Physician/Scientist

Genetics

General Genetics

Mode of Inheritance

The familial nature of Type A NPD was noted as early as 1916, when Knox et al. described the phenotype in siblings from the same family. Soon after, the occurrence of two or more affected sibs was reported by other investigators, and by 1958 it had been clearly demonstrated that the disease was familial. About equal numbers of male and female cases had been described at that time, and consanguinity had been noted in six couples with affected offspring, further supporting the autosomal recessive nature of the inheritance.

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Ethnic Predilection and Incidence

Although Types A and B NPD are panethnic, it is well documented that Type A NPD occurs more frequently among individuals of Ashkenazic Jewish ancestry than in the general population. According to Schettler and Kahlke, two-thirds of the patients reported up to 1955 were of Jewish ancestry.

In the data compiled by Videbaek and Crocker and Farber, about two-thirds of the 73 patients whose ethnic history could be traced were Jewish. Indeed, Niemann's original Type A patient was a Polish infant of Ashkenazic Jewish ancestry.

The carrier frequency (2pq) of Type A NPD in the Ashkenazic Jewish population has been estimated at about 1:80 (see "The Molecular Genetics of ASM"), suggesting a disease incidence of about 1 in 40,000. It should be noted that lipid storage has been documented in NPD fetuses, and that Type A fetuses have been reported to have a higher frequency of spontaneous abortions. Therefore, the true incidence of Type A NPD may be higher than what is reflected in the reported cases. Furthermore, in the early literature, Type A NPD was often misdiagnosed as Type 2 Gaucher disease.

The incidence of Type B NPD in the Ashkenazic Jewish population is significiantly less that of Type A NPD. However, among non-Jewish NPD patients, the Type B form is prevalant. While accurate estimates for the frequency of Type B NPD are unavailable, it occurs at a relatively high frequency within some ethnic groups. Moreover, since many Type B NPD patients have mild symptomology, the frequency of Type B NPD is likely to be higher than what is indicated by estimates in the literature.

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Allelism of Types A and B Niemann-Pick Disease

Since their original descriptions, the biochemical and genetic relationships of the clinically diverse NPD subtypes have been the subject of much speculation. In 1980, Besley et al. performed a series of somatic-cell hybridization experiments with cultured cells from Types A, B, and C patients. When cells from Types A and B patients were fused, the ASM activities were not substantially increased (i.e., the metabolic defect could not be corrected), indicating that these two disorders were allelic and resulted from abnormalities in the same gene. In contrast, when cells from Type C patients were fused with those from Type A or B patients, the levels of ASM activity were increased to near normal levels, demonstrating that this disorder had a distinct gene defect. Biochemical and molecular studies have confirmed these findings and definitively demonstrated that Types A and B NPD are caused by different mutations in the ASM gene. Patients with Types C and D NPD have mutations in the NPC1 gene, located on chromosome 18.

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