Twelve-year Outcome of Enzyme Replacement Therapy in a Male Case with Classical Fabry Disease

Abstract

The main clinical management for Fabry disease is enzyme replacement therapy (ERT) with genetically recombinant agalsidase-β. ERT for Japanese Fabry disease was started in 2004. This is a report of a classical Fabry patient treated with ERT for 12 years.
The patient is a 49-year-old Japanese male having a nonsense mutation (p. A227X) in the α-GAL gene. He had sweating abnormality (anhydrosis), mild vascular cutaneous lesions (angiokeratomas) and proteinuria in childhood, but no periodic crises of pain in the extremities. ERT was initiated at the age of 37 in 2004 with 1mg/kg algalsidase-beta for 2 weeks.
There have been no severe clinical cardiac, cerebrovascular or renal events throughout. Echocardiography shows mild hypertrophic change of interventricular septum (10.5mm at baseline, 13.0mm at the end of follow-up), but normal left-ventricular thickness and volume. Brain MRI and MR angiography show normal white matter and cerebral arteries. However, gradual deterioration of renal function has occurred during these 12 years. He had stage 1 CKD at the baseline. The urine protein-to-creatinine ratio (UP/Cr), and the estimated glomerular filtration rate calculated from creatinine (eGFRcre) were 0.41 and 121.3ml/min per 1.73m² before ERT, and 0.74 and 52.0ml/min per 1.73m² recently. The slope for eGFRcre is -3.65ml/min per 1.73m² per year, which is a faster rate than the rate of decline in a normal individual (approximately -1.00ml/min per 1.73m² per year). In the most recent analysis the slope for eGFR calculated from cystacin C (eGFRcys) is -6.16ml/min per 1.73m² per year, which seems to show more rapidly progressive kidney disease. With regard to other clinical features, right-ear hearing loss appeared at the age of 42 and angiokeratomas increased with age, but anhydrosis disappeared in the early stage of ERT.
This report indicates that, compared to the natural history of Fabry disease, ERT has the effect of delaying the onset of severe events such as cardiac and cerebrovascular disease and end-stage renal disease. However, the therapy has not been as highly effective as expected.