The natural history of fabry disease

Abstract

Glycolipid accumulation leads to organ damage and renal, cardiac and cerebrovascular events in Fabry disease. Schiffmann et al1 conducted a chart review of 279 affected males and 168 females from 27 sites. The mean rate of glomerular filtration rate (eGFR) decline was –2.93 for males, and –1.02 ml/min/1.73 m2/year for females. Proteinuria, baseline eGFR 300 mg/24 h) was found in 43% and 26% of males and females with CKD stage 1, respectively, and the proportions were higher with more severe kidney involvement. Systemic blood pressure was ≥130/80 mm Hg in 48% and 67% of patients with eGFR ≥ and <60 ml/min/1.73 m2, respectively, with no significant differences between males and females. The most recent analysis3 shows that females who progress to ESRD do so at the same age as males, indicating that there is a subset of females with burden of disease as severe as male patients. Cardiac abnormalities are characterized mainly by left ventricular (LV) wall thickening without significant dilatation, and LV hypertrophy (LVH).4 In some patients the disease mimics a typical hypertrophic obstructive cardiomyopathy. Systolic function is largely preserved in a large majority of affected individuals. In contrast, mild to moderate impairment of diastolic filling is a relatively common finding. Electrocardiographic changes in Fabry disease are multiple and include atrioventricular conduction abnormalities, signs of LVH and repolarization abnormalities. Cardiac symptoms in patients with Fabry disease include shortness of breath on effort (related to LV diastolic dysfunction), vasospastic and/or exertional angina pectoris, and syncope. Linhart et al5 described the cardiac disease in Fabry patients. Gender, age, and glomerular filtration rate were independent determinants of LVH. Takenaka et al6 reviewed the so-called cardiac variant for patients with manifestations limited to the heart, and the terminal stage cardiac manifestations and autopsy findings for 7 patients with cardiac Fabry disease. Six patients died of heart failure and one of ventricular fibrillation. Echocardiograms and autopsy findings revealed LVH in all patients. Localized basal posterior wall thinning of the left ventricle was detected in the 6 patients who died of heart failure. All patients had severe left ventricular dysfunction. With a better understanding of the natural history of Fabry disease, intervention studies and treatment expectations can be better defined, with the goal of reducing loss of eGFR to an absolute minimum (<–1.0 ml/min/ 1.73 m2/year). Current treatment studies of advanced Fabry disease7 have been dominated by renal outcome events. If progression loss of eGFR can be controlled, then outcome studies can be focused on cardiovascular events.