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

Frits A. Wijburg, Bernard Bénichou, Daniel G. Bichet, Lorne A. Clarke, Gabriela Dostalova, Alejandro Fainboim, Andreas Fellgiebel, Cassiano Forcelini, Kristina An Haack, Robert J. Hopkin, Michael Mauer, Behzad Najafian, C. Ronald Scott, Suma P. Shankar, Beth L. Thurberg, Camilla Tøndel, Anna Tylki-Szymańska, Uma Ramaswami

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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 noncapillary 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.

Original languageEnglish (US)
Article numbere0124987
JournalPloS one
Volume10
Issue number5
DOIs
StatePublished - May 1 2015

Fingerprint

Fabry Disease
Pediatrics
randomized clinical trials
Endothelial cells
Randomized Controlled Trials
Plasmas
Biopsy
Kidney
kidneys
Skin
Galactosidases
Podocytes
Iohexol
glomerular filtration rate
Endothelial Cells
Glomerular Filtration Rate
Glycolipids
blood vessels
skin (animal)
Therapeutics

Cite this

Wijburg, F. A., Bénichou, B., Bichet, D. G., Clarke, L. A., Dostalova, G., Fainboim, A., ... Ramaswami, U. (2015). Characterization of early disease status in treatment-naive male paediatric patients with fabry disease enrolled in a randomized clinical trial. PloS one, 10(5), [e0124987]. https://doi.org/10.1371/journal.pone.0124987

Characterization of early disease status in treatment-naive male paediatric patients with fabry disease enrolled in a randomized clinical trial. / Wijburg, Frits A.; Bénichou, Bernard; Bichet, Daniel G.; Clarke, Lorne A.; Dostalova, Gabriela; Fainboim, Alejandro; Fellgiebel, Andreas; Forcelini, Cassiano; Haack, Kristina An; Hopkin, Robert J.; Mauer, Michael; Najafian, Behzad; Scott, C. Ronald; Shankar, Suma P.; Thurberg, Beth L.; Tøndel, Camilla; Tylki-Szymańska, Anna; Ramaswami, Uma.

In: PloS one, Vol. 10, No. 5, e0124987, 01.05.2015.

Research output: Contribution to journalArticle

Wijburg, FA, Bénichou, B, Bichet, DG, Clarke, LA, Dostalova, G, Fainboim, A, Fellgiebel, A, Forcelini, C, Haack, KA, Hopkin, RJ, Mauer, M, Najafian, B, Scott, CR, Shankar, SP, Thurberg, BL, Tøndel, C, Tylki-Szymańska, A & Ramaswami, U 2015, 'Characterization of early disease status in treatment-naive male paediatric patients with fabry disease enrolled in a randomized clinical trial', PloS one, vol. 10, no. 5, e0124987. https://doi.org/10.1371/journal.pone.0124987
Wijburg, Frits A. ; Bénichou, Bernard ; Bichet, Daniel G. ; Clarke, Lorne A. ; Dostalova, Gabriela ; Fainboim, Alejandro ; Fellgiebel, Andreas ; Forcelini, Cassiano ; Haack, Kristina An ; Hopkin, Robert J. ; Mauer, Michael ; Najafian, Behzad ; Scott, C. Ronald ; Shankar, Suma P. ; Thurberg, Beth L. ; Tøndel, Camilla ; Tylki-Szymańska, Anna ; Ramaswami, Uma. / Characterization of early disease status in treatment-naive male paediatric patients with fabry disease enrolled in a randomized clinical trial. In: PloS one. 2015 ; Vol. 10, No. 5.
@article{6bf2a8fe9c754189b88264a76fc755fc,
title = "Characterization of early disease status in treatment-naive male paediatric patients with fabry disease enrolled in a randomized clinical trial",
abstract = "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 noncapillary 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.",
author = "Wijburg, {Frits A.} and Bernard B{\'e}nichou and Bichet, {Daniel G.} and Clarke, {Lorne A.} and Gabriela Dostalova and Alejandro Fainboim and Andreas Fellgiebel and Cassiano Forcelini and Haack, {Kristina An} and Hopkin, {Robert J.} and Michael Mauer and Behzad Najafian and Scott, {C. Ronald} and Shankar, {Suma P.} and Thurberg, {Beth L.} and Camilla T{\o}ndel and Anna Tylki-Szymańska and Uma Ramaswami",
year = "2015",
month = "5",
day = "1",
doi = "10.1371/journal.pone.0124987",
language = "English (US)",
volume = "10",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "5",

}

TY - JOUR

T1 - Characterization of early disease status in treatment-naive male paediatric patients with fabry disease enrolled in a randomized clinical trial

AU - Wijburg, Frits A.

AU - Bénichou, Bernard

AU - Bichet, Daniel G.

AU - Clarke, Lorne A.

AU - Dostalova, Gabriela

AU - Fainboim, Alejandro

AU - Fellgiebel, Andreas

AU - Forcelini, Cassiano

AU - Haack, Kristina An

AU - Hopkin, Robert J.

AU - Mauer, Michael

AU - Najafian, Behzad

AU - Scott, C. Ronald

AU - Shankar, Suma P.

AU - Thurberg, Beth L.

AU - Tøndel, Camilla

AU - Tylki-Szymańska, Anna

AU - Ramaswami, Uma

PY - 2015/5/1

Y1 - 2015/5/1

N2 - 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 noncapillary 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.

AB - 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 noncapillary 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.

UR - http://www.scopus.com/inward/record.url?scp=84947505460&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84947505460&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0124987

DO - 10.1371/journal.pone.0124987

M3 - Article

C2 - 25955246

AN - SCOPUS:84947505460

VL - 10

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 5

M1 - e0124987

ER -