Fabry Disease: prevalence of affected males and heterozygotes with pathogenic <i>GLA</i> mutations identified by screening renal, cardiac and stroke clinics, 1995–2017

Doheny, Dana; Srinivasan, Ram; Pagant, Silvère; Chen, Brenden; Yasuda, Makiko; Desnick, Robert J.

doi:10.1136/jmedgenet-2017-105080

Cited by 103 publications

(93 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The high-risk screening for FD in selected patient cohorts has been reported. Doheny et al [23] reanalyzed studies related to hemodialysis (27 reports, 23,954 males, and 12,866 females), left ventricular hypertrophy (LVH) and/or hypertrophic cardiomyopathy (HCM) (17 reports, 4,054 males, and 1,437 females), and ischemic or cryptogenic strokes (16 studies, 3,904 males, and 2,074 females). The revised prevalence was estimated as 0.21% for male and 0.15% for female hemodialysis patients, 0.94% for male and 0.90% for female cardiac patients, and 0.13% for male and 0.14% for female stroke patients.…”

Section: Discussionmentioning

confidence: 99%

Fabry disease screening in high-risk populations in Japan: A nationwide study

Yoshida

Kido

Sawada

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Fabry disease (FD) is a rare, X-linked inherited disorder caused by mutations in the GLA gene, which results in deficiency of α-galactosidase A (α-Gal A). This leads to the progressive accumulation of metabolites, which can cause malfunctions in systemic organs. A recent screening study in newborns demonstrated that the incidence of FD was more frequent than previously estimated and that there are still many undiagnosed or misdiagnosed Fabry patients. Therefore, the purpose of this study was to identify Fabry patients by performing high-risk screening in 18,171 individuals, enrolled from October 2006 to March 2019, with renal, cardiac, or neurological manifestations from all of the prefectures in Japan. A total of 601 hospitals from all the prefectures in Japan participated in this study. Results: From October 2006 to March 2019, 18,171 individuals with renal, cardiac, or neurological manifestations were enrolled. Low α-Gal A activity was detected in 846 individuals, with 224 of them diagnosed with FD by GLA sequencing. Cases with a family history of FD (n = 64) were also subjected to sequencing, without α-Gal A assay, as per individual request and 12 of them were diagnosed with a variant of FD. A total of 236 Fabry patients (97 males and 139 females) were detected from the 18,235 participants. There were 101 GLA variants, including 26 novel variants, detected in the 236 Fabry patients from 143 families, with 39 amenable variants (39%) and 79 of the 236 patients (33%) suitable for migalastat treatment. Conclusions: From the 18,235 participants, 101 GLA variants, including 26 novel variants, were identified in the 236 Fabry patients from 143 families. Migalastat was identified as a suitable treatment option in 33% of the Fabry patients and 39% of the GLA variants were detected as amenable. Therefore, the simple screening protocol, using dried blood spots, that was performed in this study could be useful for early diagnosis and selection of appropriate treatments for FD in high-risk and underdiagnosed patients suffering from various renal, cardiac, or neurological manifestations.

show abstract

Section: Discussionmentioning

confidence: 99%

Fabry disease screening in high-risk populations in Japan: A nationwide study

Yoshida

Kido

Sawada

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…In Europe and in the United States, the prevalence of Fabry disease among patients on RRT was 0.0188 (83/440,665 patients) and 0.0167 (42/250,352 patients), respectively [ 8 , 9 ]. Despite this low prevalence new prospective screening among ESRD patients have shown a >10 times higher prevalence of Fabry disease (0,12–0,3%) [ [10] , [11] , [12] ].…”

Section: Discussionmentioning

confidence: 99%

Fabry disease. A potential pitfall A family with a novel intronic mutation

Gustavo¹,

Perretta²

2018

Molecular Genetics and Metabolism Reports

View full text Add to dashboard Cite

Fabry disease is a genetic disorder characterized by the accumulation of globotriaosylceramide in cell lysosomes resulting from an X-linked deficiency of α-galactosidase A activity. It presents with multiorgan manifestations, including progressive renal disease, cardiomyopathy and premature demise. Recently, its prevalence has been reported to be higher in hemodialysis (HD) patients than in the general population. We report two cases of homozygous patients with an intronic alpha-galactosidase gene mutation and a classic phenotype of the disease. One of the patients had a kidney transplant and the donor was his brother, before Fabry disease were diagnose.

show abstract

“…Patients with the late-onset phenotype have varied ages of onset and clinical manifestations, with typical cardiac and renal symptoms [ 16 , 17 ]. Fabry disease females are heterozygous and present varying degrees of symptoms, ranging from asymptomatic to severe [ 18 , 19 , 20 ]. This phenotypic is due, most probably, to X-inactivation.…”

Section: Introductionmentioning

confidence: 99%

Misfolding of Lysosomal α-Galactosidase a in a Fly Model and Its Alleviation by the Pharmacological Chaperone Migalastat

Braunstein

Papazian

Maor

et al. 2020

IJMS

View full text Add to dashboard Cite

Fabry disease, an X-linked recessive lysosomal disease, results from mutations in the GLA gene encoding lysosomal α-galactosidase A (α-Gal A). Due to these mutations, there is accumulation of globotriaosylceramide (GL-3) in plasma and in a wide range of cells throughout the body. Like other lysosomal enzymes, α-Gal A is synthesized on endoplasmic reticulum (ER) bound polyribosomes, and upon entry into the ER it undergoes glycosylation and folding. It was previously suggested that α-Gal A variants are recognized as misfolded in the ER and undergo ER-associated degradation (ERAD). In the present study, we used Drosophila melanogaster to model misfolding of α-Gal A mutants. We did so by creating transgenic flies expressing mutant α-Gal A variants and assessing development of ER stress, activation of the ER stress response and their relief with a known α-Gal A chaperone, migalastat. Our results showed that the A156V and the A285D α-Gal A mutants underwent ER retention, which led to activation of unfolded protein response (UPR) and ERAD. UPR could be alleviated by migalastat. When expressed in the fly’s dopaminergic cells, misfolding of α-Gal A and UPR activation led to death of these cells and to a shorter life span, which could be improved, in a mutation-dependent manner, by migalastat.

show abstract

Fabry Disease: prevalence of affected males and heterozygotes with pathogenic GLA mutations identified by screening renal, cardiac and stroke clinics, 1995–2017

Cited by 103 publications

References 87 publications

Fabry disease screening in high-risk populations in Japan: A nationwide study

Fabry disease screening in high-risk populations in Japan: A nationwide study

Fabry disease. A potential pitfall A family with a novel intronic mutation

Misfolding of Lysosomal α-Galactosidase a in a Fly Model and Its Alleviation by the Pharmacological Chaperone Migalastat

Contact Info

Product

Resources

About