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Screening of family members of chronic kidney disease patients with Fabry disease mutations: a very important and underrated task

ABSTRACT

Introduction:

Fabry disease is a chronic, progressive, and multi-system hereditary condition, related to an Xq22 mutation in X chromosome, which results in deficiency of alpha-galactosidase enzyme, hence reduced capacity of globotriaosylceramide degradation.

Objectives:

to evaluate the prevalence of Fabry disease (FD) mutations, as well as its signs and symptoms, among relatives of chronic kidney disease (CKD) patients diagnosed with FD during a previously conducted study, named “Clinical and epidemiological analysis of Fabry disease in dialysis centers in Brazil”.

Methods:

a cross-sectional study was carried out, and data was collected by interviewing the relatives of patients enrolled in the Brazil Fabry Kidney Project and blood tests for both Gb3 dosage and genetic testing.

Results:

Among 1214 interviewed relatives, 115 (9.47%) were diagnosed with FD, with a predominance of women (66.10%). The most prevalent comorbidities were rheumatologic conditions and systemic hypertension (1.7% each), followed by heart, neurological, cerebrovascular diseases, and depression in 0.9% of individuals. Intolerance to physical exercise and tiredness were the most observed symptoms (1.7%), followed by periodic fever, intolerance to heat or cold, diffuse pain, burn sensation or numbness in hands and feet, reduced or absent sweating, as well as abdominal pain after meals in 0.9%.

Conclusion:

We found a prevalence of Fabry disease in 9.47% of relatives of CKD patients with this condition, remarkably with a 66.1% predominance of women, which contrasts with previous reports. The screening of family members of FD patients is important, since it can lead to early diagnosis and treatment, thus allowing better quality of life and improved clinical outcomes for these individuals.

Keywords:
Renal Insufficiency, Chronic; Fabry Disease; Triage; Family; Brazil

RESUMO

Introdução:

A doença de Fabry é uma condição hereditária crônica, progressiva e multissistêmica, relacionada a uma mutação Xq22 no cromossomo X, que resulta em deficiência da enzima alfa-galactosidase, diminuindo a capacidade de degradação da globotriaosilceramida. Objetivos: avaliar a prevalência de mutações na doença de Fabry, bem como seus sinais e sintomas, em familiares de pacientes com doença renal crônica (DRC) diagnosticados com DF durante um estudo realizado anteriormente, denominado “Análise clínica e epidemiológica da doença de Fabry em centros de diálise no Brasil”.

Métodos:

foi realizado um estudo transversal e os dados foram coletados através da entrevista com familiares de pacientes inscritos no Projeto Rim Fabry Brasil e exames de sangue para dosagem de Gb3 e testes genéticos.

Resultados:

Dos 1,214 familiares entrevistados, 115 (9,47%) foram diagnosticados com DF, com predomínio de mulheres (66,10%). As comorbidades mais prevalentes foram condições reumatológicas e hipertensão arterial sistêmica (1,7% cada), seguidas por doenças cardíacas, neurológicas, cerebrovasculares e depressão em 0,9% dos indivíduos. Intolerância ao exercício físico e cansaço foram os sintomas mais observados (1,7%), seguidos de febre periódica, intolerância ao calor ou ao frio, dor difusa, sensação de queimação ou dormência nas mãos e nos pés, sudorese reduzida ou ausente, além de dor abdominal após refeições em 0,9%.

Conclusão:

Encontramos uma prevalência da doença de Fabry em 9,47% dos familiares de pacientes com DRC com essa condição, notadamente com uma predominância de 66,1% de mulheres, o que contrasta com relatos anteriores. A triagem de familiares de pacientes com DF é importante, pois pode levar ao diagnóstico e tratamento precoces, permitindo melhor qualidade de vida e melhores resultados clínicos para esses indivíduos.

Descritores:
Insuficiência Renal Crônica; Doença de Fabry; Triagem; Família; Brasil

INTRODUCTION

Fabry disease (FD) (OMIM 301500) is caused by a deficiency of the enzyme alpha galactosidase (-Gal-A, EC 3.2.1.22), which results in impaired clearance of globotriaosylceramide (Gb3)11 Desnick RJ, Joannou YA, Eng CM. Galactosidase-A deficiency: Fabry disease: nature of the accumulated glycosphingolipids. The metabolic and molecular basis of inherited disease. New York: McGraw-Hill; 2001. p. 3742-3.. FD is a progressive, multi-system, and hereditary condition, linked to a mutation in the Xq22 region of X chromosomes22 Pastores GM, Lien YH. Biochemical and molecular genetic basis of Fabry disease. J Am Soc Nephrol. 2002;13(Suppl 2):S130-S3.,33 Boggio P, Luna PC, Abad ME, Larralde M. Fabry disease. An Bras Dermatol. 2009;84:367-76.,44 Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30.. It is considered a rare or “orphan” disease, due to its very low prevalence22 Pastores GM, Lien YH. Biochemical and molecular genetic basis of Fabry disease. J Am Soc Nephrol. 2002;13(Suppl 2):S130-S3.,44 Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30.. Gb3 accumulates within lysosomes throughout the whole body, notably the brain, heart, kidneys, nervous system, and skin, leading to several signs and symptoms and substantial morbidity and mortality33 Boggio P, Luna PC, Abad ME, Larralde M. Fabry disease. An Bras Dermatol. 2009;84:367-76.

4 Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30.

5 Möhrenschlager M, Henkel V, Ring J. Fabry disease: more than angiokeratomas. Arch Dermatol. 2004;140:1526-8.
-66 Zarate YA, Hopkin RJ. Fabry’s disease. Lancet. 2008 Oct;372(9647):1427-35..

The first symptoms of FD, such as acroparesthesia, abdominal pain, especially following meals, and diarrhea, usually occur in the first decade of life, but are very nonspecific, thus leading to late medical referral and diagnosis55 Möhrenschlager M, Henkel V, Ring J. Fabry disease: more than angiokeratomas. Arch Dermatol. 2004;140:1526-8.

6 Zarate YA, Hopkin RJ. Fabry’s disease. Lancet. 2008 Oct;372(9647):1427-35.
-77 Hopkin RJ, Bissler J, Banikazemi M, Clarke L, Eng CM, Germain DP, et al. Characterization of Fabry disease in 352 pediatric patients in the Fabry registry. Pediatr Res. 2008 Nov;64(5):550-5.. Angiokeratomas are the most characteristic clinical signs (Germain 2010; Hopkin et al 2008). FD can cause left ventricular hypertrophy (LVH), stroke and transient ischemic attacks, hearing loss, cornea verticilata, development of proteinuria, and progressive kidney disease44 Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30.

5 Möhrenschlager M, Henkel V, Ring J. Fabry disease: more than angiokeratomas. Arch Dermatol. 2004;140:1526-8.
-66 Zarate YA, Hopkin RJ. Fabry’s disease. Lancet. 2008 Oct;372(9647):1427-35.,88 Terryn W, Cochat P, Froissart R, Ortiz A, Pirson Y, Poppe B, et al. Fabry nephropathy: indications for screening and guidance for diagnosis and treatment by the European Renal Best Practice. Nephrol Dial Transplant. 2012 Mar;28(3):505-17..

The incidence of FD varies from 1:40,000 to 1:117,000, and although prevalence can vary according to different regions, no precise ethnical predisposition is known to date33 Boggio P, Luna PC, Abad ME, Larralde M. Fabry disease. An Bras Dermatol. 2009;84:367-76.,44 Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30.,66 Zarate YA, Hopkin RJ. Fabry’s disease. Lancet. 2008 Oct;372(9647):1427-35.. Studies reporting the prevalence of FD in patients with chronic kidney disease are more frequent99 Marinho LAL, Rêgo JFM, Ramos TCO, Alves TMS. Prevalência da doença de Fabry em pacientes portadores de doença renal crônica submetidos à hemodiálise em Natal-RN, Brazil. J Bras Nefrol. 2007;29(4):235-9.

10 Vale NFD, Silva ADBR, Veras AB, Monteiro FMR, Sousa JLM, Bezerra VL, et al. Diagnóstico de doença de Fabry em indivíduos submetidos à hemodiálise no estado do Piauí: o papel do exame de triagem e estudo de casos. J Bras Nefrol. 2008;30(4):259-63.

11 Porsch DB, Nunes ACF, Milani V, Rossato LB, Mattos CB, Tsao M, et al. Fabry disease in hemodialysis patients in southern Brazil: prevalence study and clinical report. Ren Fail. 2008;30:825-30.

12 Sodré LSS, Huaira RMNH, Bastos MG, Colugnati FAB, Coutinho M, Fernandes NMS. Screening for Fabry disease in kidney disease: a cross-sectional study in males and females. Kidney Blood Press Res. 2017;42:1258-65.

13 Okur I, Ezgu F, Biberoglu G, Tumer L, Erten Y, Isitman M, et al. Screening for Fabry disease in patients undergoing dialysis for chronic renal failure in Turkey: identification of new case with novel mutation. Gene. 2013 Sep;527(1):42-7.

14 Herrera J, Miranda CS. Prevalence of Fabry’s disease within hemodialysis patients in Spain. Clin Nephrol. 2014;81(2):112-20.

15 Turkmen K, Guclu A, Sahin G, Kocyigit I, Demirtas L, Erdur FM, et al. The prevalence of Fabry disease in patients with chronic kidney disease in Turkey: the TURKFAB study. Kidney Blood Press Res. 2016;41(6):1016-24.

16 Bolasco P, Sitzia I, Murtas S. Fabry disease in Southern Sardinia: epidemiological results from screening in an extensive area. Giornale Italiano di Nefrologia: Organo Ufficiale Della Societa Italiana di Nefrologia. 2017 Jul;34(4):83-102.

17 Yeniçerioglu Y, Akdam H, Dursun B, Alp A, Eyiler FS, Akin D, et al. Screening Fabry's disease in chronic kidney disease patients not on dialysis: a multicenter study. Ren Fail. 2017;39(1):104-11.

18 Choi JH, Lee BH, Heo SH, Kim GH, Kim YM, Kim DS, et al. Clinical characteristics and mutation spectrum of GLA in Korean patients with Fabry disease by a nationwide survey: underdiagnosis of late-onset phenotype. Medicine. 2017 Jul;96(29):e7387.
-1919 Kleinert J, Kotanko P, Spada M, Pagliardini S, Paschke E, Paul K, et al. Anderson-Fabry disease: a case finding study among male kidney transplant recipients in Austria. Transplant International. 2009 Feb;22(3):287-92.. Few studies have evaluated the relatives of patients with FD1414 Herrera J, Miranda CS. Prevalence of Fabry’s disease within hemodialysis patients in Spain. Clin Nephrol. 2014;81(2):112-20.

15 Turkmen K, Guclu A, Sahin G, Kocyigit I, Demirtas L, Erdur FM, et al. The prevalence of Fabry disease in patients with chronic kidney disease in Turkey: the TURKFAB study. Kidney Blood Press Res. 2016;41(6):1016-24.
-1616 Bolasco P, Sitzia I, Murtas S. Fabry disease in Southern Sardinia: epidemiological results from screening in an extensive area. Giornale Italiano di Nefrologia: Organo Ufficiale Della Societa Italiana di Nefrologia. 2017 Jul;34(4):83-102.,1818 Choi JH, Lee BH, Heo SH, Kim GH, Kim YM, Kim DS, et al. Clinical characteristics and mutation spectrum of GLA in Korean patients with Fabry disease by a nationwide survey: underdiagnosis of late-onset phenotype. Medicine. 2017 Jul;96(29):e7387.,2020 Silva CAB, Barreto FC, Reis MA, Moura Junior JA, Cruz CMS. Targeted screening of Fabry disease in male hemodialysis patients in Brazil highlights importance of family screening. Nephron. 2016;134(4):221-30.,2121 Gutiérrez-Amavizca BE, Orozco-Castellanos R, Padilla-Gutiérrez JR, Valle Y, Figuera LE. Pedigree analysis of Mexican families with Fabry disease as a powerful tool for identification of heterozygous females. Genet Mol Res. 2014 Aug;13(3):6752-8.. The only Brazilian study to evaluate relatives of FD patients found a prevalence of 0.12% of FD in men undergoing hemodialysis (HD)2020 Silva CAB, Barreto FC, Reis MA, Moura Junior JA, Cruz CMS. Targeted screening of Fabry disease in male hemodialysis patients in Brazil highlights importance of family screening. Nephron. 2016;134(4):221-30..

In men, diagnosis is made by demonstration of low enzymatic activity of α-Gal-A. In women, genetic sequencing is necessary due to the presence of two X chromosomes, hence measured α-Gal-A activity is almost always normal66 Zarate YA, Hopkin RJ. Fabry’s disease. Lancet. 2008 Oct;372(9647):1427-35.,88 Terryn W, Cochat P, Froissart R, Ortiz A, Pirson Y, Poppe B, et al. Fabry nephropathy: indications for screening and guidance for diagnosis and treatment by the European Renal Best Practice. Nephrol Dial Transplant. 2012 Mar;28(3):505-17.,2222 Wang RY, Bodamer OA, Watson MS, Wilcox WR, ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Diseases. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Genet Med. 2011 May;13(5):457-84.. A number of studies reveal different prevalence rates of FD among relatives of patients diagnosed with FD, pointing to the importance of early diagnosis, in order to allow better handling of the disease77 Hopkin RJ, Bissler J, Banikazemi M, Clarke L, Eng CM, Germain DP, et al. Characterization of Fabry disease in 352 pediatric patients in the Fabry registry. Pediatr Res. 2008 Nov;64(5):550-5.,1212 Sodré LSS, Huaira RMNH, Bastos MG, Colugnati FAB, Coutinho M, Fernandes NMS. Screening for Fabry disease in kidney disease: a cross-sectional study in males and females. Kidney Blood Press Res. 2017;42:1258-65.,1414 Herrera J, Miranda CS. Prevalence of Fabry’s disease within hemodialysis patients in Spain. Clin Nephrol. 2014;81(2):112-20.

15 Turkmen K, Guclu A, Sahin G, Kocyigit I, Demirtas L, Erdur FM, et al. The prevalence of Fabry disease in patients with chronic kidney disease in Turkey: the TURKFAB study. Kidney Blood Press Res. 2016;41(6):1016-24.
-1616 Bolasco P, Sitzia I, Murtas S. Fabry disease in Southern Sardinia: epidemiological results from screening in an extensive area. Giornale Italiano di Nefrologia: Organo Ufficiale Della Societa Italiana di Nefrologia. 2017 Jul;34(4):83-102.,1818 Choi JH, Lee BH, Heo SH, Kim GH, Kim YM, Kim DS, et al. Clinical characteristics and mutation spectrum of GLA in Korean patients with Fabry disease by a nationwide survey: underdiagnosis of late-onset phenotype. Medicine. 2017 Jul;96(29):e7387.,2020 Silva CAB, Barreto FC, Reis MA, Moura Junior JA, Cruz CMS. Targeted screening of Fabry disease in male hemodialysis patients in Brazil highlights importance of family screening. Nephron. 2016;134(4):221-30.,2121 Gutiérrez-Amavizca BE, Orozco-Castellanos R, Padilla-Gutiérrez JR, Valle Y, Figuera LE. Pedigree analysis of Mexican families with Fabry disease as a powerful tool for identification of heterozygous females. Genet Mol Res. 2014 Aug;13(3):6752-8..

The goal of the present study was to evaluate the prevalence of FD mutations and to describe the presence of signs and symptoms of this disease among relatives of FD mutations patients from the previously undertaken study entitled “Clinical and epidemiological analysis of Fabry disease in dialysis centers in Brazil - the Brazil Fabry Kidney Project”1212 Sodré LSS, Huaira RMNH, Bastos MG, Colugnati FAB, Coutinho M, Fernandes NMS. Screening for Fabry disease in kidney disease: a cross-sectional study in males and females. Kidney Blood Press Res. 2017;42:1258-65..

MATERIAL AND METHODS

This was a cross-sectional study, approved by the local ethics committee under the number 18029513.0.0000.5244.

Initially, of a total 36,442 patients with chronic kidney disease (CKD) enrolled in the Brazil Fabry Kidney project, 71 were diagnosed with FD mutations. Through medical anamnesis, 1214 relatives of those FD patients were identified as possible FD carriers, and offered informed consent agreements to continue the study through blood sampling for enzymatic dosages and genetic testing (Figure 1). No financial gain was offered to participants, and the study followed the regulations stated in the declaration of Helsinki.

Figure 1
Study design.

Blood sampling was made through paper filters, to allow dosage of α-Gal-A by tandem mass spectrometry, a screening method with sensitivity and specificity of around 96% (Centogene AG; Schillingallee 68; 18057 Rostock, Germany). When enzymatic activity was low (<2.6 µmol/L/h) or absent, DNA sampling was performed to confirm the diagnosis of FD mutation. For the genetic testing, PCR analysis of the GLA gene, as well as sequencing of the whole coding region and of the highly conserved exon-intron junction regions were performed. The GLA gene was analyzed by next generation sequencing based on amplicon. Amplicons cover the entire coding region and highly conserved splicing junctions. A minimum coverage of >20x was obtained for each amplicon. The reference sequence is: NM_000169.2. The classification of the variants was based on the recommendations of the American College of Medical Genetics. (Centogene AG; Schillingallee 68; 18057 Rostock; Germany).

The FD mutations prevalence was calculated and a descriptive data analysis was performed.

RESULTS

The prevalence of FD mutations in the studied population was 9.47% (115 of 1214), of which 66.1% were women (Figure 2). Diagnosis of FD mutations was made in people younger than 44 years in 74% of participants (Figure 3). There was no difference between age and gender regarding the prevalence of mutations (Table 1).

Figure 2
Gender proportion of patient’s relatives diagnosed with Fabry disease mutations.

Figure 3
Sample proportions of Fabry disease mutations diagnosis by age.

Table 1
Sample proportions of Fabry disease mutations (DF) diagnosis by gender and age.

Most of the relatives were asymptomatic and the most common comorbidities were rheumatologic conditions and systemic hypertension (1.7% each). Neurological, heart and cerebrovascular conditions, and depression were found in 0.9% of subjects (Table 2). Regarding signs and symptoms, intolerance to physical exercise and tiredness (1.7%), followed by periodic fever, intolerance to heat or cold, diffuse pain, burn sensation or numbness in hands and feet, reduced or absent sweating, as well as abdominal pain after meals was observed in 0.9% (Table 3).

Table 2
Comorbidities observed in index cases and relatives with Fabry disease mutations.
Table 3
Sign and symptoms observed in index cases and relatives with Fabry disease mutations.

DISCUSSION

The goal of this study was to evaluate the prevalence of FD mutations and observe the presence of signs and symptoms related to FD among relatives of CKD patients with FD mutations, as a secondary analysis related to a previous study1212 Sodré LSS, Huaira RMNH, Bastos MG, Colugnati FAB, Coutinho M, Fernandes NMS. Screening for Fabry disease in kidney disease: a cross-sectional study in males and females. Kidney Blood Press Res. 2017;42:1258-65.. We found a high prevalence of FD mutations among those relatives (9.47%), which confirmed the hypothesis that this particular population is at high risk for FD mutations1414 Herrera J, Miranda CS. Prevalence of Fabry’s disease within hemodialysis patients in Spain. Clin Nephrol. 2014;81(2):112-20.

15 Turkmen K, Guclu A, Sahin G, Kocyigit I, Demirtas L, Erdur FM, et al. The prevalence of Fabry disease in patients with chronic kidney disease in Turkey: the TURKFAB study. Kidney Blood Press Res. 2016;41(6):1016-24.
-1616 Bolasco P, Sitzia I, Murtas S. Fabry disease in Southern Sardinia: epidemiological results from screening in an extensive area. Giornale Italiano di Nefrologia: Organo Ufficiale Della Societa Italiana di Nefrologia. 2017 Jul;34(4):83-102.,2121 Gutiérrez-Amavizca BE, Orozco-Castellanos R, Padilla-Gutiérrez JR, Valle Y, Figuera LE. Pedigree analysis of Mexican families with Fabry disease as a powerful tool for identification of heterozygous females. Genet Mol Res. 2014 Aug;13(3):6752-8.. Our data contrasted with a number of previous reports, which had showed the prevalence of FD in relatives of previously diagnosed FD patients to be lower than 1.8%1515 Turkmen K, Guclu A, Sahin G, Kocyigit I, Demirtas L, Erdur FM, et al. The prevalence of Fabry disease in patients with chronic kidney disease in Turkey: the TURKFAB study. Kidney Blood Press Res. 2016;41(6):1016-24.

16 Bolasco P, Sitzia I, Murtas S. Fabry disease in Southern Sardinia: epidemiological results from screening in an extensive area. Giornale Italiano di Nefrologia: Organo Ufficiale Della Societa Italiana di Nefrologia. 2017 Jul;34(4):83-102.
-1717 Yeniçerioglu Y, Akdam H, Dursun B, Alp A, Eyiler FS, Akin D, et al. Screening Fabry's disease in chronic kidney disease patients not on dialysis: a multicenter study. Ren Fail. 2017;39(1):104-11.. Due to the rarity of this condition, other studies only described numbers of cases, without defining the prevalence of FD in relatives of FD patients, as is the case of one Latin American (24 cases)2121 Gutiérrez-Amavizca BE, Orozco-Castellanos R, Padilla-Gutiérrez JR, Valle Y, Figuera LE. Pedigree analysis of Mexican families with Fabry disease as a powerful tool for identification of heterozygous females. Genet Mol Res. 2014 Aug;13(3):6752-8., three European (23, 8 and 11 cases)1414 Herrera J, Miranda CS. Prevalence of Fabry’s disease within hemodialysis patients in Spain. Clin Nephrol. 2014;81(2):112-20.

15 Turkmen K, Guclu A, Sahin G, Kocyigit I, Demirtas L, Erdur FM, et al. The prevalence of Fabry disease in patients with chronic kidney disease in Turkey: the TURKFAB study. Kidney Blood Press Res. 2016;41(6):1016-24.
-1616 Bolasco P, Sitzia I, Murtas S. Fabry disease in Southern Sardinia: epidemiological results from screening in an extensive area. Giornale Italiano di Nefrologia: Organo Ufficiale Della Societa Italiana di Nefrologia. 2017 Jul;34(4):83-102., and one Brazilian study (23 cases)2020 Silva CAB, Barreto FC, Reis MA, Moura Junior JA, Cruz CMS. Targeted screening of Fabry disease in male hemodialysis patients in Brazil highlights importance of family screening. Nephron. 2016;134(4):221-30..

The most observed comorbidities in our study were rheumatologic conditions and systemic hypertension, in 1.7% of individuals, followed by neurological, cerebrovascular and cardiac conditions, and depression, in 0.9%. Another previous Latin American study described kidney disease, stroke, left ventricle hypertrophy, and deafness as the most common observed conditions2121 Gutiérrez-Amavizca BE, Orozco-Castellanos R, Padilla-Gutiérrez JR, Valle Y, Figuera LE. Pedigree analysis of Mexican families with Fabry disease as a powerful tool for identification of heterozygous females. Genet Mol Res. 2014 Aug;13(3):6752-8..

Our study shows similar percentages to the European and Asian studies for systemic hypertension, history of heart disease and stroke, differing in relation to diabetes, renal involvement, cardiac arrhythmia, and cardiomyopathic hypertrophy1414 Herrera J, Miranda CS. Prevalence of Fabry’s disease within hemodialysis patients in Spain. Clin Nephrol. 2014;81(2):112-20.

15 Turkmen K, Guclu A, Sahin G, Kocyigit I, Demirtas L, Erdur FM, et al. The prevalence of Fabry disease in patients with chronic kidney disease in Turkey: the TURKFAB study. Kidney Blood Press Res. 2016;41(6):1016-24.
-1616 Bolasco P, Sitzia I, Murtas S. Fabry disease in Southern Sardinia: epidemiological results from screening in an extensive area. Giornale Italiano di Nefrologia: Organo Ufficiale Della Societa Italiana di Nefrologia. 2017 Jul;34(4):83-102.,1818 Choi JH, Lee BH, Heo SH, Kim GH, Kim YM, Kim DS, et al. Clinical characteristics and mutation spectrum of GLA in Korean patients with Fabry disease by a nationwide survey: underdiagnosis of late-onset phenotype. Medicine. 2017 Jul;96(29):e7387.. Compared to the Brazilian study by Silva (2016), the percentages of left ventricular hypertrophy and systemic hypertension were similar, differing only in Fabry’s nephropathy2020 Silva CAB, Barreto FC, Reis MA, Moura Junior JA, Cruz CMS. Targeted screening of Fabry disease in male hemodialysis patients in Brazil highlights importance of family screening. Nephron. 2016;134(4):221-30..

We observed a low prevalence of signs and symptoms, and the most common were intolerance to physical exercise and tiredness, in 1.7%, followed by periodic fever, intolerance to heat or cold, diffuse pain, burn sensation or numbness in hands and feet, reduced or absent sweating, as well as abdominal pain after meals, in 0.9% of individuals, which highlights the importance of early diagnosis, allowing recognition of FD cases prior to marked systemic derangement due to more severe accumulation of Gb377 Hopkin RJ, Bissler J, Banikazemi M, Clarke L, Eng CM, Germain DP, et al. Characterization of Fabry disease in 352 pediatric patients in the Fabry registry. Pediatr Res. 2008 Nov;64(5):550-5.,2121 Gutiérrez-Amavizca BE, Orozco-Castellanos R, Padilla-Gutiérrez JR, Valle Y, Figuera LE. Pedigree analysis of Mexican families with Fabry disease as a powerful tool for identification of heterozygous females. Genet Mol Res. 2014 Aug;13(3):6752-8..

Previously, one Latin American study found angiokeratomas, hypohidrosis or anhidrosis, impaired temperature regulation with intolerance to cold and heat, acroparesthesias, cornea verticilata, diarrhea or constipation, abdominal pain, deafness, tinnitus and fatigue in patients and relatives, but there was no analysis evaluating the groups separately2121 Gutiérrez-Amavizca BE, Orozco-Castellanos R, Padilla-Gutiérrez JR, Valle Y, Figuera LE. Pedigree analysis of Mexican families with Fabry disease as a powerful tool for identification of heterozygous females. Genet Mol Res. 2014 Aug;13(3):6752-8.. Okur et al, in 2013, described two cases of FD in patients on dialysis: in case 1, the patient’s granddaughter presented cornea verticilata, and, in case 2, one relative presented proteinuria, while another presented acroparestesia and cornea verticilata1313 Okur I, Ezgu F, Biberoglu G, Tumer L, Erten Y, Isitman M, et al. Screening for Fabry disease in patients undergoing dialysis for chronic renal failure in Turkey: identification of new case with novel mutation. Gene. 2013 Sep;527(1):42-7.. A Turkish study identified in a family screening eight relatives of a FD patient to have FD, and described multiple symptoms in 75% of these1515 Turkmen K, Guclu A, Sahin G, Kocyigit I, Demirtas L, Erdur FM, et al. The prevalence of Fabry disease in patients with chronic kidney disease in Turkey: the TURKFAB study. Kidney Blood Press Res. 2016;41(6):1016-24.. Another Turkish study described hearing loss, intolerance to heat and cold, and sweating disorders to be the most commonly observed disorders in patients, however, in spite of having found 3 cases of FD between relatives, there was no description of the clinical manifestations1717 Yeniçerioglu Y, Akdam H, Dursun B, Alp A, Eyiler FS, Akin D, et al. Screening Fabry's disease in chronic kidney disease patients not on dialysis: a multicenter study. Ren Fail. 2017;39(1):104-11.. Finally, in Asia, the most typically described features in FD patients were sweating impairment (73.5%), corneal clouding (73.0%), and acroparesthesia (72.2%); although ten family members presented mutations to FD, there was no description of their signs and symptoms1818 Choi JH, Lee BH, Heo SH, Kim GH, Kim YM, Kim DS, et al. Clinical characteristics and mutation spectrum of GLA in Korean patients with Fabry disease by a nationwide survey: underdiagnosis of late-onset phenotype. Medicine. 2017 Jul;96(29):e7387..

In the aforementioned Brazilian study, most cases presented classical features of FD: cornea verticilata, hypohidrosis, acroparesthesia, angiokeratoma, lymphedema, arthralgia, generalized pains and fatigue, which was similar to our findings, whereas their relatives were mostly oligosymptomatic, hence would clearly benefit from early diagnosis and treatment2020 Silva CAB, Barreto FC, Reis MA, Moura Junior JA, Cruz CMS. Targeted screening of Fabry disease in male hemodialysis patients in Brazil highlights importance of family screening. Nephron. 2016;134(4):221-30.. In our study, the majority of relatives were oligosymptomatic and 73.9% of relatives were diagnosed with FD mutations earlier than 44 years of age, similarly to other studies in which genetic testing allowed early recognition of the disease1515 Turkmen K, Guclu A, Sahin G, Kocyigit I, Demirtas L, Erdur FM, et al. The prevalence of Fabry disease in patients with chronic kidney disease in Turkey: the TURKFAB study. Kidney Blood Press Res. 2016;41(6):1016-24.,2020 Silva CAB, Barreto FC, Reis MA, Moura Junior JA, Cruz CMS. Targeted screening of Fabry disease in male hemodialysis patients in Brazil highlights importance of family screening. Nephron. 2016;134(4):221-30.,2121 Gutiérrez-Amavizca BE, Orozco-Castellanos R, Padilla-Gutiérrez JR, Valle Y, Figuera LE. Pedigree analysis of Mexican families with Fabry disease as a powerful tool for identification of heterozygous females. Genet Mol Res. 2014 Aug;13(3):6752-8..

Among relatives of FD mutation patients, we found a proportion of 66.1% of women to be diagnosed with FD mutations, which is very different from what was previously shown in the literature, since women had rarely been screened for FD1515 Turkmen K, Guclu A, Sahin G, Kocyigit I, Demirtas L, Erdur FM, et al. The prevalence of Fabry disease in patients with chronic kidney disease in Turkey: the TURKFAB study. Kidney Blood Press Res. 2016;41(6):1016-24.,1717 Yeniçerioglu Y, Akdam H, Dursun B, Alp A, Eyiler FS, Akin D, et al. Screening Fabry's disease in chronic kidney disease patients not on dialysis: a multicenter study. Ren Fail. 2017;39(1):104-11.,2121 Gutiérrez-Amavizca BE, Orozco-Castellanos R, Padilla-Gutiérrez JR, Valle Y, Figuera LE. Pedigree analysis of Mexican families with Fabry disease as a powerful tool for identification of heterozygous females. Genet Mol Res. 2014 Aug;13(3):6752-8.. Most studies report a higher prevalence of FD in men, probably due to higher screening in men; in our opinion, women should definitely also be screened99 Marinho LAL, Rêgo JFM, Ramos TCO, Alves TMS. Prevalência da doença de Fabry em pacientes portadores de doença renal crônica submetidos à hemodiálise em Natal-RN, Brazil. J Bras Nefrol. 2007;29(4):235-9.

10 Vale NFD, Silva ADBR, Veras AB, Monteiro FMR, Sousa JLM, Bezerra VL, et al. Diagnóstico de doença de Fabry em indivíduos submetidos à hemodiálise no estado do Piauí: o papel do exame de triagem e estudo de casos. J Bras Nefrol. 2008;30(4):259-63.

11 Porsch DB, Nunes ACF, Milani V, Rossato LB, Mattos CB, Tsao M, et al. Fabry disease in hemodialysis patients in southern Brazil: prevalence study and clinical report. Ren Fail. 2008;30:825-30.
-1212 Sodré LSS, Huaira RMNH, Bastos MG, Colugnati FAB, Coutinho M, Fernandes NMS. Screening for Fabry disease in kidney disease: a cross-sectional study in males and females. Kidney Blood Press Res. 2017;42:1258-65.,1919 Kleinert J, Kotanko P, Spada M, Pagliardini S, Paschke E, Paul K, et al. Anderson-Fabry disease: a case finding study among male kidney transplant recipients in Austria. Transplant International. 2009 Feb;22(3):287-92.. In fact, as in men, women can develop classical forms of FD, and as demonstrated in a previous Latin American study, heterozygous women can show various degrees of disease severity2121 Gutiérrez-Amavizca BE, Orozco-Castellanos R, Padilla-Gutiérrez JR, Valle Y, Figuera LE. Pedigree analysis of Mexican families with Fabry disease as a powerful tool for identification of heterozygous females. Genet Mol Res. 2014 Aug;13(3):6752-8..

The main limitation of the study was that we did not have the family tree of the patients, which is inherent to our study design. Another limitation was that the levels of alpha galactosidase were not available in this database. These limitations do not invalidate our relevant study.

Screening of FD in men consists of dosage of α-Gal-A, which is much cheaper than genetic testing necessary for diagnosis of FD in women88 Terryn W, Cochat P, Froissart R, Ortiz A, Pirson Y, Poppe B, et al. Fabry nephropathy: indications for screening and guidance for diagnosis and treatment by the European Renal Best Practice. Nephrol Dial Transplant. 2012 Mar;28(3):505-17.,2222 Wang RY, Bodamer OA, Watson MS, Wilcox WR, ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Diseases. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Genet Med. 2011 May;13(5):457-84.. Screening for FD is of great importance, since life expectancy can be diminished in roughly 20 years in FD patients, with marked reduction in survival in men aged over 35 years, whereas clinical manifestations tend to occur later in women, with an estimated 15 years loss in life expectancy66 Zarate YA, Hopkin RJ. Fabry’s disease. Lancet. 2008 Oct;372(9647):1427-35.,88 Terryn W, Cochat P, Froissart R, Ortiz A, Pirson Y, Poppe B, et al. Fabry nephropathy: indications for screening and guidance for diagnosis and treatment by the European Renal Best Practice. Nephrol Dial Transplant. 2012 Mar;28(3):505-17..

CONCLUSION

We found a prevalence of FD mutations in 9.47% of relatives of CKD patients diagnosed with FD mutations, 66.1% of which were women. Our results suggest that relative screening of FD mutations, in both men and women, is necessary, not only due to the high prevalence of FD mutations found in this study, but also because FD can be oligosymptomatic for many years, meaning that early diagnosis can favor treatment success and prevention of severe complications of multi-system Gb3 deposition. Women, even though relatively protected by the presence of two X chromosomes, are susceptible to FD, and screening of this disease has often been neglected in women, possibly due to the higher costs of genetic sequencing, when compared to enzymatic dosage for diagnosing FD in men.

ACKNOWLEDGMENTS

We thank all patients for agreeing to be part of the study without any bonuses. The study was submitted to the ethics and human research committee and approved under the number 18029513.0.0000.5244.

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Publication Dates

  • Publication in this collection
    14 Sept 2020
  • Date of issue
    Jan-Mar 2021

History

  • Received
    11 Apr 2020
  • Accepted
    26 July 2020
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