title: Characterization of early disease status in treatment-naive male paediatric patients with Fabry disease enrolled in a randomized clinical trial.
abstract: METHODS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00701415.
authors.affiliation: Academic Medical Center, University Hospital of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Frits A
authors.initials: FA
authors.lastname: Wijburg
authors.affiliation: Genzyme Europe, Saint-Germain-en-Laye, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Bénichou
authors.affiliation: Hôpital du Sacré-Cœur de Montréal and University of Montreal, Montreal, QC, Canada.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Bichet
authors.affiliation: University of British Columbia, Child and Family Research Institute, Vancouver, BC, Canada.
authors.forename: Lorne A
authors.initials: LA
authors.lastname: Clarke
authors.affiliation: Charles University Prague, General University Hospital Prague, Prague, Czech Republic.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Dostalova
authors.affiliation: Hospital de Niños Ricardo Gutierrez, Hospital de Día Polivalente, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Fainboim
authors.affiliation: University Medical Center Mainz, Mainz, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Fellgiebel
authors.affiliation: Hospital São Vicente de Paulo, Passo Fundo, RS, Brazil.
authors.forename: Cassiano
authors.initials: C
authors.lastname: Forcelini
authors.affiliation: Sanofi, Chilly-Mazarin, France.
authors.forename: Kristina
authors.initials: K
authors.lastname: An Haack
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hopkin
authors.affiliation: Departments of Pediatrics and Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Mauer
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Behzad
authors.initials: B
authors.lastname: Najafian
authors.affiliation: University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Scott
authors.affiliation: Emory University School of Medicine, Decatur, Georgia, United States of America.
authors.forename: Suma P
authors.initials: SP
authors.lastname: Shankar
authors.affiliation: Department of Pathology, Genzyme, Framingham, Massachusetts, United States of America.
authors.forename: Beth L
authors.initials: BL
authors.lastname: Thurberg
authors.affiliation: Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Camilla
authors.initials: C
authors.lastname: Tøndel
authors.affiliation: Klinika Pediatrii, Żywienia i Chorób Metabolicznych Instytut "Pomnik - Centrum Zdrowia Dziecka", Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Tylki-Szymańska
authors.affiliation: Royal Free Hospital, London, United Kingdom.
authors.forename: Uma
authors.initials: U
authors.lastname: Ramaswami
mesh_terms: D000293:Adolescent; D001706:Biopsy; D001921:Brain / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003710:Demography; D004730:Endothelium, Vascular / Q000473:pathology; D000795:Fabry Disease / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology / Q000652:urine; D005838:Genotype; D005919:Glomerular Filtration Rate; D006017:Glycolipids / Q000097:blood; D006801:Humans; D007472:Iohexol; D007668:Kidney / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D008297:Male; D009154:Mutation / Q000235:genetics; D011788:Quality of Life; D012867:Skin / Q000098:blood supply; D013107:Sphingolipids / Q000097:blood; D014281:Trihexosylceramides / Q000097:blood / Q000235:genetics / Q000652:urine
chemical_list: D006017:Glycolipids; D013107:Sphingolipids; D014281:Trihexosylceramides; C063288:globotriaosyl lysosphingolipid; D007472:Iohexol; C018549:globotriaosylceramide