The reproductive pathology of acid sphingomyelinase deficient mice and development of methods to prevent Niemann-Pick disease

The present studies were conducted to investigate the reproductive pathology of male and female acid sphingomyelinase deficient (ASMKO) mice and to develop methods for the discrimination of normal from mutant sperm and preimplantation embryos. These methods establish a “Proof of Principle” for selection techniques that could provide carriers of Niemann-Pick Disease (NPD) with options that prevent or reduce the risk of birth of an affected child. The ASMKO mouse model provided an appropriate system to investigate the nature of NPD reproductive pathogenesis and to develop the relevant selection methods. The studies show that both male and female homozygous and heterozygous mice experience gonadal and gamete lipid accumulation. Biochemical, physiologic, and morphologic studies of mature gametes strongly suggest that abnormalities in these cells result in reduced fecundity for both sexes. For male ASMKO mice, an etiology of mature sperm dysfunction appears to be abnormal regulatory volume decrease during spermiogenesis and epididymal maturation, presumably due to lipid accumulation. In situ, analytical discrimination of mature mutant and wild type sperm from heterozygous mice by physical and flow cytometric methods suggested that sorting of sperm populations may enrich for the wild type ASM allele. This was confirmed by PCR analysis of sorted sperm populations. The studies also show that in situ analysis of ASM activity in preimplantation embryos may provide a means of selection for heterozygous mating pairs of ASMKO mice. Taken together, the documented abnormalities suggest that a similar reproductive phenotype may occur in human NPD patients, and that prefertilization selection of mature sperm from a carrier NPD male, or the in vitro biochemical selection of normal embryos from carrier females, may reduce or eliminate the conception of an affected fetus. The prevention of hereditary lysosomal storage disorders by gamete or embryo selection would thus establish a novel approach to assisted reproductive technologies.