Vast phenotypic heterogeneity is often encountered in individuals sharing the same inherited gene defects. Identification of the genetic and epigenic mechanisms responsible for the heterogeneity observed in genetic disorders affecting the nervous system are essential for the logical and successful development of development of diagnostic techniques, therapeutic strategies, and for genetic counseling. Gaucher disease, an inherited enzyme deficiency affecting 10,000 to 20,000 Americans which is the most common of the sphingolipidoses, is useful as a model because of the presentation of both neuronopathic and non-neuronopathic phenotypes. Phenotypic heterogeneity in Gaucher disease is studied through both clinical and molecular evaluations of diverse patient populations, as well as through analyses of animal models created by gene targeting. The Gaucher mouse, homozygous for a null allele, has a devastating clinical course and has aided in the recognition of a subgroup of type 2 Gaucher patients who die in the neonatal period. Both the Gaucher mice and neonatal patients have skin changes, and our studies have substantiated the important role of glucocerebrosidase in the maturation of functionally normal skin and provided a possible novel and rapid technique for the presymptomatic discrimination of Gaucher phenotypes. Molecular analyses reveal significant genotypic heterogeneity among clinically similar Gaucher patients, and it is thus still difficult to assign patients a clinical prognosis based solely upon Polymerase Chain Reaction determined genotype. We have now established that the human glucocerebrosidase locus is much more complicated than previously appreciated, with a homologous pseudogene sequence and several novel brain expressed genes located in close proximity. Many mutant alleles encountered in patients arise by recombinational events occurring within this region. The clinical significance and the mechanisms and locations of these rearrangements, as well as the contribution of other factors affecting gene expression, are being studied. Molecular characterization of patients with unusual or severe clinical manifestations are also providing valuable insights into the etiology of clinical heterogeneity. The techniques and information obtained from the study of clinical heterogeneity and gene expression in Gaucher diease will provide insights applicable to understanding and formulating novel therapeutic strategies for other genetic disorders affecting the nervous system
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