Twin pairs showing discordance of phenotype in adult Gaucher's disease

Abstract

Background: Non-neuronopathic (type 1) Gaucher's disease, a recessive disorder caused by glucocerebrosidase deficiency, shows marked variability in the severity and extent of clinical expression: many individuals who harbour two mutant alleles remain mildly affected or asymptomatic. Despite much effort, it is not possible accurately to predict disease severity from the genotype, or to identify those patients destined to develop severe disease and meriting early treatment.

Aim: To determine the degree to which variance in Gaucher disease is determined by non-heritable factors.

Design: Case reports of monozygotic and dizygotic twin pairs.

Results: For the monozygotic twin pair, homozygous for the frequent N370S glucocerebrosidase allele, there was no evidence that significant lipid storage was ever initiated in the unaffected twin. In contrast, pathological storage of glucocerebroside has been present in the macrophages of both members of the dizygotic twin pair (compound heterozygotes for the N370S and L444P alleles) from an early age but, by the age of 57 years, only one has developed symptoms.

Discussion: Non-heritable factors influence Gaucher disease expression in genetically predisposed individuals. Understanding the interactions between heritable and non-heritable factors will be critical for an analysis of pathogenesis, and the treatment of individuals predisposed to Gaucher disease.