly, but not only, cellular sphingomyelin catabolism, causing a progressive sphingomyelin accumulation, which furthermore triggers a secondary accumulation of lipids (cholesterol, glucosylceramide, GM2) by inhibiting their turnover in late endosomes and lysosomes. However, ASM appears to be involved in a variety of major cellular functions with a regulatory significance for an increasing number of metabolic disorders. The biochemical characteristics of ASM, their potential effect on cellular lipid turnover, as well as a potential impact on physiological processes will be discussed.

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Section: Emerging Functions Of Asm a Promiscuous Phospholipase C Cleaving Membrane Lipids Including Cer1p And Bmpmentioning

confidence: 99%

Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism

Breiden¹,

Sandhoff

2021

IJMS

View full text Add to dashboard Cite

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“…Renal involvement in ASMD has been reported in a few cases only. [11][12][13][14][15] These patients were young, representing severe phenotypes of ASMD with extensive manifestations at a young age, opposed to our patient who has the chronic visceral phenotype with an attenuated course of disease. In three out of four cases, findings of lipid accumulation in the kidneys were established postmortem without a clinical history of kidney injury.…”

Section: Discussionmentioning

confidence: 60%

“…[11][12][13][14] The publication by Thurberg is the only one reporting a mutation; however, this publication concerns a child with the infantile neurovisceral subtype of ASMD. 15 Renal involvement is rare in ASMD. Since the macrophage is the primary storage cell, similar to Gaucher disease (OMIM 230800), it was expected that the pathology resembled the pattern seen in the rare cases of renal involvement as described in Gaucher disease.…”

Section: Discussionmentioning

confidence: 99%

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Renal involvement in a patient with the chronic visceral subtype of acid sphingomyelinase deficiency resembles Fabry disease

et al. 2021

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Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease (LSD) in which sphingomyelin accumulates due to deficient acid sphingomyelinase. In the chronic visceral subtype, organ manifestations are generally limited to the spleen, liver, and lungs. We report a male patient with the chronic visceral subtype who developed proteinuria and renal insufficiency at the age of 49. In renal tissue, foam cells were observed in the glomeruli as well as sphingomyelin accumulation within podocytes, mesangial cells, endothelial cells, and tubular epithelial cells. Although macrophages are the primary storage cells in both ASMD and Gaucher disease, comparison to the histopathological findings in Gaucher and Fabry disease revealed a diffuse storage pattern in multiple renal cell types, closer resembling the pattern found in Fabry disease.

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“…In this study, low HDL-C was indeed detected in all 5 patients who had lipid profile tested. It has been hypothesized that low HDL-C may be attribute to the accumulation of sphingomyelin within the liver [ 21 ]. However, low HDL-C is also commonly detected in infants with liver manifestations, especially in those with cholestasis.…”

Section: Discussionmentioning

confidence: 99%

Neonatal cholestasis is an early liver manifestation of children with acid sphingomyelinase deficiency

et al. 2022

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Background Patients with acid sphingomyelinase deficiency (ASMD) may be referred to a hepatologist for liver manifestations. This study summarized the liver manifestations of patients with ASMD in the early disease course. Methods This study enrolled ASMD patients diagnosed by genetic tests between July 2016 and December 2020 in a national pediatric liver center. The significance of low High-density lipoprotein cholesterol (HDL-C) for aid diagnosis of ASMD in infancy was explored by reviewing 160 consecutive infants with liver manifestations, who underwent both genetic tests and lipid profile studies, between January 2020 and December 2020. Results A total of 7 patients were diagnosed as ASMD, and 10 known disease-causing variants were identified. Hepatosplenomegaly, elevated transaminases, and liver foam cells were observed in all the 7 patients at age ranging from 4 to 31 months. Low HDL-C was detected in 5 patients, cherry red spot in 4 patients, development delay in 3 patients, and interstitial lung diseases in 1 patient. Three ASMD patients developed cholestasis around 1 month of age, and bilirubin levels normalized at age ranging from 3 to 10 months. They had persistently elevated transaminases and hepatosplenomegaly, and died within 4 years of age. Among the 160 infants with liver manifestations, 125 (78.1%) had low HDL-C. Fifty-four had both low HDL-C and splenomegaly, including 48 cholestatic infants, but only 1 (1.9%, 1/54) infant without cholestasis was diagnosed as ASMD. Conclusions ASMD can manifest as neonatal cholestasis in the early disease course. Cholestasis is a pitfall when low HDL-C is used for aid diagnosis of ASMD in infants with splenomegaly.

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Autopsy pathology of infantile neurovisceral ASMD (Niemann-Pick Disease type A): Clinicopathologic correlations of a case report

Cited by 14 publications

References 22 publications

Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism

Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism

Renal involvement in a patient with the chronic visceral subtype of acid sphingomyelinase deficiency resembles Fabry disease

Neonatal cholestasis is an early liver manifestation of children with acid sphingomyelinase deficiency

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