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ASMD

Acid sphingomyelinase deficiency (ASMD) (historically known as Niemann-Pick disease type A, A/B, and B) is an autosomal recessive disorder caused by pathogenic variants in the SMPD1 gene that results in a deficiency of the acid sphingomyelinase enzyme, leading to a subsequent accumulation of sphingomyelin and other lipids throughout the body, predominantly in the liver, spleen, and lungs.

Prevalence and Incidence

• Birth prevalence is approximately 0.4 to 0.6 in every 100,000 newborns. 
• ASMD occurs in persons of both sexes equally and is present in persons of all races. 
• Real birth prevalence is likely to be higher as many cases remain undiagnosed or inaccurately diagnosed due to low disease knowledge and awareness.6

Age of onset

• ASMD type A typically presents within the first few months of life.
• ASMD type A/B usually presents in infancy or childhood, whereas ASMD type B may present from childhood to adulthood, with a slower disease progression compared to ASMD type A.

 

ASMD has a spectrum of clinical phenotypes that range from a severe infantile form (ASMD type A), with severe and rapid neurodegeneration and death typically by the age of 3, to chronic progressive forms (ASMD type A/B and ASMD type B).

The most common presentations of ASMD are hepatosplenomegaly and interstitial lung disease. Other manifestations include:

• Recurrent respiratory infections.

• Liver dysfunction.

• Dyslipidemia, characterized by low HDL cholesterol.

• Thrombocytopenia.

• Bleeding.

• Delayed growth and puberty in children.

• Fatigue.

• Bone and joint pain.

• Osteopenia.

Neurological involvement is present in ASMD type A and type A/B.

A definitive diagnosis of ASMD requires the determination of the level of ASM in circulating leukocytes, fibroblast skin cultures, or dried blood spots. A diagnosis of ASMD is confirmed when ASM activity is absent or significantly reduced.

Sequencing of the SMPD1 gene may provide additional diagnostic confirmation if two pathogenic variants are found.

Enzyme replacement therapy (ERT) is an effective treatment option for non-CNS manifestations of ASMD in childhood and adults.

If ERT is not available or considered inappropriate, disease management is aimed at symptom control including dietary modifications and/or statin therapy to lower cholesterol levels, oxygen to treat severe cases of interstitial lung disease, and blood transfusions to treat patients with acute episodes of bleeding due to splenomegaly and low platelet counts.   Bone marrow transplantation has been associated with reductions in liver and spleen size, although complications secondary to the transplant procedure may be severe.

Life expectancy is typically reduced in patients with ASMD. Respiratory dysfunction and liver failure are the leading causes of death in patients with ASMD type B and A/B.

References

 

1.    Schuchman EH, Desnick RJ. Types A and B Niemann-Pick disease. Mol Genet Metab. 2017;120:27-33.

2.    McGovern, M. M., Dionisi-Vici, C., et all (2017). Consensus recommendation for a diagnostic guideline for acid sphingomyelinase deficiency. Genetics in medicine : official journal of the American College of Medical Genetics, 19(9), 967–974. https://doi.org/10.1038/gim.2017.7

3. McGovern MM, Avetisyan R, Sanson BJ, Lidove O. Disease manifestations and burden of illness in patients with acid sphingomyelinase deficiency (ASMD). Orphanet J Rare Dis. 2017 Feb 23;12(1):41. doi: 10.1186/s13023-017-0572-x. PMID: 28228103; PMCID: PMC5322625.

4.    Geberhiwot T, Wasserstein M, Wanninayake S, Bolton SC, Dardis A, Lehman A, Lidove O, Dawson C, Giugliani R, Imrie J, Hopkin J, Green J, de Vicente Corbeira D, Madathil S, Mengel E, Ezgü F, Pettazzoni M, Sjouke B, Hollak C, Vanier MT, McGovern M, Schuchman E. Consensus clinical management guidelines for acid sphingomyelinase deficiency (Niemann-Pick disease types A, B and A/B). Orphanet J Rare Dis. 2023 Apr 17;18(1):85. doi: 10.1186/s13023-023-02686-6. PMID: 37069638; PMCID: PMC10108815.

5.    Cassiman D, Packman S, Bembi B, Turkia HB, Al-Sayed M, Schiff M, Imrie J, Mabe P, Takahashi T, Mengel KE, Giugliani R, Cox GF. Cause of death in patients with chronic visceral and chronic neurovisceral acid sphingomyelinase deficiency (Niemann-Pick disease type B and B variant): Literature review and report of new cases. Mol Genet Metab. 2016 Jul;118(3):206-213. doi: 10.1016/j.ymgme.2016.05.001. Epub 2016 May 11. Erratum in: Mol Genet Metab. 2018 Dec;125(4):360. doi: 10.1016/j.ymgme.2017.09.005. PMID: 27198631.

6.    Mengel E, Muschol N, Weinhold N, Ziagaki A, Neugebauer J, Antoni B, Langer L, Gasparic M, Guillonneau S, Fournier M, Laredo F, Pulikottil-Jacob R. A retrospective study of morbidity and mortality of chronic acid sphingomyelinase deficiency in Germany. Orphanet J Rare Dis. 2024 Apr 13;19(1):161. doi: 10.1186/s13023-024-03174-1. PMID: 38615062; PMCID: PMC11015682. 7.    Pulikottil-Jacob R, Dehipawala S, Smith B, Athavale A, Gusto G, Chandak A, Khachatryan A, Banon T, Fournier M, Guillonneau S, Pollissard L, Munoz-Rojas MV. Survival of patients with chronic acid sphingomyelinase deficiency (ASMD) in the United States: A retrospective chart review study. Mol Genet Metab Rep. 2023 Dec 24;38:101040. doi: 10.1016/j.ymgmr.2023.101040. PMID: 38188692; PMCID: PMC10767269.