Niemann-Pick Disease Center

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

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.

Inheriting NPD

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.

Schuchman, E.H., Suchi, M., Takahashi, T., Sandhoff, K., and Desnick, R.J.: Human acid sphingomyelinase: Isolation, nucleotide sequence and expression of the full-length and alternatively spliced cDNAs. J. Biol. Chem. 66:8531-8539, 1991.

Levran, O., Desnick, R.J., and Schuchman, E.H.: Niemann-Pick disease: A frequent missense mutation in the acid sphingomyelinase gene of Ashkenazi Jewish type A and B patients. Proc. Natl. Acad. Sci. USA. 88:3748-3752, 1991.

Levran, O., Desnick, R.J., and Schuchman, E.H.: Niemann-Pick type B disease: Identification of a single codon deletion in the acid sphingomyelinase gene and genotype/phenotype correlations in type A and B patients. J. Clin. Invest. 88:806-810, 1991.

Schuchman, E.H., Levran, O., Pereira, L.V., and Desnick, R.J.: Structural organization and complete nucleotide sequence of the gene encoding human acid sphingomyelinase. Genomics, 12:197-205, 1992.

Suchi, M., Dinur, T., Desnick, R.J., Gatt, S., Pereira, L., Gilboa, E., and Schuchman, E.H.: Retroviral-mediated transfer of the human acid sphingomyelinase cDNA: Correction of the metabolic defect in cultured Niemann-Pick disease cells. Proc. Natl. Acad. Sci. USA., 89:3227-3231, 1992.

Levran, O., Desnick, R.J., and Schuchman, E.H.: A common missense mutation (L302P) in Ashkenazi Jewish type A Niemann-Pick disease patients. Transient expression studies demonstrate the causative nature of the two common Ashkenazi Jewish Niemann-Pick disease mutations. Blood, 80:2081-2087, 1992.

Levran, O., Desnick, R.J., and Schuchman, E.H.: Type A Niemann-Pick disease: A frame-shift mutation in the acid sphingomyelinase gene (fsP330) occurs in about 8% of Ashkenazi Jewish alleles. Hum. Mut., 2:317-319, 1993.

Horinouchi, K., Erlich, S., Perl, D., Ferlinz, K., Bisgaier, C.L., Sandhoff, K., Desnick, R.J., Stewart, C.L., and Schuchman, E.H.: Acid sphingomyelinase deficient mice: A model of Types A and B Niemann-Pick disease. Nat. Genet., 10:288-293, 1995.

Yeyati, P., Agmon, V., Fillat, C., Dagan, D., Desnick, R.J., Gatt, S., and Schuchman, E.H.: Preparative isolation of metabolically corrected Niemann-Pick disease cells for gene therapy. Evidence for bystander correction by transduced cells. Hum. Gene Ther., 6:975-983, 1995.

Miranda, S.R.P., and Schuchman, E.H. Niemann-Pick disease: Mutation update, genotype/phenotype correlations, and prospects for genetic testing. Genetic Testing 1:13-19, 1997.

Miranda, S.R.P., Erlich, S., Visser, J.W.M., Gatt, S., Dagan, A., Friedrich, V.L. Jr., and Schuchman, E.H.: Bone marrow transplantation in acid sphingomyelinase deficient mice: Engraftment and cell migration into the brain as a function of radiation, age, and phenotype. Blood 90:444-452, 1997.

Miranda, S.R.P., Erlich, S., Friedrich, V.L. Jr., Haskins, M.E., Gatt, S., and Schuchman, E.H.: Biochemical, pathological, and clinical response to transplantation of normal bone marrow cells into acid sphingomyelinase deficient mice. Transplantation 65:884-892, 1998.

Erlich, S., Miranda, S.R.P., Visser, J.W.M., Dagan, A., Gatt, S., and Schuchman, E.H.: Fluorescence-based selection of gene-corrected hematopoietic stem and progenitor cells from acid sphingomyelinase deficient mice: Implications for Niemann-Pick disease gene therapy and the development of improved stem cell gene transfer procedures. Blood 93:80-86, 1999.

He, X., Miranda, S.R.P., Dagan, A., Gatt, S., and Schuchman, E.H.: Overexpression of human acid sphingomyelinase in Chinese hamster ovary cells: Purification and characterization of the recombinant enzyme. Biochim. Biophys. Acta 1432:251-264, 1999.

Schuchman, E.H.: Hematopoietic stem cell gene therapy for Niemann-Pick disease and other lysosomal storage diseases. Special Issue of Chemistry and Physics of Lipids 102: 179-188, 1999.

Miranda, S.R.P., He, X., Gatt, S., Dagan, A., and Schuchman, E.H.: Infusion of recombinant human acid sphingomyelinase into Niemann-Pick disease mice leads to visceral, but not neurological correction of the pathophysiology. FASEB J. 14:1988-1995, 2000.

Miranda, S.R.P., Erlich, S., Friedrich, V.L., Gatt, S., and Schuchman, E.H.: Treatment of newborn acid sphingomyelinase deficient mice by retroviral-mediated hematopoietic stem cell gene therapy. Gene Therapy 7:1768-1776, 2000.

Schuchman, E.H., Erlich, S., and Gatt, S.: Fluorescence-based selection of seletion of gene-corrected cells using acid sphingomyelinase as a marker. Meth. Enzy. 312:330-338, 2000.

Marathe, S., Miranda, S.R.P., Johns, A., Kuriakose, G., Williams, K.J., Schuchman, E.H., and Tabas, I.: Correction of the lysosomal storage disease, but not the secretory sphingomyelinase, in acid sphingomyelinase deficient mice. Hum. Mol. Genet. 9:1967-1976, 2000.

Dhami, R., He, X., Gordon, R.E., Elleder, M., and Schuchman, E.H.: Analysis of the lung pathology and alveolar macrophage function in the acid sphingomyelinase deficient mouse model of Niemann-Pick disease. Lab. Invest. 81:987-999, 2001.

Schuchman, E.H., and Desnick, R.J.: Types A and B Niemann-Pick disease: Deficiencies of acid sphingomyelinase activity. In: The Metabolic Basis of Inherited Disease 8th Ed., C.R. Scriver, A.L. Beaudet, W.S. Sly, and D. Valle, eds., McGraw Hill, New York, 3589-3610, 2001.