Chapter 144

## Abstract

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.”

7. 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.

8. 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 enzyme in Chinese hamster ovary (CHO) cells, providing recombinant protein for the future evaluation of enzyme replacement in type B NPD. Retroviral-mediated gene transfer also corrects the metabolic defect in cultured NPD fibroblasts and hematopoietic stem cells.

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