TRIAL DESIGN: This analysis characterizes the degree of early organ involvement in a cohort of oligo-symptomatic untreated young patients with Fabry disease enrolled in an ongoing randomized, open-label, parallel-group, phase 3B clinical trial. METHODS: Males aged 5-18 years with complete α-galactosidase A deficiency, without symptoms of major organ damage, were enrolled in a phase 3B trial evaluating two doses of agalsidase beta. Baseline disease characteristics of 31 eligible patients (median age 12 years) were studied, including cellular globotriaosylceramide (GL-3) accumulation in skin (n = 31) and kidney biopsy (n = 6; median age 15 years; range 13-17 years), renal function, and glycolipid levels (plasma, urine). RESULTS: Plasma and urinary GL-3 levels were abnormal in 25 of 30 and 31 of 31 patients, respectively. Plasma lyso-GL-3 was elevated in all patients. GL-3 accumulation was documented in superficial skin capillary endothelial cells (23/31 patients) and deep vessel endothelial cells (23/29 patients). The mean glomerular filtration rate (GFR), measured by plasma disappearance of iohexol, was 118.1 mL/min/1.73 m(2) (range 90.4-161.0 mL/min/1.73 m(2)) and the median urinary albumin/creatinine ratio was 10 mg/g (range 4.0-27.0 mg/g). On electron microscopy, renal biopsy revealed GL-3 accumulation in all glomerular cell types (podocytes and parietal, endothelial, and mesangial cells), as well as in peritubular capillary and non-capillary endothelial, interstitial, vascular smooth muscle, and distal tubules/collecting duct cells. Lesions indicative of early Fabry arteriopathy and segmental effacement of podocyte foot processes were found in all 6 patients. CONCLUSIONS: These data reveal that in this small cohort of children with Fabry disease, histological evidence of GL-3 accumulation, and cellular and vascular injury are present in renal tissues at very early stages of the disease, and are noted before onset of microalbuminuria and development of clinically significant renal events (e.g. reduced GFR). These data give additional support to the consideration of early initiation of enzyme replacement therapy, potentially improving long-term outcome. TRIAL REGISTRATION: ClinicalTrials.gov NCT00701415.

Academic Medical Center University Hospital of Amsterdam Amsterdam The Netherlands

Charles University Prague General University Hospital Prague Prague Czech Republic

Cincinnati Children's Hospital Medical Center Cincinnati Ohio United States of America

Department of Pathology Genzyme Framingham Massachusetts United States of America

Department of Pathology University of Washington Seattle Washington United States of America

Department of Pediatrics Haukeland University Hospital Bergen Norway

Departments of Pediatrics and Medicine University of Minnesota Minneapolis Minnesota United States of America

Emory University School of Medicine Decatur Georgia United States of America

Genzyme Europe Saint Germain en Laye France

Hôpital du Sacré Cœur de Montréal and University of Montreal Montreal QC Canada

Hospital de Niños Ricardo Gutierrez Hospital de Día Polivalente Ciudad Autónoma de Buenos Aires Argentina

Hospital São Vicente de Paulo Passo Fundo RS Brazil

Klinika Pediatrii Żywienia i Chorób Metabolicznych Instytut Pomnik Centrum Zdrowia Dziecka Warsaw Poland

Royal Free Hospital London United Kingdom

Sanofi Chilly Mazarin France

University Medical Center Mainz Mainz Germany

University of British Columbia Child and Family Research Institute Vancouver BC Canada

University of Washington School of Medicine Seattle Washington United States of America

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NCT00701415