Frequency of Fabry disease in male and female haemodialysis patients in Spain

Gaspar, Paulo; Herrera, Julio; Rodrigues, Daniel Nava; Cerezo, S.; Delgado, Rodrigo; Andrade, Carlos Fernández; Forascepi, R; Macías, J. F.; Pino, María Dolores del Pino y; Prados, María de los Ángeles Hernández; Alegria, Pilar R de; Torres, Gerardo; Vidau, Pedro; Sá-Miranda, Clara

doi:10.1186/1471-2350-11-19

Cited by 55 publications

(47 citation statements)

References 23 publications

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“…Published reports on male dialysis patients screened for FD (summarized in Table 4) show that when 0.5% or fewer of the patients were given genetic testing, 100% were positive for FD (2,4,6,7,9). In those in which $4% of the patients were tested, 33% or fewer had diagnosable FD (8,10,11). These results show that a-Gal A activity alone does not permit the selective identification of patients who are at high risk for FD.…”

Section: Discussionmentioning

confidence: 58%

“…In published studies, all but one (3) had a very high rate of re-sampling in cases that were identified as false positives: 66.7% (6), 90.9% (7), 92.5% (5), and 93.1% (9). If the genetic test from which the GLA mutation was not detected was defined as the unnecessary genetic tests, similarly, unnecessary genetic tests were carried out in a high percentage of patients in some studies: 60.0% (5), 66.7% (8), 86.7% (11), and 96.0% (10). Unnecessary genetic tests of some studies were 0% (2-4,6,7,9).…”

Section: Discussionmentioning

confidence: 99%

“…This enzyme deficiency causes the systemic lysosomal accumulation of glycolipids, primarily globotriaosylceramide (Gb3), in the vascular endothelium and other tissues. Morbidity and mortality from FD, caused by renal failure, cardiac disease, and early onset stroke, increase with age, and screens of male patients on dialysis show an FD prevalence of 0.2%-1.7% (2)(3)(4)(5)(6)(7)(8)(9)(10)(11). The advent of an effective treatment, enzyme replacement therapy (ERT), has increased the importance of identifying people with FD.…”

Section: Introductionmentioning

confidence: 99%

“…a-Gal A deficiency screens have used plasma (2,3,6,7) and dried blood spot (5,(9)(10)(11) samples; low leukocyte a-Gal A activity is also used to identify candidates for further testing (3,(5)(6)(7)9). Patients positive for the a-Gal A activity screen (i.e., with low activity) are subsequently tested for mutations in the a-Gal A gene (GLA) (2)(3)(4)(5)(6)(7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

“…Patients positive for the a-Gal A activity screen (i.e., with low activity) are subsequently tested for mutations in the a-Gal A gene (GLA) (2)(3)(4)(5)(6)(7)(8)(9)(10)(11). The genetic tests revealed that a-Gal A activity screening lacks specificity, in that some patients without GLA mutations test positive (5,8,10,11). In addition, many females who are heterozygous for pathogenic GLA mutations have normal plasma a-Gal A activity, so screening studies for FD have predominantly focused on male dialysis patients (3,4,6).…”

Section: Introductionmentioning

confidence: 99%

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Screening of Male Dialysis Patients for Fabry Disease by Plasma Globotriaosylsphingosine

Maruyama

Takata²,

Tsubata

et al. 2013

Clinical Journal of the American Society of Nephrology

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Summary Background and objectives Previous reports of Fabry disease screening in dialysis patients indicate that α-galactosidase A activity alone cannot specifically and reliably identify appropriate candidates for genetic testing; a marker for secondary screening is required. Elevated plasma globotriaosylsphingosine is reported to be a hallmark of classic Fabry disease. The purpose of this study was to examine the usefulness of globotriaosylsphingosine as a secondary screening target for Fabry disease. Design, setting, participants, & measurements This study screened 1453 patients, comprising 50% of the male dialysis patients in Niigata Prefecture between July 1, 2010 and July 31, 2011. Screening for Fabry disease was performed by measuring the plasma α-galactosidase A enzyme activity and the globotriaosylsphingosine concentration, by high-performance liquid chromatography. Genetic testing and genetic counseling were provided. Results A low level of plasma α-galactosidase A activity (≤4.0 nmol/h per milliliter) was observed in 47 patients (3.2%). Of these, 3 (0.2%) had detectable globotriaosylsphingosine levels. These patients all had α-galactosidase A gene mutations: one was p.Y173X and two were the nonpathogenic p.E66Q. The patient with p.Y173X started enzyme replacement therapy. Subsequent screening of his family identified the same mutation in his elder sister and her children. Genetic testing for 33 of the other 44 patients detected 7 patients with p.E66Q. Thus, the plasma lyso-Gb3 screen identified Fabry disease with high sensitivity (100%) and specificity (94.3%). Conclusions Plasma globotriaosylsphingosine is a promising secondary screening target that was effective for selecting candidates for genetic counseling and testing and for uncovering unrecognized Fabry disease cases.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Screening of Male Dialysis Patients for Fabry Disease by Plasma Globotriaosylsphingosine

Maruyama

Takata²,

Tsubata

et al. 2013

Clinical Journal of the American Society of Nephrology

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

Effraimidis

Rasmussen

Bundgaard

et al. 2020

J of Inher Metab Disea

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The identification of pathogenic GLA variants plays a central role in the establishment of a definite Fabry disease (FD) diagnosis. We aimed to review and interpret the published data on the p.Asp313Tyr (p.D313Y) variant pathogenicity and clinical relevance. We performed a systematic review of peer‐reviewed publications and case‐reports on individuals and populations harbouring the p.Asp313Tyr variant. Overall, 35 studies were included in this review. We collected data regarding the clinical manifestations, alpha‐galactosidase A enzyme activity, levels of the biomarkers globotriaosylceramide (Gb3) and sphingosine‐globotriaosylceramide (lyso‐Gb3) and histological findings of p.Asp313Tyr carriers. The prevalence of p.Asp313Tyr in populations at risk for FD (kidney, heart, neurologic disorders, or symptomatic populations) was calculated. We found high residual enzyme activity, low frequency of clinical features specific for FD, non‐elevated lysoGb3/Gb3 concentrations and lack of intracellular Gb3 accumulation in biopsies in the p.Asp313Tyr carriers. The prevalence of the variant in populations at risk for FD was comparable to the reported frequency in the general population. A possible higher frequency was only observed in neurologic disorders. p.Asp313Tyr can be classified as neutral or variant of unknown significance. Further investigations will be helpful to clarify a possible association between the variant and manifestations in the brain vessels.

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Renal globotriaosylceramide deposits for Fabry disease linked to uncertain pathogenicity gene variant c.352C>T/p.Arg118Cys: A family study

Cerón‐Rodríguez

Ramón-Garcı́a

Barajas-Colón

et al. 2019

Molec Gen & Gen Med

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BackgroundFabry disease (FD) has an extensive phenotypic expression associated with GLA gene variants. The GLA gene variant c.352C>T/p.Arg118Cys was considered with uncertain pathogenicity because of the finding of high residual alpha‐galactosidase A (α‐Gal A) enzyme activity, the absence of Mendelian segregation with an FD phenotype with many individuals remaining asymptomatic at old ages and the lack of globotriaosylceramide (Gb3) deposits in tissues. Gb3 deposits are found in kidneys before the progression to overt microalbuminuria and decreased glomerular filtration.MethodsWe describe a family with c.352C>T/p.Arg118Cys variant and pathognomonic signs of FD renal damage in masculine children.ResultsThe proband died of end‐stage renal failure and we analyzed GLA gene in his offspring and found the variant in all daughters and five of seven grandchildren. In patients who we measure plasma and urinary Gb3, α‐Gal A enzyme activity, and plasma globotriaosylsphingosine (Lyso‐Gb3), these were normal or almost normal. A kidney biopsy was performed in two boys and one girl with normal renal function and characteristic signs of FD as enlarged and vacuolated epithelial cells, myelin figures, myelin‐like figures, lamellated structures in podocytes and endothelial cells, were found in boys. These boys received agalsidase beta 1 mg/kg IV infusion every other week to prevent further renal damage.ConclusionThis is the first report that shows a link between FD renal Gb3 deposits and c.352C>T/p.Arg118Cys variant, supporting pathogenicity of a variant considered until now with uncertain pathogenicity.

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Frequency of Fabry disease in male and female haemodialysis patients in Spain

Cited by 55 publications

References 23 publications

Screening of Male Dialysis Patients for Fabry Disease by Plasma Globotriaosylsphingosine

Screening of Male Dialysis Patients for Fabry Disease by Plasma Globotriaosylsphingosine

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

Renal globotriaosylceramide deposits for Fabry disease linked to uncertain pathogenicity gene variant c.352C>T/p.Arg118Cys: A family study

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