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