Acid Sphingomyelinase Deficiency

Clinical characteristics The phenotype of acid sphingomyelinase deficiency (ASMD) occurs along a continuum. Individuals with the severe early-onset form, infantile neurovisceral ASMD, were historically diagnosed with Niemann-Pick disease type A (NPD-A). The later-onset, chronic visceral form of ASMD is also referred to as Niemann-Pick disease type B (NPD-B). A phenotype with intermediate severity is also known as chronic neurovisceral ASMD (NPD-A/B). The most common presenting symptom in NPD-A is hepatosplenomegaly, usually detectable by age three months; over time the liver and spleen become massive in size. Psychomotor development progresses no further than the 12-month level, after which neurologic deterioration is relentless. Failure to thrive typically becomes evident by the second year of life. 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 of life. NPD-B generally presents later than NPD-A, and the manifestations are less severe. NPD-B is characterized by progressive hepatosplenomegaly, gradual deterioration in liver and pulmonary function, osteopenia, and atherogenic lipid profile. No central nervous system (CNS) manifestations occur. Individuals with NPD-A/B have symptoms that are intermediate between NPD-A and NPD-B. The presentation in individuals with NPD-A/B varies greatly, although all are characterized by the presence of some CNS manifestations. Survival to adulthood can occur in individuals with NPD-B and NPD-A/B. Diagnosis/testing The diagnosis of ASMD is established by detection of biallelic pathogenic variants in SMPD1 and/or residual acid sphingomyelinase enzyme activity that is less than 10% of controls (in peripheral blood lymphocytes or cultured skin fibroblasts). Management Treatment of manifestations: Feeding therapy and/or feeding tube as needed for nutritional support; supportive management of coagulopathy and end-stage liver disease manifestations; transfusion of blood products for life-threatening bleeding; partial splenectomy may be considered for individuals with severe hypersplenism; supplemental oxygen for symptomatic pulmonary disease; physical and occupational therapy to maximize function and to prevent contractures; early intervention and developmental support for those with developmental issues; treatment of hyperlipidemia in adults; calcium and vitamin D for osteopenia/osteoporosis; sedatives for irritability and sleep disturbance as indicated. Prevention of primary manifestations: Hematopoietic stem cell transplantation (HSCT) can correct the metabolic defect, improve blood counts, and reduce increased liver and spleen volumes but does not stabilize neurologic disease. The morbidity and mortality associated with HSCT limit its use. Prevention of secondary complications: Monitor liver function in individuals receiving hepatotoxic medications (e.g., statins for hypercholesterolemia). Surveillance: Periodic assessments of nutritional status; annual EKG; echocardiogram every two to four years; liver transaminases (ALT, AST), albumin, clotting factors, and platelet count at least annually; assess for fatigue, abdominal pain, and/or increased bleeding at least annually; radiologic measurements of liver and spleen size as needed; assess for shortness of breath at each visit; annual pulmonary function testing; chest radiograph every two to four years; assess neurologic function and frequency of headaches at least annually; monitor developmental progress, educational needs, and occupational and physical therapy needs at each visit; fasting lipid profile at least annually; assess for extremity pain at each visit; bone density assessment every two to four years; assess need for family support and resources at each visit. Agents/circumstances to avoid: Contact sports in those who have splenomegaly. Genetic counseling All forms of ASMD (NPD-A, NPD-A/B, and NPD-B) are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SMPD1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Once the SMPD1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible. Biochemical prenatal diagnosis for a pregnancy at 25% risk is also possible by testing of acid sphingomyelinase enzyme activity.