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Q J Med 2004; 97: 199-204
QJM vol. 97 no. 4 (c) Association of Physicians 2004; all rights reserved.

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

R.H. Lachmann1, I.R. Grant2, D. Halsall3 and T.M. Cox1

From the 1Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, 2Department of Haematology, King George Hospital, Goodmayes, and 3Principal Biochemist, Addenbrooke's Hospital, Cambridge, UK

Received 29 October 2003 and in revised form 3 February 2004

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.

Address correspondence to Professor T.M. Cox, Department of Medicine, Box 157, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ. e-mail: jbg20{at}medschl.cam.ac.uk


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