Abstract
BackgroundFabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency leading to renal, cardiac, cerebrovascular disease and premature death. Treatment with α-galactosidase A (enzyme replacement therapy, ERT) stabilises disease in some patients, but long term effectiveness is unclear.MethodsRenal, cardiac, and cerebral outcomes were prospectively studied in males and females with Fabry disease treated with ERT. Additionally, the occurrence of major cardiac events, stroke, end-stage renal disease and death was compared to a natural history (NH) cohort meeting treatment criteria.ResultsOf 75 patients on ERT (median treatment duration 5.2 years, range 0.05-11.0), prospective follow-up was available for 57 adult patients (30 males) and 6 adolescents. Renal function declined in males (-3.4 ml/min/1.73 m2 per year, SE 0.2; p < 0.001) despite ERT, but followed the normal course in females (-0.8 ml/min/1.73 m2 per year, SE 0.3; p = 0.001). Cardiac mass increased during ERT in males (+ 1.2 gram/m2.7, SE 0.3; p < 0.001), but remained stable in females (-0.3 gram/m2.7 per year, SE 0.4; p = 0.52). ERT did not prevent the occurrence of cerebral white matter lesions. Comparison of ERT treated to untreated patients revealed that the odds to develop a first complication increased with age (OR 1.05 (95% CI: 1.0-1.1) per year, p = 0.012). For development of a first or second complication the odds declined with longer treatment duration (OR 0.81 (95% CI: 0.68-0.96) per year of ERT, p = 0.015;OR 0.52 (0.31-0.88), p = 0.014 respectively).ConclusionsLong term ERT does not prevent disease progression, but the risk of developing a first or second complication declines with increasing treatment duration. ERT in advanced Fabry disease seems of doubtful benefit.
Highlights
Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency leading to renal, cardiac, cerebrovascular disease and premature death
Fabry disease is an X-linked lysosomal storage disorder caused by deficiency of α-galactosidase A [1,2] leading to accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3)
Enzyme replacement therapy (ERT) cohort and natural history (NH) cohort The Academic Medical Center serves as the Dutch Fabry disease referral center
Summary
Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency leading to renal, cardiac, cerebrovascular disease and premature death. Treatment with α-galactosidase A (enzyme replacement therapy, ERT) stabilises disease in some patients, but long term effectiveness is unclear. Fabry disease is an X-linked lysosomal storage disorder caused by deficiency of α-galactosidase A [1,2] leading to accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3). Males with classical disease manifestations usually have no residual α- galactosidase A activity and can present with acroparesthesia, anhidrosis, angiokeratoma during childhood followed by renal, cardiac and cerebrovascular complications and early death [3]. With preserved residual enzyme activity, can exhibit a more attenuated course [5]. LysoGb3, a new marker in Fabry disease, can be used to distinguish patients with an
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