Acid Sphingomyelinase Deficiency

ASMD, ASM Deficiency, ASM-deficient Niemann-Pick disease, Acide Sphingomyelinase-deficient Niemann-Pick disease, Niemann-Pick Disease


Acid Sphingomyelinase Deficiency (ASMD), also known as Niemann-Pick Disease Types A (NPD A) and Type B (NPD B), is a rare lysosomal storage disease. It is a serious and potentially life-threatening genetic disorder that causes accumulation of the unmetabolized lipid sphingomyelin in cells, resulting in damage to major organ systems.

ASMD is represented by a broad clinical spectrum of disease, with neurological and visceral involvement, including an acute infantile neurovisceral form (also known as Niemann-Pick disease type A) which is uniformly fatal in infancy, a chronic visceral form (also known as Niemann-Pick disease type B) which presents with significant disease-related morbidities in multiple organ systems but without neurological symptoms, and a chronic neurovisceral form (also known as variant or intermediate type) which falls between the two ends of the clinical spectrum.

Symptoms - Acid Sphingomyelinase Deficiency

Infantile neurovisceral ASMD has an onset in early infancy and is marked by progressive and eventually massive hepatosplenomegaly, progressive neurological symptoms, pulmonary damage, and cholesterol abnormalities from the earliest age studied, as well as markedly reduced platelet counts. Other symptoms include respiratory and gastrointestinal, cherry red maculae, feeding problems, failure to thrive, and irritability.

Chronic visceral ASMD has a variable age of onset from infancy to adulthood. Patients with chronic visceral ASMD show similar morbidities of hepatosplenomegaly, progressive pulmonary dysfunction, thrombocytopenia, and dyslipidemia. These patients do not show the acute neurodegeneration seen in patients with infantile neurovisceral ASMD. They may develop clinically significant skeletal disease, cardiac valve abnormalities, stunted growth, and delayed puberty associated with the advancement of disease in the various organ systems.

Chronic neurovisceral ASMD presents with similar symptoms as the chronic visceral form of the disease, but these patients also develop neurologic symptoms of gross motor delay, ataxia and learning disability.

Causes - Acid Sphingomyelinase Deficiency

ASMD is an autosomal recessive genetic disorder caused by mutations in the SMPD1 gene that encodes for the enzyme acid sphingomyelinase (ASM), which metabolizes sphingomyelin.

Sphingomyelin is a major plasma membrane phospholipid involved in various cellular processes, including cell proliferation and cell cycle progression. When not metabolized, sphingomyelin accumulates in cells of the monocyte-macrophage system; this accumulation can cause substantial organ damage, particularly in the liver, spleen, and lung, and in severe cases, neuronopathic damage. 

Prevention - Acid Sphingomyelinase Deficiency

Currently, there are no approved treatment options for patients with ASMD

Diagnosis - Acid Sphingomyelinase Deficiency

The rarity of ASMD, heterogeneity of its manifestations, and challenging differential diagnosis can result in delayed diagnosis and management of patients.

An initial diagnosis is often based on biochemical testing showing low residual ASM enzyme activity using dried blood spots as blood-based assays. Additional confirmatory testing options of ASM activity include leukocytes, peripheral blood lymphocytes, and skin fibroblast cultures.

Additional diagnostic confirmation can be achieved using molecular genetic testing to identify
2 disease-causing alleles in the SMPD1 gene; however, molecular testing should not be substituted for the assessment of reduced ASM activity through biochemical testing.  Identifying the disease-causing alleles facilitates individual genetic counseling and carrier screening. 

Prognosis - Acid Sphingomyelinase Deficiency

Infantile neurovisceral ASMD is uniformly fatal, typically by 3 years of age. Although patients with chronic ASMD may die in childhood due to complications of the disease, many patients survive into adulthood. In chronic visceral ASMD, the leading causes of death are respiratory and liver failure.

Treatment - Acid Sphingomyelinase Deficiency

There are currently no curative therapies for ASMD. Some experimental approaches including bone marrow transplantation, total lung lavage and amniotic cell transplant have been attempted but do not have a favorable benefit/risk ratio owing to their uncertain impact on short- and long-term disease outcomes and considerable risk of complications. Splenectomy may be required in cases of extensive spleen necrosis with loss of function or rupture; however, it is generally not recommended as it may exacerbate pulmonary disease. Thus, management of patients with ASMD is limited to supportive care and palliation, which requires a multidisciplinary approach. Physical and occupational therapy in infants with NPD A may be beneficial but should be directed with realistic goals. Patients with progressive pulmonary disease may require chronic oxygen therapy and modification of their daily activities. Vaccination against influenza and Streptococcus pneumoniae species should be considered to minimize the risk of pneumonia. Standard lipid-lowering agents are indicated for the treatment of ASMD-associated lipid abnormalities in adult patients. Although some patients have undergone growth hormone treatment for short stature with consequent acceleration of linear growth, most patients have a period of catch-up growth with continued acquisition of height into their twenties. To date, no treatment approach has been reported to positively affect low bone density, and there are no effective treatments to reduce hepatosplenomegaly. Because of low platelet count and risk of hematoma or bleeding, sports involving strong physical contact, such as soccer and wrestling, must be avoided. Many patients rarely become anemic enough to require transfusions. However, patients with clinically significant cytopenia and a history of excessive bleeding may require multiple blood transfusions.

Enzyme replacement therapy (ERT) with recombinant human ASM is a potentially disease-modifying therapeutic approach currently in clinical development for the treatment of ASMD. ERT represents a known mechanism of action that has been used successfully in other lysosomal storage disorders. Results of a 26-weeks phase 1b study in five adult patients with NPD B established initial proof of concept for the safety and efficacy of recombinant human ASM in this patient group, including reductions in sphingomyelin storage seen in liver biopsies, spleen and liver volumes and serum chitotriosidase activity, and improvements in infiltrative lung disease, lipid profiles, platelet counts and QoL assessments. A phase 1/2 clinical trial in pediatric patients and a phase 2/3 trial in adult patients with ASMD are ongoing

Resources - Acid Sphingomyelinase Deficiency

Consensus recommendation for a diagnostic guideline for acid sphingomyelinase deficiency.

Schuchman EH, Desnick RJ. Niemann-Pick disease types A and B: acid sphingomyelinase deficiencies. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 144.

Wasserstein MP, Desnick RJ, Schuchman EH, et al. The natural history of type B Niemann-Pick disease: results from a 10-year longitudinal study. Pediatrics 2004;e672-676.

by Scott Harwood
by Scott Harwood