Enzyme replacement therapy is standard of care for patients with Gaucher disease, as it significantly improves skeletal, visceral, and hematological symptoms. Few pathological studies have documented the extent of pathological findings in treated patients. Autopsy findings in five treated patients, who ultimately developed parkinsonism, ranged from the complete absence of Gaucher pathology to extensive involvement of multiple tissues, without correlation to age, genotype, spleen status, or dose/duration of therapy. Additional autopsies may elucidate modifiers and biomarkers contributing to disease burden and response to therapy.

The molecular, genetic and enzymological abnormalities in Gaucher's disease have been delineated during the past decade. Although our understanding of the primary predisposition to the Gaucher's disease phenotypes has improved, the relationships remain poorly understood between the mutant alleles, the resultant enzyme variants, the saposin C (activator protein) locus and phenotypes. Of the more than 100-disease associated alleles, about 8 to 10 have significant frequencies in various ethnic and demographic groups. The N370S(1226G) allele is very frequent in Caucasian populations, but absent in Asian groups. In the Ashkenazi Jewish population, the N370S homozygosity predisposes to Gaucher's disease, but over 50% of such patients escape medical detection because of their mild to absent involvement, i.e. N370S may be a prediposing polymorphic variant. Clarification of genotype/phenotype relationships and the identification of modifier loci that impact on Gaucher's disease phenotypes remain a critical area for research. Greater understanding of these issues will facilitate genetic counselling and appropriate interventive therapy to prevent the morbid long-term manifestations of Gaucher's disease.