La maladie de Fabry. Aspects cliniques et génétiques. Perspectives thérapeutiques

Abstract

Introduction. – This review presents the clinical and genetic aspects of Fabry disease, along with recent advances in research. Current knowledge and key points. – Fabry disease is an X-linked inborn error of metabolism due to a deficient activity of the lysosomal enzyme alpha-galactosidase A. The enzymatic defect leads to the systemic accumulation of neutral glycosphingolipids in plasma and tissues. Clinical manifestations in affected hemizygous males are primarily due to progressive disease of small vessels, including angiokeratoma, autonomic dysfunction, and lifelong debilitating pain. Renal failure and vasculopathy of the heart and brain lead to early demise in adulthood. Demonstration of alpha-galactosidase A deficiency in leukocytes or plasma is the definitive method for the diagnosis of affected hemizygous males. Most female carriers are clinically symptomatic, they may present isolated acroparesthesia, cardiac symptoms, or the characteristic benign corneal dystrophy. Due to random X-chromosomal inactivation, enzymatic detection of carriers is often inconclusive. A reliable molecular test for detection of heterozygosity is therefore highly desirable for accurate genetic counselling. The GLA gene has been mapped to chromosome Xq22, and cloned. Several studies have shown the molecular heterogeneity of the disease. Currently, no standard treatment exists for Fabry disease. Symptomatic treatment is provided as appropriate. In addition, renal transplantation or dialysis is available for patients experiencing end-stage renal failure. Future prospects and projects.– The ability to produce high doses of recombinant alpha-galactosidase A in vitro has opened the way to preclinical studies in the mouse model and led to the development of the first clinical trials with enzyme replacement therapy in patients with Fabry disease.