Lyso-Gb3 Indicates that the Alpha-Galactosidase A Mutation D313Y is not Clinically Relevant for Fabry Disease

Niemann, Markus; Rolfs, Arndt; Giese, Anne Katrin; Mascher, Hermann; Breunig, Frank; Ertl, Georg; Wanner, Christoph; Weidemann, Frank

doi:10.1007/8904_2012_154

Cited by 58 publications

(60 citation statements)

References 17 publications

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“…A seventh had a single disease-neutral variant (p.D313Y), which was previously associated with pseudodeficient α-GAL-A activity and leukoaraiosis. [13][14][15][16] The eighth patient had a single variant (p.R118C) classified as GVUS. 8 Clinically, no patients exhibited the classic early-onset phenotype of Fabry.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of Fabry Disease and Outcomes in Young Canadian Patients With Cryptogenic Ischemic Cerebrovascular Events

Lanthier

Saposnik²,

Lebovic³

et al. 2017

Stroke

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Background and Purpose-Previous studies reported Fabry disease in 0% to 4% of young patients with cryptogenic ischemic stroke (IS). We sought to determine the prevalence of Fabry and outcomes among young Canadians with cryptogenic IS or transient ischemic attack (TIA). Methods-We prospectively enrolled individuals aged 18 to 55 with IS or speech or motor TIA, and no cause identified despite predetermined investigation. α-galactosidase-A gene was sequenced for Fabry diagnosis. National Institutes of Health Stroke Scale score was measured at presentation to quantify stroke severity. Modified Rankin Scale determined functional outcomes ≤7 days after presentation and 6 months later. Results-We enrolled 365 patients with IS and 32 with TIA. α-galactosidase-A sequencing identified a single carrier of a genetic variant of unknown significance (p.R118C) and no well-recognized pathogenic variants. Mean National Institutes of Health Stroke Scale score was 3.1. Proportion of patients with modified Rankin Scale of 0 to 2 was 70.7% at ≤7 days and 87.4% at 6 months. National Institutes of Health Stroke Scale score at presentation and diabetes mellitus predicted 6-month modified Rankin Scale. Thirteen patients experienced 5 recurrent IS and 9 TIA during follow-up. No patient died. Most patients (98.7%) returned home. Among previous workers, 43% had residual working limitations. Conclusions-In this Canadian cohort of patients with cryptogenic IS or TIA, the prevalence of Fabry was 0.3% if p.R118C variant is considered as pathogenic. This suggests that more cost-effective methods should be applied for diagnosis of Fabry rather than systematic genetic screening in this population. Overall, cryptogenic IS in young adults is associated with favorable outcomes.

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Section: Discussionmentioning

confidence: 99%

Prevalence of Fabry Disease and Outcomes in Young Canadian Patients With Cryptogenic Ischemic Cerebrovascular Events

Lanthier

Saposnik²,

Lebovic³

et al. 2017

Stroke

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“…Second: in females coinheriting a negatively acting GLA 5 0 UTR SNP in trans with a pathogenic GLA mutation, the compound heterozygosity may significantly decrease the REA and aggravate the clinical phenotype since the aGal activity would be subnormal in all cells, irrespective of which of the two X chromosomes is inactivated. Third: in individuals carrying GLA variants associated with small decreases in REA, which otherwise would not be the cause of FD clinical phenotypes -like the p.Arg118Cys (Ferreira et al 2015) and the p.Asp313Tyr (Yasuda et al 2003;Niemann et al 2013) -the additive effect of a negatively acting GLA 5 0 UTR SNP in cis could decrease REA into the typical range of mutations associated with later-onset phenotypic variants of FD (Ferreira et al 2015), thereby modifying the expected phenotype. This might also affect the probability of identifying individuals carrying such mutations in large case-finding studies of FD among high-risk patients, when the primary screening method is based on aGal activity analysis.…”

Section: Discussionmentioning

confidence: 99%

The Modulatory Effects of the Polymorphisms in GLA 5′-Untranslated Region Upon Gene Expression Are Cell-Type Specific

2015

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Lysosomal a-galactosidase A (aGal) is the enzyme deficient in Fabry disease (FD). The 5 0 -untranslated region (5 0 UTR) of the aGal gene (GLA) shows a remarkable degree of variation with three common single nucleotide polymorphisms at nucleotide positions c.-30G>A, c.-12G>A and c.-10C>T. We have recently identified in young Portuguese stroke patients a fourth polymorphism, at c.-44C>T, co-segregating in cis with the c.-12A allele. In vivo, the c.-30A allele is associated with higher enzyme activity in plasma, whereas c.-10T is associated with moderately decreased enzyme activity in leucocytes. Limited data suggest that c.-44T might be associated with increased plasma aGal activity. We have used a luciferase reporter system to experimentally assess the relative modulatory effects on gene expression of the different GLA 5 0 UTR polymorphisms, as compared to the wild-type sequence, in four different human cell lines. Group-wise, the relative luciferase expression patterns of the various GLA variant isoforms differed significantly in all four cell lines, as evaluated by non-parametric statistics, and were cell-type specific. Some of the post hoc pairwise statistical comparisons were also significant, but the observed effects of the GLA 5 0 UTR polymorphisms upon the luciferase transcriptional activity in vitro did not consistently replicate the in vivo observations. These data suggest that the GLA 5 0 UTR polymorphisms are possible modulators of the aGal expression. Further studies are needed to elucidate the biological and clinical implications of these observations, particularly to clarify the effect of these polymorphisms in individuals carrying GLA variants associated with high residual enzyme activity, with no or mild FD clinical phenotypes.

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“…However, it should be noted that in these studies, genetic testing was not used to confirm the diagnosis suggested by a low α-Gal A enzyme activity in plasma, DBS or in leukocytes. A possible consequence of this choice would be a larger number of false positive (FP) results, for example, with carriers of the D313Y polymorphism, who present with a pseudodeficiency of α-Gal A (they have a low plasma enzyme level, while the activity in leukocytes is normal) [24,25]. Additionally, the population studied also can present with a higher rate of FP with enzyme activity approximately 40-50% lower among non-FD carrier patients under dialysis compared to those who are not receiving dialysis therapy [26].…”

Section: Discussionmentioning

confidence: 99%

Targeted Screening of Fabry Disease in Male Hemodialysis Patients in Brazil Highlights Importance of Family Screening

Silva

Barreto

Reis

et al. 2016

Nephron

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Introduction: Fabry disease (FD) is a lysosomal storage disorder caused by enzyme α galactosidase A (α-Gal A) deficiency due to mutations in the galactosidase alpha (GLA) gene. It leads to damage several organs, such as the kidneys, due to progressive accumulation of glycosphingolipids. Objective: To estimate the prevalence of FD among male hemodialysis (HD) patients in a northern state of Brazil. Methods: Screening was performed using a dried blood spot on filter paper to identify patients with low α-Gal A enzyme activity (≤2.2 µmol/l/h). Those with low enzyme activity underwent genetic analysis of the GLA gene. Family screening was conducted in the index cases. Results: 2,583 male HD patients (age: 52 (18-91 years)) were screened. The α-Gal A assay identified 72 males (2.78%) with low enzyme activity. Genotyping identified 3 patients with GLA mutations: W204X, A368T, both previously reported; and C52F, a novel missense mutation. Only the patient with W204X mutation had classic FD. The prevalence rate was 0.12%. Family screening of the index cases identified 23 family members with the same mutations. Conclusions: The prevalence of FD amongst male HD patients found in the Northern of Brazil was low (0.12%). However, family screening of the 3 index cases identified family members at an early stage of the disease, which may benefit from earlier treatment.

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Lyso-Gb3 Indicates that the Alpha-Galactosidase A Mutation D313Y is not Clinically Relevant for Fabry Disease

Cited by 58 publications

References 17 publications

Prevalence of Fabry Disease and Outcomes in Young Canadian Patients With Cryptogenic Ischemic Cerebrovascular Events

Prevalence of Fabry Disease and Outcomes in Young Canadian Patients With Cryptogenic Ischemic Cerebrovascular Events

The Modulatory Effects of the Polymorphisms in GLA 5′-Untranslated Region Upon Gene Expression Are Cell-Type Specific

Targeted Screening of Fabry Disease in Male Hemodialysis Patients in Brazil Highlights Importance of Family Screening

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