Fabry Disease Screening in Patients With Kidney Transplant: A Single-Center Study in Turkey

Erdogmus, Siyar; Kutlay, Sim; Kumru, Gizem; Sendogan, Damla Ors; Ertürk, Şehsuvar; Keven, Kenan; Ceylaner, Gülay; Şengül, Şule

doi:10.6002/ect.2019.0279

Cited by 8 publications

(9 citation statements)

References 33 publications

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“…The variant c.427G > A, p.A143T (rs104894845) was revealed in a 69-year-old female with HCM, and it has been frequently described as a pathogenic variant [ 22 , 52 ], VUS [ 16 , 19 , 34 ], and likely benign or benign variant [ 5 , 29 , 46 ]. It was also described in the literature as a variant with incomplete penetrance that causes the development of the late form of FD in patients with HCM [ 56 ] and as a variant causing isolated HCM [ 2 ].…”

Section: Resultsmentioning

confidence: 99%

The prevalence of Fabry disease among 1009 unrelated patients with hypertrophic cardiomyopathy: a Russian nationwide screening program using NGS technology

Savostyanov

Pushkov

Жанин

et al. 2022

Orphanet J Rare Dis

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Background There is a vast number of screening studies described in the literature from the beginning of the twenty-first century to the present day. Many of these studies are related to the estimation of Fabry disease (FD) morbidity among patients from high-risk groups, including adult patients with hypertrophic cardiomyopathy (HCM) and left ventricular hypertrophy (LVH). These studies show diverse detection frequencies (0–12%) depending on the methodology. Our study is the only example of large-scale selective FD screening based on the implementation of next-generation sequencing technology (NGS) as a first-level test to estimate FD morbidity in the Russian population over 18 years of age burdened with HCM. Methods The study included 1009 patients (578 males and 431 females), with a median age of 50 years, who were diagnosed with HCM according to current clinical guidelines. In the first stage of screening, all patients underwent molecular genetic testing (NGS method) of target regions. These regions included the coding sequences of 17 genes and mutations that can lead to the development of HCM. Lysosomal globotriaosylsphingosine (lyso-Gb3) concentrations and α-galactosidase A (α-gal A) enzyme activity were measured in the second stage of screening to reveal pathogenic or likely pathogenic variants in the GLA gene. Results We revealed 8 (0.8%) patients (3 (37.5%) males and 5 (62.5%) females) with an average age of 59 ± 13.3 years who had pathogenic, likely pathogenic variants and variants of uncertain significance (VUS) in the GLA gene (NM_000169.2) as a result of selective screening of 1009 Russian patients with HCM. FD was confirmed via biochemical tests in a male with the pathogenic variant c.902G > A, p.R301Q as well as in two females with likely pathogenic variants c.897C > A, p.D299E and c.1287_1288dup, p.*430Fext*?. These tests showed reduced enzymatic activity and increased substrate concentration. However, a female with the pathogenic variant c.416A > G, p.N139S and with normal enzymatic activity only had increased substrate concentrations. The revealed nucleotide variants and high values of biochemical indicators (lyso-Gb3) in these 4 patients allowed us to estimate the FD diagnosis among 1009 Russian patients with HCM. Mild extracardiac manifestations were observed in these four patients; however, both biochemical values within the reference range in females with the c.971T > G, p.L324W (VUS) variant. α-gal A activity and lyso-Gb3 concentrations were also within the normal range in two males with hemizygous variants, c.546T > C, p.D182D and c.640-794_640-791del (we regarded them as VUS), and in one female with the c.427G > A, p.A143T variant (with conflicting interpretations of pathogenicity). Conclusion The prevalence rate of FD among 1,009 adult Russian patients with HCM was 0.4%. We recommend FD screening among adult patients of both sexes with HCM and an undefined genetic cause via NGS method with subsequent analysis of α-gal A activity and lyso-Gb3 concentration in patients with pathogenic, likely pathogenic variants, and VUS. This strategy identifies patients with an atypical form of FD that is characterized by high residual activity of α-gal A, low concentrations of lyso-Gb3, and minor extracardiac manifestations.

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Section: Resultsmentioning

confidence: 99%

The prevalence of Fabry disease among 1009 unrelated patients with hypertrophic cardiomyopathy: a Russian nationwide screening program using NGS technology

Savostyanov

Pushkov

Жанин

et al. 2022

Orphanet J Rare Dis

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“…However, very few studies investigated the incidence of unrecognized FD in kidney transplant recipients [ 12 , 33 , 34 , 35 ]. Doheny et al [ 14 ] reported an incidence of 0.54% unrecognized GLA mutations in male kidney transplant recipients (11 of 2031 patients).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, of the 1043 female transplant patients screened, none had a pathogenic mutation, while three had benign GLA variants. Erdogmus et al [ 12 ], in a recent screening study among 301 kidney transplant recipients, identified one male patient with a pathogenic mutation (0.3%) and two female patients with a GLA mutation of unknown significance (0.6%).…”

Section: Discussionmentioning

confidence: 99%

“…Progressive renal impairment is a pervasive clinical manifestation of Fabry disease. Studies on FD screening in a hemodialysis population found a prevalence of FD ranging between 0.02% to 1.2% [ 10 , 11 , 12 , 13 , 14 ]. Usually, the first signs are represented by glomerular hyperfiltration associated with mesangial cell proliferation, and they appear between 10 and 20 years of age in male patients with the classic phenotype [ 5 , 15 , 16 ].…”

Section: Introductionmentioning

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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“…The results of studies conducted on kidney transplant patients declare that Fabry disease is detected more frequently in this group than in the general population (6)(7)(8)(9)(10)(11). In a few studies conducted in our society, the prevalence varies from 0.09% to 0.5% (8)(9)(10). Therefore, kidney transplant patients can be considered a risky population.…”

Section: Introductionmentioning

confidence: 99%

Fabry disease screening in kidney transplant patients: A single-center study in Türkiye

Aktaş¹,

Okyay²,

Selen³

et al. 2022

GMJ

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Aims: This study aimed to screen for Fabry disease in adult kidney transplant patients at a nephrology clinic in Türkiye. Methods:This cross-sectional, single-center study prospectively enrolled kidney transplant recipients regardless of the etiology of renal failure. α-galactosidase A (α-GLA) enzyme activity and α-GLA gene analysis were used to screen for Fabry disease. The screening was initiated by measuring enzyme activity in males, and those with <2.5 nmol/mL/hour activity underwent gene analysis. Females were screened directly by gene analysis, independent of the enzyme activity. Results:We screened 125 patients (age: 48.9±10.1, male: 70.4%). Gene analysis was performed on a 68-year-old male patient with enzyme activity at the lower end of the reference range. No mutations associated with Fabry disease were detected. The enzyme activity test was considered false positive. A heterozygous c.937G>T (p. D313Y) mutation was detected in the gene analysis of a 29-year-old female patient. However, systemic evaluation did not reveal any clinical findings consistent with Fabry disease. Screening tests were within normal limits in other patients. Although there were abnormal screening findings in 2 patients, none was diagnosed with Fabry disease. Conclusions:Screening studies for Fabry disease in kidney transplant patients may contribute to the determination of the true prevalence.

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Fabry Disease Screening in Patients With Kidney Transplant: A Single-Center Study in Turkey

Cited by 8 publications

References 33 publications

The prevalence of Fabry disease among 1009 unrelated patients with hypertrophic cardiomyopathy: a Russian nationwide screening program using NGS technology

The prevalence of Fabry disease among 1009 unrelated patients with hypertrophic cardiomyopathy: a Russian nationwide screening program using NGS technology

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

Fabry disease screening in kidney transplant patients: A single-center study in Türkiye

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