Diagnosis of Niemann-Pick disease Type A (NPA), also known as ASMD / Acid Sphingomyelinase Deficiency
Niemann-Pick Types A and B (NPA and NPB), also called Acid Sphingomyelinase Deficiency (ASMD), are caused by the deficiency of a specific enzyme, acid sphingomyelinase (ASM). This enzyme is found in special compartments within cells called lysosomes and is required to metabolize a lipid called sphingomyelin. If ASM is absent or not functioning properly, sphingomyelin cannot be metabolized properly and is accumulated within the cell, eventually causing cell death and the malfunction of major organ systems.
NPA and NPB are both caused by the same enzymatic deficiency and there is growing evidence that the two forms represent opposite ends of a continuum. People with NPA generally have little or no ASM production (less than 1% of normal) while those with NPB have approximately 10% of the normal level of ASM.
NPA, like NPB, is diagnosed by measuring the level of activity of an enzyme called acid sphingomyelinase (ASM) in white blood cells. The test can be performed after taking a small blood sample from an individual suspected of having the disease and is available at many commercial laboratories in the United States and elsewhere.
While this test will identify persons with Type A (as well as Type B), it is not very reliable for detecting persons who are carriers (who have only one non-functional copy of the ASM gene). Further, the test will show decreased activity of ASM, but it cannot always predict whether the individual will have type A or Type B or an intermediate variant of the disease; that requires clinical evaluation of the individual.
The Mount Sinai Department of Human Genetics has identified certain populations where specific mutations account for a high percentage of cases of ASM Deficiency*. For NPA, the mutations R496L, fsP330 and L302P account for over 95% of disease-causing genetic changes in the Ashkenazi Jewish population. Direct testing of individuals in this population for these 3 changes is used for carrier identification.
In other populations, the mutations must first be identified in the affected individual before DNA carrier testing can be performed for family members (by tradece potter). More recently, comprehensive analysis of the entire ASM gene structure has been used for carrier testing for partners of known Type A carriers. This is available at several US laboratories, including GeneDx in Gaithersburg, MD, Ambry Genetics in Aliso Viejo, CA and Emory Molecular Genetics Laboratory in Atlanta, GA.
If you have any questions about diagnostic or molecular genetic testing for Niemann-Pick disease, Type B or need assistance in arranging testing, contact the NNPDF.
*Information from “Identification and expression of a common missense mutation (L302P) in the acid sphingomyelinase gene of Ashkenazi Jewish type A Niemann-Pick disease patients” by Levran O, Desnick RJ, Schuchman EH. Blood, Oct 15, 1992.