RT Book, Section A1 Schuchman, Edward H. A1 Desnick, Robert J. A2 Valle, David L. A2 Antonarakis, Stylianos A2 Ballabio, Andrea A2 Beaudet, Arthur L. A2 Mitchell, Grant A. SR Print(0) ID 1181464885 T1 Niemann-Pick Disease Types A and B: Acid Sphingomyelinase Deficiencies T2 The Online Metabolic and Molecular Bases of Inherited Disease YR 2019 FD 2019 PB McGraw-Hill Education PP New York, NY SN 9780071459969 LK ommbid.mhmedical.com/content.aspx?aid=1181464885 RD 2024/10/10 AB Types A and B Niemann-Pick disease (NPD) are lysosomal storage disorders that result from the deficient activity of acid sphingomyelinase (ASM; EC 3.1.4.12) and the accumulation of sphingomyelin. Type A NPD is a fatal disorder of infancy characterized by failure to thrive, hepatosplenomegaly, and a rapidly progressive neurodegenerative course that leads to death by 2 to 3 years of age. In contrast, type B NPD is a phenotypically variable disorder that is usually diagnosed in childhood by the presence of hepatosplenomegaly. Most type B patients have little or no neurologic involvement and survive into adulthood. In more severely affected type B patients, progressive pulmonary infiltration causes the major disease complications.The pathologic hallmark of types A and B NPD is the histochemically characteristic lipid-laden foam cell, often referred to as the “Niemann-Pick cell.” These histiocytic cells result from the accumulation of sphingomyelin and other lipids in the monocyte-macrophage system, the primary site of pathology in this disease.Patients with type A NPD have dramatically reduced ASM activities in their cells and tissues, generally less than 5 percent of normal depending on the enzyme source and assay system used. Type B patients, who have milder disease, have slightly higher residual ASM activities.Types A and B NPD are both inherited as autosomal recessive traits. Somatic-cell hybridization and molecular genetic studies demonstrate that both disorders result from allelic mutations within the ASM gene. Type B NPD is panethnic, whereas Ashkenazi Jewish have a higher incidence of type A NPD; the estimated carrier frequency for type A NPD in this population is about 1:80.The full-length cDNA and genomic sequences encoding human and murine ASM have been isolated and characterized. The human ASM gene has been mapped to the chromosomal region 11p15.1-p15.4. Although the ASM mRNA is alternatively spliced, there is only one functional transcript that encodes a 629-residue polypeptide that is cotranslationally glycosylated. Following translation/glycosylation, some of the ASM polypeptides are transported to lysosomes, while the remainder are released from cells in a form that requires Zn2+ cations for maximal activity.Eighteen published mutations have been identified in the ASM gene that cause types A and B NPD. Three mutations, R496L, L302P, and fsP330, account for about 92 percent of the mutant alleles in Ashkenazi Jewish type A NPD patients. Similarly, a single lesion, ΔR608, is a common mutation in type B patients and encodes sufficient residual activity to be “neuroprotective.”The diagnosis of types A and B NPD is readily made by enzymatic determination of ASM activity in cell and/or tissue extracts. However, heterozygote detection is unreliable by enzyme assay and requires molecular studies. Prenatal diagnosis by enzymatic and/or molecular analyses of cultured amniocytes and chorionic villi has been accomplished.Currently, there is no specific therapy for type A or B NPD. Bone marrow transplantation (BMT) studies in a “knock-out” mouse model of NPD suggest that this may be a successful therapeutic approach for type B NPD, but is unlikely to alleviate the major neurologic complications of type A NPD. The ASM cDNA has been used to overexpress catalytically active ...