BACKGROUND: Fabry disease (FD, OMIM #301500) is a rare, progressive, X-linked, inherited genetic disease caused by a functional deficiency of lysosomal α-galactosidase, leading to the accumulation of glycosphingolipids in virtually all of the body's cell types and fluids. Patients with rare genetic diseases and non-specific symptoms often experience substantial diagnostic delays, which can negatively impact the prompt initiation of treatment. If FD is not treated specifically, end organ damage (such as chronic renal failure, hypertrophic cardiomyopathy with arrhythmia, and strokes) impairs quality of life and reduces life expectancy. PATIENTS AND METHODS: For 83 consecutive patients with FD referred to the Russian reference center for lysosomal storage diseases, family trees were built and genetic testing (cascade genotyping) was offered to family members. RESULTS: The pathogenic GLA variant associated with FD was identified for all 83 probands. Family testing using cascade genotyping enabled the identification of 165 additional cases of FD among the tested 331 at-risk family members. DISCUSSION: This is the first study to have described family screening in a large Russian cohort of patients with FD and chronic kidney disease. Raising awareness of FD among clinicians is important for earlier diagnosis and specific treatment.

2nd Department of Internal Medicine 1st Faculty of Medicine Charles University 12808 Prague Czech Republic

Division of Medical Genetics University of Versailles 78180 Montigny France

Faculty of Medicine Lomonosov Moscow State University 119991 Moscow Russia

Faculty of Medicine University of Puthisastra Phnom Penh 12211 Cambodia

Geneo Referral Centre for Fabry Disease Filière G2M MetabERN European Reference Network Paris Saclay University 92380 Garches France

Tareev Clinic of Internal Disease Sechenov 1st Moscow State Medical University 119991 Moscow Russia

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Eng C.M., Resnick-Silverman L.A., Niehaus D.J., Astrin K.H., Desnick R.J. Nature and frequency of mutations in the alpha-galactosidase A gene that cause Fabry disease. Am. J. Hum. Genet. 1993;53:1186–1197. PubMed PMC

Germain D.P., Biasotto M., Tosi M., Meo T., Kahn A., Poenaru L. Fluorescence-assisted mismatch analysis (FAMA) for exhaustive screening of the alpha-galactosidase A gene and detection of carriers in Fabry disease. Hum. Genet. 1996;98:719–726. PubMed

Desnick R.J., Brady R., Barranger J., Collins A.J., Germain D.P., Goldman M., Grabowski G., Packman S., Wilcox W.R. Fabry disease, an under-recognized multisystemic disorder: Expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann. Intern. Med. 2003;138:338–346. doi: 10.7326/0003-4819-138-4-200302180-00014. PubMed DOI

Germain D.P. Fabry disease. Orphanet J. Rare Dis. 2010;5:30. doi: 10.1186/1750-1172-5-30. PubMed DOI PMC

Ortiz A., Germain D.P., Desnick R.J., Politei J., Mauer M., Burlina A., Eng C., Hopkinh R.J., Laneyi D., Linhart A., et al. Fabry disease revisited: Management and treatment recommendations for adult patients. Mol. Genet. Metab. 2018;123:416–427. doi: 10.1016/j.ymgme.2018.02.014. PubMed DOI

Aerts J.M., Groener J.E., Kuiper S., Donker-Koopman W.E., Strijland A., Ottenhoff R., van Roomen C., Mirzaian M., Wijburg F.A., Linthorst G.E., et al. Elevated globotriaosylsphingosine is a hallmark of Fabry disease. Proc. Natl. Acad. Sci. USA. 2008;105:2812–2817. doi: 10.1073/pnas.0712309105. PubMed DOI PMC

Politei J.M., Bouhassira D., Germain D.P., Goizet C., Guerrero-Sola A., Hilz M.J., Hutton E.J., Karaa A., Liguori R., Üçeyler N., et al. Pain in Fabry disease: Practical recommendations for diagnosis and treatment. CNS Neurosci. Ther. 2016;22:568–576. doi: 10.1111/cns.12542. PubMed DOI PMC

Wanner C., Oliveira J., Ortiz A., Mauer M., Germain D.P., Linthorst G.E., Serra A.L., Maródi L., Mignani R., Cianciaruso B., et al. Prognostic indicators of renal disease progression in adults with Fabry disease: Natural history data from the Fabry Registry. Clin. J. Am. Soc. Nephrol. 2010;5:2220–2228. doi: 10.2215/CJN.04340510. PubMed DOI PMC

Linhart A., Germain D.P., Olivotto I., Akhtar M.M., Anastasakis A., Hughes D., Namdar M., Pieroni M., Hagège A., Cecchi F., et al. An expert consensus document on the management of cardiovascular manifestations of Fabry disease. Eur. J. Heart Fail. 2020;22:1076–1096. doi: 10.1002/ejhf.1960. PubMed DOI

Kolodny E., Fellgiebel A., Hilz M., Sims K., Caruso P., Phan T.G., Politei J., Manara R., Burlina A. Cerebrovascular involvement in Fabry disease: Current status of knowledge. Stroke. 2015;46:302–313. PubMed

Demuth K., Germain D.P. Endothelial markers and homocysteine in patients with classic Fabry disease. Acta Paediatr. 2002;91:57–61. doi: 10.1111/j.1651-2227.2002.tb03112.x. PubMed DOI

Echevarria L., Benistan K., Toussaint A., Dubourg O., Hagege A.A., Eladari D., Jabbour F., Beldjord C., de Mazancourt P., Germain D.P. X-chromosome inactivation in female patients with Fabry disease. Clin. Genet. 2016;89:44–54. doi: 10.1111/cge.12613. PubMed DOI

Germain D.P., Arad M., Burlina A., Elliott P.M., Falissard B., Feldt-Rasmussen U., Hilz M.J., Hughes D.A., Ortiz A., Wanner C., et al. The effect of enzyme replacement therapy on clinical outcomes in female patients with Fabry disease-A systematic literature review by a European panel of experts. Mol. Genet. Metab. 2019;126:224–235. doi: 10.1016/j.ymgme.2018.09.007. PubMed DOI

Germain D.P., Fouilhoux A., Decramer S., Tardieu M., Pillet P., Fila M., Rivera S., Deschênes G., Lacombe D. Consensus recommendations for diagnosis, management and treatment of Fabry disease in paediatric patients. Clin. Genet. 2019;96:107–117. doi: 10.1111/cge.13546. PubMed DOI PMC

Mehta A., Beck M., Eyskens F., Feliciani C., Kantola I., Ramaswami U., Rolfs A., Rivera A., Waldek S., Germain D.P. Fabry disease: A review of current management strategies. QJM. 2010;103:641–659. doi: 10.1093/qjmed/hcq117. PubMed DOI

Germain D.P., Hughes D.A., Nicholls K., Bichet D.G., Giugliani R., Wilcox W.R., Feliciani C., Shankar S.P., Ezgu F., Amartino H., et al. Treatment of Fabry’s Disease with the Pharmacologic Chaperone Migalastat. N. Engl. J. Med. 2016;375:545–555. doi: 10.1056/NEJMoa1510198. PubMed DOI

Wanner C., Arad M., Baron R., Burlina A., Elliott P.M., Feldt-Rasmussen U., Fomin V.V., Germain D.P., Hughes D.A., Jovanovic A., et al. European expert consensus statement on therapeutic goals in Fabry disease. Mol. Genet. Metab. 2018;124:189–203. doi: 10.1016/j.ymgme.2018.06.004. PubMed DOI

Lin C.J., Chien Y.H., Lai T.S., Shih H.M., Chen Y.C., Pan C.F., Chen H.H., Hwu W.L., Wu C.J. Results of Fabry disease screening in male pre-end stage renal disease patients with unknown etiology found through the Platform of a Chronic Kidney Disease Education Program in a Northern Taiwan Medical Center. Kidney Blood Press. Res. 2018;43:1636–1645. doi: 10.1159/000494678. PubMed DOI

Lv Y.L., Wang W.M., Pan X.X., Wang Z.H., Chen N., Ye Z.Y., Xu J. A successful screening for Fabry disease in a Chinese dialysis patient population. Clin. Genet. 2009;76:219–221. doi: 10.1111/j.1399-0004.2009.01166.x. PubMed DOI

Merta M., Reiterova J., Ledvinova J., Poupetová H., Dobrovolny R., Rysavá R., Maixnerová D., Bultas J., Motáň J., Slivkova J., et al. A nationwide blood spot screening study for Fabry disease in the Czech Republic haemodialysis patient population. Nephrol. Dial. Transpl. 2007;22:179–186. doi: 10.1093/ndt/gfl528. PubMed DOI

Nakao S., Kodama C., Takenaka T., Tanaka A., Yasumoto Y., Yoshida A., Kanzaki T., Enriquez A.L.D., Eng C.M., Tanaka H., et al. Fabry disease: Detection of undiagnosed hemodialysis patients and identification of a “renal variant” phenotype. Kidney Int. 2003;64:801–807. doi: 10.1046/j.1523-1755.2003.00160.x. PubMed DOI

Okur I., Ezgu F., Biberoglu G., Tumer L., Erten Y., Isitman M., Eminoglua F.T., Hasanoglua A. Screening for Fabry disease in patients undergoing dialysis for chronic renal failure in Turkey: Identification of new case with novel mutation. Gene. 2013;527:42–47. doi: 10.1016/j.gene.2013.05.050. PubMed DOI

Silva C.A., Barreto F.C., Dos Reis M.A., Moura Junior J.A., Cruz C.M. Targeted screening of Fabry disease in male hemodialysis patients in Brazil highlights importance of family screening. Nephron. 2016;134:221–230. doi: 10.1159/000448740. PubMed DOI

Moiseev S., Fomin V., Savostyanov K., Pushkov A., Moiseev A., Svistunov A., Namazova-Baranova L. The prevalence and clinical features of Fabry disease in hemodialysis patients: Russian Nationwide Fabry Dialysis Screening Program. Nephron. 2019;141:249–255. doi: 10.1159/000495886. PubMed DOI PMC

Turkmen K., Guclu A., Sahin G., Kocyigit I., Demirtas L., Erdur F.M., Sengül E., Ozkan O., Emre H., Turgut F., et al. The prevalence of Fabry disease in patients with chronic kidney disease in Turkey: The TURKFAB Study. Kidney Blood Press. Res. 2016;41:1016–1024. doi: 10.1159/000452605. PubMed DOI

Veloso V.S.P., Ataides T.L., Canziani M.E.F., Veloso M.P., da Silva N.A., Barreto D.V., Pereira E.R.S., de Moura L.A.R., Barreto F.C. A novel missense GLA mutation (p.G35V) detected in hemodialysis screening leads to severe systemic manifestations of Fabry disease in men and women. Nephron. 2018;138:147–156. doi: 10.1159/000479895. PubMed DOI

Adalsteinsdottir B., Palsson R., Desnick R.J., Gardarsdottir M., Teekakirikul P., Maron M., Appelbaum E., Neisius U., Maron B.J., Burke M.A. Fabry disease in families with hypertrophic cardiomyopathy: Clinical manifestations in the classic and later-onset phenotypes.; et al. Circ. Cardiovasc. Genet. 2017;10:e001639. doi: 10.1161/CIRCGENETICS.116.001639. PubMed DOI

Hagège A.A., Caudron E., Damy T., Roudaut R., Millaire A., Etchecopar-Chevreuil C., Tran T., Jabbour F., Boucly C., Prognon P., et al. FOCUS study investigators. Screening patients with hypertrophic cardiomyopathy for Fabry disease using a filter-paper test: The FOCUS study. Heart. 2011;97:131–136. doi: 10.1136/hrt.2010.200188. PubMed DOI

Maron M.S., Xin W., Sims K.B., Butler R., Haas T.S., Rowin E.J., Desnick R.J., Maron B.J. Identification of Fabry disease in a tertiary referral cohort of patients with hypertrophic cardiomyopathy. Am. J. Med. 2018;131:e1–e200. doi: 10.1016/j.amjmed.2017.09.010. PubMed DOI

Moiseev S., Karovaikina E., Moiseev A., Bulanov N., Fomin V. Strategies of screening for Fabry disease in patients with unexplained left ventricular hypertrophy. Mayo Clin. Proc. 2019;94:1644–1646. doi: 10.1016/j.mayocp.2019.05.003. PubMed DOI

De Brabander I., Yperzeele L., Ceuterick-De Groote C., Brouns R., Baker R., Belachew S., Delbecq J., de Keulenaer G., Dethy S., Eyskens F., et al. Phenotypical characterization of α-galactosidase A gene mutations identified in a large Fabry disease screening program in stroke in the young. Clin. Neurol. Neurosurg. 2013;115:1088–1093. doi: 10.1016/j.clineuro.2012.11.003. PubMed DOI

Doheny D., Srinivasan R., Pagant S., Chen B., Yasuda M., Desnick R.J. Fabry Disease: Prevalence of affected males and heterozygotes with pathogenic GLA mutations identified by screening renal, cardiac and stroke clinics, 1995–2017. J. Med. Genet. 2018;55:261–268. doi: 10.1136/jmedgenet-2017-105080. PubMed DOI

Germain D.P., Moiseev S., Suárez-Obando F., Al Ismaili F., Al Khawaja H., Altarescu G., Barreto F.C., Haddoum F., Hadipour F., Maksimova I., et al. The benefits and challenges of family screening in rare genetic diseases–lessons from Fabry disease. Mol. Genet. Genom. Med. 2021;9:e1666. doi: 10.1016/j.ymgme.2019.11.142. PubMed DOI PMC

Germain D.P., Brand E., Burlina A., Cecchi F., Garman S.C., Kempf J., Laney D.A., Linhart A., Maródi L., Nicholls K., et al. Phenotypic characteristics of the p.Asn215Ser (p.N215S) GLA mutation in male and female patients with Fabry disease: A multicenter Fabry Registry study. Mol. Genet. Genom. Med. 2018;6:492–503. doi: 10.1002/mgg3.389. PubMed DOI PMC

Laney D.A., Fernhoff P.M. Diagnosis of Fabry disease via analysis of family history. J. Genet. Couns. 2008;17:79–83. doi: 10.1007/s10897-007-9128-x. PubMed DOI

Gragnaniello V., Burlina A.P., Polo G., Giuliani A., Salviati L., Duro G., Cazzorla C., Rubert L., Maines E., Germain D.P., et al. Newborn Screening for Fabry Disease in Northeastern Italy: Results of Five Years of Experience. Biomolecules. 2021;11:951. doi: 10.3390/biom11070951. PubMed DOI PMC

Vigneau C., Germain D.P., Larmet D., Jabour F., Hourmant M., SNOUFY Investigators Group Screeninf for Fabry disease in male patients with end-stage renal disease in Western France. Nephrol. Ther. 2021;17:180–184. doi: 10.1016/j.nephro.2021.03.002. PubMed DOI

Frabasil J., Durand C., Sokn S., Gaggioli D., Carozza P., Carabajal R., Politei J., Schenone A.B. Prevalence of Fabry disease in male dialysis patients: Argentinean screening study. JIMD Rep. 2019;48:45–52. doi: 10.1002/jmd2.12035. PubMed DOI PMC

Sachdev B., Takenaka T., Teraguchi H., Tei C., Lee P., McKenna W.J., Elliott P.M. Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy. Circulation. 2002;105:1407–1411. doi: 10.1161/01.CIR.0000012626.81324.38. PubMed DOI

Spada M., Pagliardini S., Yasuda M., Tukel T., Thiagarajan G., Sakuraba H., Ponzonea A., Desnick R.J. High incidence of later-onset Fabry disease revealed by newborn screening. Am. J. Hum. Genet. 2006;79:31–40. doi: 10.1086/504601. PubMed DOI PMC

Germain D.P., Avan P., Chassaing A., Bonfils P. Patients affected with Fabry disease have an increased incidence of progressive hearing loss and sudden deafness: An investigation of twenty-two hemizygous male patients. BMC Med. Genet. 2002;3:10. doi: 10.1186/1471-2350-3-10. PubMed DOI PMC

Magage S., Lubanda J.C., Susa Z., Bultas J., Karetova D., Dobrovolny R., Hrebıcek M., Germain D.P., Linhart A. Natural history of the respiratory involvement in Anderson-Fabry disease. J. Inherit. Metab. Dis. 2007;30:790–799. doi: 10.1007/s10545-007-0616-9. PubMed DOI

Reisin R., Perrin A., García-Pavía P. Time delays in the diagnosis and treatment of Fabry disease. Int. J. Clin. Pract. 2017;71:e12914. doi: 10.1111/ijcp.12914. PubMed DOI

Germain D.P., Poenaru L. Fabry disease: Identification of novel α-galactosidase A mutations and molecular carrier detection by use of fluorescent chemical cleavage of mismatches. Biochem. Biophys. Res. Commun. 1999;257:708–713. doi: 10.1006/bbrc.1999.0310. PubMed DOI

Rozenfeld P.A., Masllorens F.M., Roa N., Rodriguez F., Bonnano M., Yvorra C., Ceci R. Fabry pedigree analysis: A successful program for targeted genetic approach. Mol. Genet. Genom. Med. 2019;7:e00794. doi: 10.1002/mgg3.794. PubMed DOI PMC