The impact of apolipoprotein E genotypes on age at onset of symptoms and phenotypic expression in Wilson's disease

Wilson's disease is a disorder of biliary copper excretion that may result in severe neurological symptoms and advanced liver disease. The wide variat ion of phenotypic disease expression cannot be fully explained by the diffe rent,mutations of the Wilson disease gene, In neurological disorders, such as Alzheimer's disease, temporal robe epilepsy and cerebral trauma, the pre sence of the apolipoprotein E (ApoE) allele epsilon 4 is associated with an increased vulnerability of the brain to the effects of the disease, wherea s the presence of the ApoE genotype epsilon 3/3 appears to provide moderate neuroprotection, We examined whether this hypothesis holds true for the de velopment of neurological symptoms in patients with Wilson's disease. The A poE genotype and the H1069Q mutation (the most common in Wilson's disease) status were determined by polymerase chain reaction-based mutation assays i n 121 well-characterized, symptomatic index patients with Wilson's disease. An investigation profile was established in which the patients were groupe d according:to the clinical symptoms at presentation, the ApoE genotypes an d the status of the H1069Q mutation. Fifty-nine per cent of the 121 patient s had the allele combination ApoE epsilon 3/3 (21% ApoE epsilon 3/4, 19% Ap oE epsilon 3/2, 1% ApoE epsilon 4/2). The distribution of ApoE genotypes di d not deviate from known distributions in healthy European subjects. Within the group of 40 H1069Q-homozygous patients, the onset of symptoms was sign ificantly delayed in patients with the ApoE epsilon 3/3 genotype (25 +/- 6 years at presentation) compared with patients with the ApoE epsilon 3/4 gen otype (20 +/- 3 years at presentation), In this study, the ApoE genotype wa s established as an important factor delaying the onset of neurological and hepatic symptoms, but not modifying phenotypic disease expression in a hom ogenous group of patients with Wilson's disease tall H1069Q-homozygotes, si milar genetic background), The presence of ApoE epsilon 3/3 attenuates clin ical manifestations in Wilson's disease by mechanisms which might involve t he antioxidant and membrane-stabilizing properties of the ApoE 3 protein.