Is the alpha‐galactosidase A variant <scp>p.Asp313Tyr</scp> (<scp>p.D313Y</scp>) pathogenic for Fabry disease? A systematic review

Effraimidis, Grigoris; Rasmussen, Åse Krogh; Bundgaard, Henning; Sørensen, Søren Schwartz; Feldt‐Rasmussen, Ulla

doi:10.1002/jimd.12240

Cited by 18 publications

(15 citation statements)

References 56 publications

(176 reference statements)

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“…This mutation was also encountered in the other four patients, who were asymptomatic with normal LysoGb3 values. This variant is considered of uncertain significance, following the American College of Medical Genetics and Genomics (ACMG) recommendations, and is widely reported in literature to have a low clinical significance [ 36 , 37 ], although there are some reports of patients carrying this variant, presenting with neurological symptoms [ 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…A recent systematic review [ 37 ] evaluating the clinical relevance of D313Y variant, found that most patients with D313Y variant had normal residual enzyme activity and normal Lyso-Gb3 levels. Moreover, the prevalence of this variant was comparable to that of the not-Fabry high-risk populations (kidney and /or heart disease), although a slight increased incidence was found in patients with neurological disorders [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

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Screening for Fabry Disease in Kidney Transplant Recipients: Experience of a Multidisciplinary Team

et al. 2020

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Fabry disease (FD) is a rare cause of end-stage renal disease requiring kidney transplantation. Data on the incidence of unrecognized FD in kidney transplant recipients are scarce and probably underestimated. This study evaluated the incidence of FD in a population of kidney recipients, with a particular focus of the multidisciplinary approach for an early clinical assessment and therapeutic approach. Two hundred sixty-five kidney transplant recipients were screened with a genetic analysis for α-galactosidase A (GLA) mutation, with measurement of α-Gal A enzyme activity and Lyso Gb3 levels. Screening was also extended to relatives of affected patients. Seven patients (2.6%) had a GLA mutation. Two patients had a classic form of FD with Fabry nephropathy. Among the relatives, 15 subjects had a GLA mutation, and two had a Fabry nephropathy. The clinical and diagnostic assessment was completed after a median of 3.2 months, and mean time from diagnosis to treatment was 4.6 months. This study reported a high incidence of unrecognized GLA mutations in kidney transplant recipients. Evaluation and management by a multidisciplinary team allowed for an early diagnosis and treatment, and this would result in a delay in the progression of the disease and, finally, in better long-term outcomes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Screening for Fabry Disease in Kidney Transplant Recipients: Experience of a Multidisciplinary Team

et al. 2020

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“…The carriers of the p.D313Y variant do not manifest the classical early-onset FD phenotype. The recent meta-analysis by Effraimidis et al collected all current data about p.D313Y and concluded that carriers described in literature had high residual enzyme activity, low frequency of clinical features specific for FD, non-elevated lyso-Gb3/Gb3 concentrations and lack of intracellular Gb3 accumulation in skin and kidney biopsies [ 18 ]. The prevalence of the variant in populations with cardiac (0.20%) and renal (0.42%) disease was comparable to the reported frequency in the general population.…”

Section: Discussionmentioning

confidence: 99%

“…The prevalence of the variant in populations with cardiac (0.20%) and renal (0.42%) disease was comparable to the reported frequency in the general population. A possible higher frequency was only observed in neurologic disorders–in stroke patients, 0.59%, and in small fiber neuropathy patients 0.80% [ 18 ]. Based on the published data and our findings, we think the possible higher frequency of p.D313Y variant in cerebrovascular disease might represent a low-effect stroke risk factor.…”

Section: Discussionmentioning

confidence: 99%

Nationwide screening for Fabry disease in unselected stroke patients

et al. 2021

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Background and aims Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by disease-associated variants in the alpha-galactosidase A gene (GLA). FD is a known cause of stroke in younger patients. There are limited data on prevalence of FD and stroke risk in unselected stroke patients. Methods A prospective nationwide study including 35 (78%) of all 45 stroke centers and all consecutive stroke patients admitted during three months. Clinical data were collected in the RES-Q database. FD was diagnosed using dried blood spots in a stepwise manner: in males—enzymatic activity, globotriaosylsphingosine (lyso-Gb3) quantification, if positive followed by GLA gene sequencing; and in females GLA sequencing followed by lyso-Gb3. Results 986 consecutive patients (54% men, mean age 70 years) were included. Observed stroke type was ischemic 79%, transient ischemic attack (TIA) 14%, intracerebral hemorrhage (ICH) 7%, subarachnoid hemorrhage 1% and cerebral venous thrombosis 0.1%. Two (0.2%, 95% CI 0.02–0.7) patients had a pathogenic variant associated with the classical FD phenotype (c.1235_1236delCT and p.G325S). Another fourteen (1.4%, 95% CI 0.08–2.4) patients had a variant of GLA gene considered benign (9 with p.D313Y, one p.A143T, one p.R118C, one p.V199A, one p.R30K and one p.R38G). The index stroke in two carriers of disease-associated variant was ischemic lacunar. In 14 carriers of GLA gene variants 11 strokes were ischemic, two TIA, and one ICH. Patients with positive as compared to negative GLA gene screening were younger (mean 60±SD, min, max, vs 70±SD, min, max, P = 0.02), otherwise there were no differences in other baseline variables. Conclusions The prevalence of FD in unselected adult patients with acute stroke is 0.2%. Both patients who had a pathogenic GLA gene variant were younger than 50 years. Our results support FD screening in patients that had a stroke event before 50 years of age.

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“…Here, we present a simple and sensitive method for the analysis of plasma lyso-Gb3 by liquid chromatography–tandem mass spectrometry (LC-MS/MS), with a rapid sample preparation consisting of assisted protein precipitation with Phree cartridges, and successfully validation using lyso-Gb3-D7 as an internal standard. The method was applied to a set of plasma samples from FD patients and healthy controls, along with subjects carrying a non-pathogenic polymorphism [ 35 ]. Based on the results obtained, the reported method can be used as a reliable tool for FD diagnosis and to clarify diagnoses in patients with borderline enzymatic α-Gal A activity, or to confirm non-pathogenic polymorphisms of the GLA gene.…”

Section: Introductionmentioning

confidence: 99%

A Rapid and Simple UHPLC-MS/MS Method for Quantification of Plasma Globotriaosylsphingosine (lyso-Gb3)

et al. 2021

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Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by α-galactosidase A gene (GLA) mutations, resulting in loss of activity of the lysosomal hydrolase, α-galactosidase A (α-Gal A). As a result, the main glycosphingolipid substrates, globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), accumulate in plasma, urine, and tissues. Here, we propose a simple, fast, and sensitive method for plasma quantification of lyso-Gb3, the most promising secondary screening target for FD. Assisted protein precipitation with methanol using Phree cartridges was performed as sample pre-treatment and plasma concentrations were measured using UHPLC-MS/MS operating in MRM positive electrospray ionization. Method validation provided excellent results for the whole calibration range (0.25–100 ng/mL). Intra-assay and inter-assay accuracy and precision (CV%) were calculated as <10%. The method was successfully applied to 55 plasma samples obtained from 34 patients with FD, 5 individuals carrying non-relevant polymorphisms of the GLA gene, and 16 healthy controls. Plasma lyso-Gb3 concentrations were larger in both male and female FD groups compared to healthy subjects (p < 0.001). Normal levels of plasma lyso-Gb3 were observed for patients carrying non-relevant mutations of the GLA gene compared to the control group (p = 0.141). Dropping the lower limit of quantification (LLOQ) to 0.25 ng/mL allowed us to set the optimal plasma lyso-Gb3 cut-off value between FD patients and healthy controls at 0.6 ng/mL, with a sensitivity of 97.1%, specificity of 100%, and accuracy of 0.998 expressed by the area under the ROC curve (C.I. 0.992 to 1.000, p-value < 0.001). Based on the results obtained, this method can be a reliable tool for early phenotypic assignment, assessing diagnoses in patients with borderline GalA activity, and confirming non-relevant mutations of the GLA gene.

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Is the alpha‐galactosidase A variant p.Asp313Tyr (p.D313Y) pathogenic for Fabry disease? A systematic review

Cited by 18 publications

References 56 publications

Screening for Fabry Disease in Kidney Transplant Recipients: Experience of a Multidisciplinary Team

Screening for Fabry Disease in Kidney Transplant Recipients: Experience of a Multidisciplinary Team

Nationwide screening for Fabry disease in unselected stroke patients

A Rapid and Simple UHPLC-MS/MS Method for Quantification of Plasma Globotriaosylsphingosine (lyso-Gb3)

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