Abstract
Despite enzyme replacement therapy, disease progression is observed in patients with Fabry disease. Identification of factors that predict disease progression is needed to refine guidelines on initiation and cessation of enzyme replacement therapy. To study the association of potential biochemical and clinical prognostic factors with the disease course (clinical events, progression of cardiac and renal disease) we retrospectively evaluated 293 treated patients from three international centers of excellence. As expected, age, sex and phenotype were important predictors of event rate. Clinical events before enzyme replacement therapy, cardiac mass and eGFR at baseline predicted an increased event rate. eGFR was the most important predictor: hazard ratios increased from 2 at eGFR <90 ml/min/1.73m2 to 4 at eGFR <30, compared to patients with an eGFR >90. In addition, men with classical disease and a baseline eGFR <60 ml/min/1.73m2 had a faster yearly decline (-2.0 ml/min/1.73m2) than those with a baseline eGFR of >60. Proteinuria was a further independent risk factor for decline in eGFR. Increased cardiac mass at baseline was associated with the most robust decrease in cardiac mass during treatment, while presence of cardiac fibrosis predicted a stronger increase in cardiac mass (3.36 gram/m2/year). Of other cardiovascular risk factors, hypertension significantly predicted the risk for clinical events. In conclusion, besides increasing age, male sex and classical phenotype, faster disease progression while on enzyme replacement therapy is predicted by renal function, proteinuria and to a lesser extent cardiac fibrosis and hypertension.
Highlights
Fabry disease (FD, OMIM 301500) is a rare X-linked lysosomal storage disorder caused by deficiency of the lysosomal enzyme alpha galactosidase A due to mutations in the GLA gene (Xq22.1)
It is of interest to see how important these differences are: men with classical FD have for example a five times higher risk for events compared to women with non-classical FD, and with every 10 years increase in age, the risk of events doubles
The strongest association were observed for the presence of clinical event before the initiation of ERT and estimated glomerular filtration rate (eGFR)
Summary
Fabry disease (FD, OMIM 301500) is a rare X-linked lysosomal storage disorder caused by deficiency of the lysosomal enzyme alpha galactosidase A (aGAL, enzyme commission number: 3.2.1.22) due to mutations in the GLA gene (Xq22.1). Accumulation of glycosphingolipids, globotriaosylceramide (Gb3), in various cell types results in multi-system disease [1, 2]. Long term disease manifestations include progressive renal failure, hypertrophic cardiomyopathy, cardiac rhythm disturbances and stroke [3]. Classical disease in men is characterized by multi-organ involvement, absent to very low aGAL activity and the presence of specific FD symptoms including cornea verticillata, angiokeratoma and neuropathic pain [5]. Non-classical men and women generally have a more attenuated disease course [6,7,8]
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