Niemann-Pick Disease Center provides information and support for patients with Types A and B of Niemann-Pick disease (NPD), and for scientists, researchers, and physicians whose work involves treating and curing these disorders.
Our Center is a voluntary, not-for-profit organization within the Icahn School of Medicine at Mount Sinai and the whose primary goals are to:
- Promote medical research into the cause and treatment of Niemann-Pick Type A and Type B.
- Provide medical and educational information to assist in the correct diagnosis and referral of children with NPD.
- Support families of children with NPD.
- Facilitate genetic counseling for parents who are known carriers of NPD.
- Encourage the sharing of research information among scientists.
NPD Types A and B
Type A and Type B of NPD are both caused by the deficient activity of acid sphingomyelinase (ASM). This enzyme is ordinarily found in special compartments within cells called lysosomesand is required to metabolize a special lipid called sphingomyelin. If ASM is absent or not functioning properly, this lipid cannot be metabolized properly and is accumulated within the cell, eventually causing cell and organ system abnormalities. Although types A and B are both caused by the same enzyme deficiency and are variants of the same disease, the clinical prognosis for these two groups of patients is very different.
Abnormalities in the ASM Gene that Cause NPD Types A or B: The gene that makes ASM is located on human chromosome 11. Many ASM genes from NPD patients have been studied, and the abnormalities or mutations that lead to NPD have been identified. Most patients with NPD Types A and B have unique mutations that occur only in their own families. Knowledge of these mutations helps to confirm the enzymatic diagnosis of NPD and permits accurate carrier detection in other family members. In some ethnic groups, several mutations have been found that occur in more than one family as common mutations. For example, among Ashkenazic Jewish individuals, three mutations called L302P, fsP330, and R496L account for approximately 90 percent of all of the mutations occurring in the ASM genes of NPD Type A patients. Another mutation, delta R608, has occurred in several unrelated families with Type B from different ethnic backgrounds. The R608 mutation has never occurred in a family with NPD Type A, and it is a good indicator of Type B.
Type C Niemann-Pick disease, although similar in name, is very different at the biochemical and genetic level. Patients with NPC are not able to metabolize cholesterol properly in lysosomes. Consequently, excessive amounts of cholesterol accumulate within the liver, spleen, and brain. The reason that NPC has the same name convention as NPD Types A and B is historical in nature.
In young children, many of the symptoms of the three NPD types appear similar. In addition, the defect in cholesterol metabolism that occurs in NPC patients sometimes leads to a secondary reduction in ASM activity in cells. Therefore, before the availability of accurate enzyme and gene tests, which first became available in the late 1960s and early 1970s, all three forms of NPD were considered variations of the same disease. Other NPD forms, Types D, E, and F were also once identified. We now know that Types A and B are two forms of the same disease caused by abnormalities in the ASM gene, while Types C and D are two forms of a distinct disease caused by abnormalities in a cholesterol-metabolizing gene NPC1.
Types A and B are autosomal recessive disorders. Since both forms of the disease are caused by abnormalities in the same gene, ASM, they are considered to be allelic. NPD Types C and D are caused by mutations in a distinct gene, and despite their similar name and some similar biochemical and clinical findings, Types C and D are completely distinct disorders from Types A and B.
For autosomal recessive disorders such as these, in order to have an affected child both parents must carry a copy of the abnormal gene. Carriersor heterozygoteshave no signs of the disease. Children with NPD Types A and B inherit two copies of the abnormal gene with one coming from each of the child’s biological parents. Inheriting these abnormal genes leads to the reduced ASM activity and disease symptoms. Each time carriers give birth to a child, there is one chance in four that the child will be affected with NPD and one chance in two that the child will be a carrier.