Nefrolojide Fabry Hastalığı: Tanı ve Tedavi
Synopsis
Fabry disease is an X-linked, multisystemic lysosomal storage disorder caused by alpha-galactosidase A deficiency resulting from pathogenic variants in the GLA gene. Renal involvement is one of the major clinical manifestations of the disease and may lead to proteinuria, progressive decline in kidney function, and end-stage kidney disease. This chapter reviews the genetic and molecular basis, pathophysiology, renal and extrarenal clinical manifestations, diagnostic approaches, and current treatment options for Fabry disease from a nephrological perspective. The diagnostic roles of alpha-galactosidase A enzyme activity measurement, GLA gene analysis, lyso-Gb3 levels, and kidney biopsy are discussed, with particular emphasis on the importance of early diagnosis and family screening. Therapeutic strategies, including enzyme replacement therapy, migalastat, supportive nephroprotective approaches, and emerging treatment modalities, are also evaluated. This chapter aims to highlight the essential role of nephrologists in the early recognition of Fabry disease, timely initiation of appropriate treatment, and prevention of progressive renal complications.
References
Spada M, Pagliardini S, Yasuda M, et al. High incidence of later-onset Fabry disease revealed by newborn screening. Am J Hum Genet. 2006;79(1):31-40. doi:10.1086/504601.
Wilcox WR, Oliveira JP, Hopkin RJ, et al. Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry. Mol Genet Metab. 2008;93(2):112-128. doi:10.1016/j.ymgme.2007.09.013.
Mehta A, Beck M, Eyskens F, et al. Fabry disease: a review of current management strategies. QJM. 2010;103(9):641-659. doi:10.1093/qjmed/hcq117.
Anania M, Pieruzzi F, Giacalone I, et al. Identification of four new mutations in the GLA gene associated with Anderson-Fabry disease. Int J Mol Sci. 2025;26(2):473. doi:10.3390/ijms26020473.
Ortiz A, Germain DP, Desnick RJ, et al. Fabry disease revisited: management and treatment recommendations for adult patients. Mol Genet Metab. 2018;123(4):416-427. doi:10.1016/j.ymgme.2018.02.014.
Čerkauskaitė A, Čerkauskienė R, Miglinas M, et al. Genotype-phenotype correlation in a new Fabry-disease-causing mutation. Medicina (Kaunas). 2019;55(5):122. doi:10.3390/medicina55050122.
Zhou H, Wang S, Chen Y, et al. Fabry disease with genetic variants of unknown significance and concomitant immunoglobulin A nephropathy. Kidney Blood Press Res. 2024;49(1):799-811. doi:10.1159/000541207.
Najafian B, Tøndel C, Svarstad E, et al. Accumulation of globotriaosylceramide in podocytes in Fabry nephropathy is associated with progressive podocyte loss. J Am Soc Nephrol. 2020;31(4):865-875. doi:10.1681/ASN.2019050497.
Rozenfeld P, Feriozzi S, Braun F. The role of tubular cells in the pathogenesis of Fabry nephropathy. Front Cardiovasc Med. 2024;11:1386042. doi:10.3389/fcvm.2024.1386042.
Capelli I, Martano L, Berti GM, et al. The role of kidney biopsy in Fabry disease. Biomedicines. 2025;13(4):767. doi:10.3390/biomedicines13040767.
Torra R. Renal manifestations in Fabry disease and therapeutic options. Kidney Int Suppl. 2008;(111):S29-S32. doi:10.1038/ki.2008.522.
Linhart A, Kampmann C, Zamorano JL, et al. Cardiac manifestations of Anderson-Fabry disease: results from the international Fabry outcome survey. Eur Heart J. 2007;28(10):1228-1235. doi:10.1093/eurheartj/ehm153.
Echevarria L, Benistan K, Toussaint A, et al. X-chromosome inactivation in female patients with Fabry disease. Clin Genet. 2016;89(1):44-54. doi:10.1111/cge.12613.
Desnick RJ, Wasserstein MP, Banikazemi M. Fabry disease (alpha-galactosidase A deficiency): renal involvement and enzyme replacement therapy. Contrib Nephrol. 2001;136:174-192. doi:10.1159/000060184.
Nowak A, Mechtler TP, Desnick RJ, et al. Plasma LysoGb3: a useful biomarker for the diagnosis and treatment of Fabry disease heterozygotes. Mol Genet Metab. 2017;120(1-2):57-61. doi:10.1016/j.ymgme.2016.10.006.
Tøndel C, Kanai T, Larsen KK, et al. Foot process effacement is an early marker of nephropathy in young classic Fabry patients without albuminuria. Nephron. 2015;129(1):16-21. doi:10.1159/000369309.
Effraimidis G, Rasmussen ÅK, Dunoe M, et al. Systematic cascade screening in the Danish Fabry Disease Centre: 20 years of a national single-centre experience. PLoS One. 2022;17(11):e0277767. doi:10.1371/journal.pone.0277767.
Moiseev S, Tao E, Moiseev A, et al. The benefits of family screening in rare diseases: genetic testing reveals 165 new cases of Fabry disease among at-risk family members of 83 index patients. Genes (Basel). 2022;13(9):1619. doi:10.3390/genes13091619.
Tsurumi M, Suzuki S, Hokugo J, et al. Long-term safety and efficacy of agalsidase beta in Japanese patients with Fabry disease: aggregate data from two post-authorization safety studies. Expert Opin Drug Saf. 2021;20(5):589-601. doi:10.1080/14740338.2021.1891221.
Germain DP, Charrow J, Desnick RJ, et al. Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease. J Med Genet. 2015;52(5):353-358. doi:10.1136/jmedgenet-2014-102797.
Schiffmann R, Kopp JB, Austin HA 3rd, et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA. 2001;285(21):2743-2749. doi:10.1001/jama.285.21.2743.
Germain DP, Waldek S, Banikazemi M, et al. Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease. J Am Soc Nephrol. 2007;18(5):1547-1557. doi:10.1681/ASN.2006080816.
Lenders M, Stypmann J, Duning T, et al. Serum-mediated inhibition of enzyme replacement therapy in Fabry disease. J Am Soc Nephrol. 2016;27(1):256-264. doi:10.1681/ASN.2014121226.
McCafferty EH, Scott LJ. Migalastat: a review in Fabry disease. Drugs. 2019;79(5):543-554. doi:10.1007/s40265-019-01090-4.
Germain DP, Hughes DA, Nicholls K, et al. Treatment of Fabry's disease with the pharmacologic chaperone migalastat. N Engl J Med. 2016;375(6):545-555. doi:10.1056/NEJMoa1510198.
Domm JM, Wootton SK, Medin JA, et al. Gene therapy for Fabry disease: progress, challenges, and outlooks on gene-editing. Mol Genet Metab. 2021;134(1-2):117-131. doi:10.1016/j.ymgme.2021.07.006.
Beraza-Millor M, Rodríguez-Castejón J, Del Pozo-Rodríguez A, et al. Systematic review of genetic substrate reduction therapy in lysosomal storage diseases: opportunities, challenges and delivery systems. BioDrugs. 2024;38(5):657-680. doi:10.1007/s40259-024-00674-1.
Linhart A, Dostálová G, Nicholls K, et al. Safety and efficacy of pegunigalsidase alfa in patients with Fabry disease who were previously treated with agalsidase alfa: results from BRIDGE, a phase 3 open-label study. Orphanet J Rare Dis. 2023;18(1):332. doi:10.1186/s13023-023-02937-6.
Suarez MLG, Thongprayoon C, Hansrivijit P, et al. Outcomes of kidney transplantation in Fabry disease: a meta-analysis. Diseases (Basel). 2020;9(1):2. doi:10.3390/diseases9010002.
Capelli I, Aiello V, Gasperoni L, et al. Kidney transplant in Fabry disease: a revision of the literature. Medicina (Kaunas). 2020;56(6):284. doi:10.3390/medicina56060284.
Weidemann F, Niemann M, Breunig F, et al. Long-term effects of enzyme replacement therapy on Fabry cardiomyopathy: evidence for a better outcome with early treatment. Circulation. 2009;119(4):524-529. doi:10.1161/CIRCULATIONAHA.108.794529.
Waldek S, Patel MR, Banikazemi M, et al. Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry Registry. Genet Med. 2009;11(11):790-796. doi:10.1097/GIM.0b013e3181bb05bb.
