Maladie de Fabry : une maladie du métabolisme par déficit d’une enzyme lysosomale (alpha-galactosidase), de transmission héréditaire liée au chromosome X accessible au traitement enzymatique de substitution

Abstract

Fabry disease is an inherited deficiency of the lysosomal hydrolase alpha-galactosidase A (alpha GalA) due to mutations in the Gal gene at Xq22. The result is intralysosomal accumulation of glycosphingolipids. In males who carry the mutation, severe multisystem disease develops in childhood or adolescence. Attacks of acute pain lasting a few minutes to a few days occur in the hands and feet, joints, muscles, and abdomen, sometimes with a fever and an acute phase reaction. Highly suggestive skin lesions called angiokeratomas develop, as well as cornea verticillata characterized by corneal deposits without visual impairment. Stroke seizures, heart disorders (conduction disturbances, valve disease, and left heart failure) and kidney disorders (proteinuria and chronic renal failure) develop in the third or fourth decade of life. Women who are heterozygous for the Gal gene can transmit the disease to their sons but are usually free of symptoms although many have cornea verticillata. However, they may have moderate or severe disease related to uneven chromosome X inactivation. Late-onset variants with predominant neurological, cardiac, or renal manifestations have been described, and also a few cases of osteoporosis or aseptic osteonecrosis. The diagnosis is difficult when the family history is negative for Fabry disease. Tests on plasma and leukocytes show very low levels or absence of alpha GalA activity in affected men, confirming the diagnosis. The Gal gene mutation should be looked for to detect heterozygous women. Symptomatic treatments include analgesics, antihypertensives, antiplatelet agents or anticoagulants to treat ischemic events, and hemodialysis or kidney transplantation to treat chronic renal failure. The prescription of enzyme replacement therapy with agalsidase alpha or beta is a major breakthrough in the treatment of patients suffering from Fabry disease. Enzyme replacement therapy relieves the pain and decreases the risk of the complications. Other lysosomal metabolic diseases as Farber disease or Niemann-Pick disease are due to a specific enzyme deficit, but without enzyme replacement therapy.