Acid sphingomyelinase (ASM) deficiency has been categorized in the past as either neuronopathic (Niemann-Pick disease type A [NPD-A]), with death in early childhood, or non-neuronopathic (Niemann-Pick disease type B [NPD-B]). While forms intermediate to these two extremes occur, all ASM deficiency that is not NPD-A is designated in this review as NPD-B, despite its wide range of manifestations and severity. The first symptom in NPD-A is hepatosplenomegaly, usually noted by age three months; over time the liver and spleen become massive. Psychomotor development progresses no further than the 12-month level, after which neurologic deterioration is relentless. A classic cherry-red spot of the macula of the retina, which may not be present in the first few months, is eventually present in all affected children. Interstitial lung disease caused by storage of sphingomyelin in pulmonary macrophages results in frequent respiratory infections and often respiratory failure. Most children succumb before the third year. NPD type B, later in onset and milder in manifestations than NPD type A, is characterized by hepatosplenomegaly with progressive hypersplenism and stable liver dysfunction, gradual deterioration in pulmonary function, and atherogenic lipid profile. Progressive and/or clinically significant neurologic manifestations occur infrequently. Survival to adulthood can occur.
The diagnosis of ASM deficiency is established when residual ASM enzyme activity in peripheral blood lymphocytes or cultured skin fibroblasts is less than 10% of controls. SMPD1 is the only gene known to be associated with ASM deficiency. Sequence analysis of SMPD1 detects mutations in more than 95% of individuals with enzymatically confirmed ASM deficiency. Targeted mutation analysis for common population-specific mutations is available for individuals of Ashkenazi Jewish background with NPD-A, individuals of North African descent with NPD-B, and certain other populations.
Acid sphingomyelinase (ASM) deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives is possible if both disease-causing alleles in the family are known. Prenatal diagnosis for pregnancies at 25% risk is possible by biochemical testing of ASM enzyme activity and/or by molecular genetic testing if both disease-causing alleles in the family are known.