Chicago Center for Jewish Genetics Disorders - Ashkenazi Disorders: Niemann-Pick Disease

Ashkenazi Disorders: Mendelian

Gene: Niemann-Pick disease, Type A (NPDA) is caused by mutations in the lysosomal sphingomyelinase gene (SMPD1), which is located at 11p15.4-p15.1. This gene encodes an enzyme that catalyzes the cleavage of sphingomyelin to phosphorylcholine and ceramide.

Mutations and testing: Three mutations in the SMPD1 gene are responsible for approximately 92% of mutations leading to Niemann-Pick disease type A in the Ashkenazi Jewish population. These are R496L, L302P, and fsP33. There is one additional mutation (delta-R608) that has been associated with the milder form Niemann-Pick disease, Type B. These four mutations account for greater than 95% of the mutant alleles in the Ashkenazi Jewish population. NPDA results from complete lack of enzyme activity, while NPD Type B is due to diminished enzyme activity. Type B is NO more common in the Ashkenazi Jewish population than in the general population.

Traits: NPDA results from the accumulation of sphingomyelin, which causes damage to the central nervous system, liver, and lungs. Neurological symptoms consist of mental retardation and developmental delay, spasticity, seizures, myoclonic jerks, vertical supranuclear ophthalmoplegia (inability to look up or down), and ataxia. Occular problems can also include corneal clouding and a macular cherry red spot. Hepatomegaly is commonly seen, and may be associated with jaundice and ascites. The spleen may also be enlarged. NPDA symptoms begin in the first few months of life, and often appear as feeding or swallowing difficulties, a swollen abdomen due to hepatosplenomegaly, and progressive loss of early motor skills. Rapid, progressive deterioration occurs and most patients die by 2 to 3 years of age.

Treatment: There is no effective treatment. Supportive care aims at providing the affected child with comfort. Bone marrow transplantation and enzyme replacement therapy are being considered as future therapies.

Other: There are also Niemann-Pick, Type C, Type D, and Type E but these are separate disorders that are very different at the biochemical and genetic level. These disorders are due to an inability to metabolize cholesterol and can eventually lead to a secondary reduction in sphingomyelinase activity. This secondary effect historically led to the same name for these genetically unrelated diseases.

Reviewed by Dr. Joel Charrow, Children's Memorial Hospital.
1/03

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This page last updated on January 10, 2003.