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Niemann-Pick Disease

Last updated: 2003-09-11

The first case of infantile-onset Niemann-Pick disease was described in 1914 by the German neurologist Albert Niemann.

Subsequently, five subtypes have been identified, but only Type A is more frequent in Ashkenazi Jewish populations. Type A disease is a severe neurodegenerative disorder of infancy. By six months of age, affected babies experience feeding difficulty, recurrent vomiting and enlargement of the spleen and liver, which causes the abdomen to appear distended. Some have a characteristic "cherry-red spot" in the retina of the eye. Death usually occurs by two to three years of age, due to infections such as pneumonia.

Type B disease is a milder disorder with no neurologic involvement. Affected individuals usually come to medical attention in childhood due to enlarged livers and spleens. With adolescence and adulthood the major symptoms are associated with pulmonary disease, due to involvement of the lungs. Patients with Type B disease may survive into the fourth and fifth decades of life. Type B Niemann-Pick disease can also occur among Ashkenazi Jewish individuals, but it is not as common as Type A Niemann-Pick disease in this group.

The specific biochemical defect in both Types A and B Niemann-Pick disease is the deficiency of an enzyme, sphingomyelinase, which normally degrades a fatty substance known as sphingomyelin. The enzyme defect leads to the accumulation of sphingomyelin, primarily in the liver, spleen, lymph nodes, and brain. Individuals affected with Type A disease have little or no (0-5% of normal) sphingomyelinase activity, whereas persons with Type B have 5-10% of normal activity, thereby accounting for their milder manifestations.

The gene for sphingomyelinase is located on chromosome 11. Analyses revealed that three common mutations in the gene were responsible for over 90% of Type A disease in Ashkenazi Jews. Another mutation was found to be a common cause of Type B Niemann-Pick disease in both Jewish and non-Jewish patients.

Both Type A and B Niemann-Pick disease are inherited in an autosomal recessive manner. When both parents are carriers of sphingomyelinase gene mutations, there is a 1 in 4 (25%) chance in each pregnancy to have an affected child. It has been estimated that approximately two-thirds of all infants with Niemann-Pick Type A disease are of Ashkenazi Jewish descent, and approximately 1/80 Ashkenazi Jews are carriers of Type A. The carrier rate of Niemann-Pick Type B disease is not known, but it is no more common among Ashkenazi Jews than it is in other populations.

The diagnosis of Type A or B disease can be made either by demonstration of the enzyme defect, or by identification of the specific mutation(s) in the sphingomyelinase gene. Prenatal diagnosis is most often made by gene mutation analysis, using cells obtained from either CVS or amniocentesis. Prenatal diagnosis of Niemann-Pick may also be made by measurement of acid sphingomyelinase activity. Carrier screening of Ashkenazi Jewish individuals is now available using gene mutation analysis, but is targeted primarily towards Niemann-Pick Type A.