Fabry Disease: from Diagnosis to Therapy

Abstract

Fabry disease (FD) is an accelerating, X-linked hereditary disorder of glycosphingolipid metabolism which occurs due to improper lysosomal α-galactosidase A activity. Its pan-ethnic and the annually reported occurrence may underestimate the true frequency of the disease. Classically affected hemizygous males, with no residual α-galactosidase A activity may display all the characteristics like cardiovascular (cardiomyopathy), cutaneous (angiokeratoma), renal (kidney failure), neurological (pain), cerebrovascular and cochleo-vestibular signs of the disease while heterozygous females have similar symptoms ranging from very mild to severe. Incomplete action of lysosomal α-galactosidase A results in gradual increase of globotriaosylceramide within lysosomes, supposed to set off a flow of cellular events. Enzyme analysis may occasionally help to detect heterozygote but in females results are often questionable because of random X-chromosomal inactivation that obligates the molecular testing (genotyping). Due to ethical reasons determination of enzyme activity through prenatal diagnosis is carried out only in male's fetus. The subsistence of atypical variants and the unavailability of a specific therapy complicate the genetic counseling. Enzyme replacement therapy (ERT) is the only specific therapeutic option that introduced recombinant human α-galactosidase A. End stage renal disease and critical cardiovascular or cerebrovascular complications limit the life-expectancy of untreated males and females. Oral therapy drives the research forward into active site specific chaperones. Adjunctive therapy of ERT with chemical chaperone therapy can arrest disease succession.