Reduction of podocyte globotriaosylceramide content in adult male patients with Fabry disease with amenable GLA mutations following 6 months of migalastat treatment

Michael Mauer, Alexey Sokolovskiy, Jay A. Barth, Jeffrey P. Castelli, Hadis N. Williams, Elfrida R. Benjamin, Behzad Najafian

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Objective Deficiency of a-galactosidase A (aGal-A) in Fabry disease leads to the accumulation mainly of globotriaosylceramide (GL3) in multiple renal cell types. Glomerular podocytes are relatively resistant to clearance of GL3 inclusions by enzyme replacement therapy (ERT). Migalastat, an orally bioavailable small molecule capable of chaperoning misfolded αGal-A to lysosomes, is approved in the European Union for the long-term treatment of patients with Fabry disease and amenable GLA (α-galactosidase A enzyme) mutations. We aimed to examine if migalastat reduces GL3 content of podocytes in Fabry disease. Methods and analysis We compared paired renal biopsies of eight adult men with amenable Fabry disease mutations at baseline and after 6 months of treatment with 150 mg migalastat every other day using quantitative unbiased electron microscopic morphometric methods. Results Migalastat treatment led to a reduction in mean total GL3 inclusion volume per podocyte in renal biopsies from baseline to 6 months. This reduction correlated precisely with reduced mean podocyte volume. There was also a direct relationship between reduction in podocyte foot process width and the reduction in mean total podocyte GL3 content following 6 months of migalastat treatment, suggestive of reduced podocyte injury. Conclusion Migalastat treatment of 6 months duration in eight male patients with Fabry disease demonstrated effective GL3 clearance from the podocyte, an important and relatively ERT-resistant glomerular cell.

Original languageEnglish (US)
Pages (from-to)781-786
Number of pages6
JournalJournal of medical genetics
Volume54
Issue number11
DOIs
StatePublished - Nov 1 2017

Fingerprint

Galactosidases
Fabry Disease
Podocytes
Mutation
Enzymes
Enzyme Replacement Therapy
Therapeutics
Kidney
Biopsy
migalastat
globotriaosylceramide
European Union
Lysosomes
Electrons

Cite this

Reduction of podocyte globotriaosylceramide content in adult male patients with Fabry disease with amenable GLA mutations following 6 months of migalastat treatment. / Mauer, Michael; Sokolovskiy, Alexey; Barth, Jay A.; Castelli, Jeffrey P.; Williams, Hadis N.; Benjamin, Elfrida R.; Najafian, Behzad.

In: Journal of medical genetics, Vol. 54, No. 11, 01.11.2017, p. 781-786.

Research output: Contribution to journalArticle

Mauer, Michael ; Sokolovskiy, Alexey ; Barth, Jay A. ; Castelli, Jeffrey P. ; Williams, Hadis N. ; Benjamin, Elfrida R. ; Najafian, Behzad. / Reduction of podocyte globotriaosylceramide content in adult male patients with Fabry disease with amenable GLA mutations following 6 months of migalastat treatment. In: Journal of medical genetics. 2017 ; Vol. 54, No. 11. pp. 781-786.
@article{9da5e2511feb425ba8329047c4871797,
title = "Reduction of podocyte globotriaosylceramide content in adult male patients with Fabry disease with amenable GLA mutations following 6 months of migalastat treatment",
abstract = "Objective Deficiency of a-galactosidase A (aGal-A) in Fabry disease leads to the accumulation mainly of globotriaosylceramide (GL3) in multiple renal cell types. Glomerular podocytes are relatively resistant to clearance of GL3 inclusions by enzyme replacement therapy (ERT). Migalastat, an orally bioavailable small molecule capable of chaperoning misfolded αGal-A to lysosomes, is approved in the European Union for the long-term treatment of patients with Fabry disease and amenable GLA (α-galactosidase A enzyme) mutations. We aimed to examine if migalastat reduces GL3 content of podocytes in Fabry disease. Methods and analysis We compared paired renal biopsies of eight adult men with amenable Fabry disease mutations at baseline and after 6 months of treatment with 150 mg migalastat every other day using quantitative unbiased electron microscopic morphometric methods. Results Migalastat treatment led to a reduction in mean total GL3 inclusion volume per podocyte in renal biopsies from baseline to 6 months. This reduction correlated precisely with reduced mean podocyte volume. There was also a direct relationship between reduction in podocyte foot process width and the reduction in mean total podocyte GL3 content following 6 months of migalastat treatment, suggestive of reduced podocyte injury. Conclusion Migalastat treatment of 6 months duration in eight male patients with Fabry disease demonstrated effective GL3 clearance from the podocyte, an important and relatively ERT-resistant glomerular cell.",
author = "Michael Mauer and Alexey Sokolovskiy and Barth, {Jay A.} and Castelli, {Jeffrey P.} and Williams, {Hadis N.} and Benjamin, {Elfrida R.} and Behzad Najafian",
year = "2017",
month = "11",
day = "1",
doi = "10.1136/jmedgenet-2017-104826",
language = "English (US)",
volume = "54",
pages = "781--786",
journal = "Journal of Medical Genetics",
issn = "0022-2593",
publisher = "BMJ Publishing Group",
number = "11",

}

TY - JOUR

T1 - Reduction of podocyte globotriaosylceramide content in adult male patients with Fabry disease with amenable GLA mutations following 6 months of migalastat treatment

AU - Mauer, Michael

AU - Sokolovskiy, Alexey

AU - Barth, Jay A.

AU - Castelli, Jeffrey P.

AU - Williams, Hadis N.

AU - Benjamin, Elfrida R.

AU - Najafian, Behzad

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Objective Deficiency of a-galactosidase A (aGal-A) in Fabry disease leads to the accumulation mainly of globotriaosylceramide (GL3) in multiple renal cell types. Glomerular podocytes are relatively resistant to clearance of GL3 inclusions by enzyme replacement therapy (ERT). Migalastat, an orally bioavailable small molecule capable of chaperoning misfolded αGal-A to lysosomes, is approved in the European Union for the long-term treatment of patients with Fabry disease and amenable GLA (α-galactosidase A enzyme) mutations. We aimed to examine if migalastat reduces GL3 content of podocytes in Fabry disease. Methods and analysis We compared paired renal biopsies of eight adult men with amenable Fabry disease mutations at baseline and after 6 months of treatment with 150 mg migalastat every other day using quantitative unbiased electron microscopic morphometric methods. Results Migalastat treatment led to a reduction in mean total GL3 inclusion volume per podocyte in renal biopsies from baseline to 6 months. This reduction correlated precisely with reduced mean podocyte volume. There was also a direct relationship between reduction in podocyte foot process width and the reduction in mean total podocyte GL3 content following 6 months of migalastat treatment, suggestive of reduced podocyte injury. Conclusion Migalastat treatment of 6 months duration in eight male patients with Fabry disease demonstrated effective GL3 clearance from the podocyte, an important and relatively ERT-resistant glomerular cell.

AB - Objective Deficiency of a-galactosidase A (aGal-A) in Fabry disease leads to the accumulation mainly of globotriaosylceramide (GL3) in multiple renal cell types. Glomerular podocytes are relatively resistant to clearance of GL3 inclusions by enzyme replacement therapy (ERT). Migalastat, an orally bioavailable small molecule capable of chaperoning misfolded αGal-A to lysosomes, is approved in the European Union for the long-term treatment of patients with Fabry disease and amenable GLA (α-galactosidase A enzyme) mutations. We aimed to examine if migalastat reduces GL3 content of podocytes in Fabry disease. Methods and analysis We compared paired renal biopsies of eight adult men with amenable Fabry disease mutations at baseline and after 6 months of treatment with 150 mg migalastat every other day using quantitative unbiased electron microscopic morphometric methods. Results Migalastat treatment led to a reduction in mean total GL3 inclusion volume per podocyte in renal biopsies from baseline to 6 months. This reduction correlated precisely with reduced mean podocyte volume. There was also a direct relationship between reduction in podocyte foot process width and the reduction in mean total podocyte GL3 content following 6 months of migalastat treatment, suggestive of reduced podocyte injury. Conclusion Migalastat treatment of 6 months duration in eight male patients with Fabry disease demonstrated effective GL3 clearance from the podocyte, an important and relatively ERT-resistant glomerular cell.

UR - http://www.scopus.com/inward/record.url?scp=85032204086&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85032204086&partnerID=8YFLogxK

U2 - 10.1136/jmedgenet-2017-104826

DO - 10.1136/jmedgenet-2017-104826

M3 - Article

C2 - 28756410

AN - SCOPUS:85032204086

VL - 54

SP - 781

EP - 786

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

IS - 11

ER -