Fabry disease and the heart: an overview of the natural history and the effect of enzyme replacement therapy

Abstract

Fabry disease is a genetic disorder caused by the deficiency of a-galactosidase A, resulting in the lysosomal accumulation of glycosphingolipids. Fabry disease may result in cardiac, cerebral and renal complications. Cardiac abnormalities in patients with Fabry disease were first described in the 1960s. In the 1990s a form of Fabry disease confined to the heart was reported; however, this variant is extremely rare and a more appropriate concept is of cardiac predominance of the disease in some patients. Up to 60% of males with classic Fabry disease have cardiac abnormalities, including left ventricular hypertrophy, valvular dysfunction and conduction abnormalities. Recent data suggest that left ventricular mass and systolic function in patients with Fabry disease improve after 12 months of enzyme replacement therapy (ERT); however, many of the patients studied are relatively young and have mild cardiac abnormalities, suggesting that more research into the efficacy of ERT in older patients is necessary.Conclusion: Cardiac manifestations are common in patients with Fabry disease and are not confined to a 'cardiac variant' of the disease.

Direct multiplex assay of enzymes in dried blood spots by tandem mass spectrometry for the newborn screening of lysosomal storage disorders

“…Thus, the technology has been extended from the theoretical concept of a common platform used for diagnosis to a sensitive technology that can used for large-scale screening of newborns independently of selection by clinical symptoms. This is of clinical importance because the disorders of Gaucher, Fabry, MPS I and Pompe currently have available, for clinical use or trials, enzyme replacement therapy that either has been demonstrated to improve (Gaucher, Fabry;Scott et al 2003;Shah and Elliott 2005) or is expected to improve (MPS I, Pompe;Desnick 2004;Miebach 2005) the clinical status of affected individuals. In the case of Krabbe and Niemann-Pick disease, there is evidence that presymptomatic detection and intervention by the use of umbilical stem cell transplantation markedly improves the clinical course of the disease (Escolar et al 2005;Krivit 2004).…”

Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life

“…1 Affected patients have an impaired ability to degrade membrane glycosphingolipids containing a terminal ␣-glycosidic galactose, especially globotriaosylceramide/ceramide trihexoside (GL 3 ), which accumulates in tissues. Storage in the vascular endothelium increases the risk for cerebrovascular accidents (CVA) and myocardial microvascular ischemia [2][3][4] ; in the heart causes dysrhythmias, hypertrophic cardiomyopathy, and valvular insufficiency 5 ; in the kidney leads to progressive renal insufficiency and eventually failure 6 ; in the peripheral nervous system gives rise to gastrointestinal dysmotility, hypohidrosis, temperature intolerance, dysregulation of vascular tone, and characteristic acroparesthesias of the hands and feet. [7][8][9] Obstructive lung disease and impaired exercise tolerance are also seen.…”

Place de la maladie de Fabry dans les cardiomyopathies hypertrophiques

“…Les patients à risque de mort subite, si redouté, ne représentent que moins de 5 % de l'ensemble de la population des CMH et, globalement, la survie à long terme pour la majorité des patients n'est pas très différente de celle de la population générale, du moins pour les formes autosomiques dominantes. Ainsi, pour une présentation initiale qui peut être similaire, les pronostics de ces maladies sont très différents : le plus souvent favorables dans la CMH, cause majeure de décès avec une réduction de l'espérance de vie de 15 à 20 ans dans la maladie de Fabry [1,2,4].…”

“…L'atteinte cardiaque de la maladie de Fabry est très fréquente, non spécifique (HVG chez plus de 70 % des cas après l'âge de 30 ans, fuite mitrale, blocs de branche ou auriculo-ventriculaire, PR court, coronaropathie, insuffisance cardiaque…). Elle peut être isolée avec HVG progressive et sévère chez les hommes hémizygotes comme chez les femmes hétérozygotes [4,5]. Le réel problème en milieu cardiologique adulte est le diagnostic d'une HVG sans cause identifiée se présentant comme une maladie cardiaque isolée ou largement prédominante.…”