Characterization of early disease status in treatment-naive male paediatric patients with Fabry disease enrolled in a randomized clinical trial

PLoS One. 2015 May 8;10(5):e0124987. doi: 10.1371/journal.pone.0124987. eCollection 2015.


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: NCT00701415.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Biopsy
  • Brain / pathology
  • Child
  • Child, Preschool
  • Demography
  • Endothelium, Vascular / pathology
  • Fabry Disease / blood
  • Fabry Disease / drug therapy*
  • Fabry Disease / physiopathology
  • Fabry Disease / urine
  • Genotype
  • Glomerular Filtration Rate
  • Glycolipids / blood
  • Humans
  • Iohexol
  • Kidney / pathology
  • Kidney / physiopathology
  • Kidney / ultrastructure
  • Male
  • Mutation / genetics
  • Quality of Life
  • Skin / blood supply
  • Sphingolipids / blood
  • Trihexosylceramides / blood
  • Trihexosylceramides / genetics
  • Trihexosylceramides / urine


  • Glycolipids
  • Sphingolipids
  • Trihexosylceramides
  • globotriaosyl lysosphingolipid
  • Iohexol
  • globotriaosylceramide

Associated data


Grant support

This study was funded by Genzyme, a Sanofi company. Three of the authors, B.B., B.L.T., and K.A.H., are full-time paid employees of Genzyme/Sanofi. The specific roles of all authors are articulated in the 'Author Contributions' section. The authors received editorial/writing support in the preparation of this manuscript (provided by Niina Nuottamo and Alessia Piazza of Excerpta Medica, funded by Genzyme), but were responsible for all content and editorial decisions. The funder had a role in study design, data collection and analysis.