Yüksek akrabalık oranına sahip bir bölgede yeni GLA mutasyonu: Türkiye'de Fabry hastalığı taramasından elde edilen bulgular

Yıl 2025, Cilt: 8 Sayı: 6, 1055 - 1059, 25.10.2025

Sibel Ada , Şeyda Gül Özcan , Orçun Altunören , Necmi Eren , Tayfur Toptaş

https://doi.org/10.32322/jhsm.1759818

Öz

Giriş:
Fabry hastalığı (FH), α-galaktosidaz A (α-Gal A) enzim eksikliğine bağlı olarak gelişen X'e bağlı kalıtılan lizozomal depo hastalığıdır. Çoklu organ sistemlerinde globotriaosilseramidin birikimine neden olur. Erken tanı özellikle yüksek riskli popülasyonlarda hâlâ önemli bir zorluktur. Bu çalışmanın amacı, akraba evliliği oranının yüksek olduğu Doğu ve Güneydoğu Anadolu bölgelerinde hemodiyaliz hastalarında Fabry hastalığı prevalansını belirlemektir.
Yöntem:
2015–2019 yılları arasında beş ilde düzenli hemodiyaliz tedavisi alan 613 erişkin hasta kuru kan örneği ile α-Gal A aktivitesi açısından tarandı. Enzim düzeyi düşük saptanan hastalarda lökosit enzim analizi ve GLA gen dizilemesi ile doğrulayıcı testler yapıldı.

Bulgular:
Hastaların %15,7’sinde α-Gal A aktivitesi düşük bulundu. Genetik analiz yapılan 58 bireyde erkeklerde mutasyon tespit edilmedi. Ancak, birbiriyle akraba olmayan iki kadın hastada daha önce gnomAD veya ClinVar veri tabanlarında bildirilmeyen aynı GLA gen varyantı c.116C>A (p.T39K) saptandı. Bu kohortta genetik olarak doğrulanmış FH prevalansı %0,32 olarak hesaplandı.

Sonuç:
Bu çalışma, Türkiye'nin Doğu ve Güneydoğu bölgelerinde gerçekleştirilen ilk bölgesel Fabry hastalığı tarama çalışmasıdır. Yüksek akrabalık oranına sahip bir popülasyonda yeni bir GLA mutasyonunun tespit edilmesi, hemodiyaliz hastalarında genetik taramanın önemini ve bölgeye özgü tanı ve genetik danışmanlık stratejilerine olan ihtiyacı vurgulamaktadır.

Anahtar Kelimeler

Fabry hastalığı , Hemodiyaliz taraması , GLA geni , Akrabalık

Novel GLA mutation in a high-consanguinity region: insights from Fabry disease screening in Turkiye

Öz

Aims: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by deficient α-galactosidase A (α-Gal A) activity, leading to the accumulation of globotriaosylceramide in multiple organ systems. Its early diagnosis remains a challenge, particularly in high-risk populations. This study aimed to determine the prevalence of FD among hemodialysis patients in Eastern and Southeastern Turkiye, regions with a high rate of consanguineous marriages.
Methods: Between 2015 and 2019, 613 adult patients undergoing maintenance hemodialysis across five provinces were screened for α-Gal A activity using dried blood spot testing. Patients with reduced enzyme levels underwent confirmatory testing through leukocyte enzyme assays and GLA gene sequencing.
Results: Reduced α-Gal A activity was identified in 15.7% of patients. Genetic analysis in 58 individuals revealed no mutations in males. However, two unrelated female patients were found to carry the same GLA gene variant, c.116C>A (p.T39K), which has not been previously reported in gnomAD or ClinVar databases. The overall prevalence of genetically confirmed FD in this cohort was 0.32%.
Conclusion: This is the first regional screening study of FD in Eastern and Southeastern Turkiye. The identification of a novel GLA mutation in a high-consanguinity population underscores the importance of genetic screening in dialysis patients and highlights the need for region-specific diagnostic and counseling strategies.

Anahtar Kelimeler

Fabry disease , hemodialysis screening , GLA gene , consanguinity

Kaynakça

• Desnick R. α-Galactosidase A deficiency: Fabry disease. The metabolic and molecular bases of inherited disease. 1995:2741-84.
• Mauhin W, Lidove O, Masat E, et al. Innate and adaptive immune response in Fabry disease. JIMD Rep. 2015;22:1-10. doi:10.1007/8904_2014_371
• Biancini GB, Vanzin CS, Rodrigues DB, et al. Globotriaosylceramide is correlated with oxidative stress and inflammation in Fabry patients treated with enzyme replacement therapy. Biochim Biophys Acta. 2012; 1822(2):226-232. doi:10.1016/j.bbadis.2011.11.001
• Arends M, Wanner C, Hughes D, et al. Characterization of classical and nonclassical Fabry disease: a multicenter study. J Am Soc Nephrol. 2017;28(5):1631-1641. doi:10.1681/ASN.2016090964
• Kampmann C, Baehner F, Whybra C, et al. Cardiac manifestations of Anderson-Fabry disease in heterozygous females. J Am Coll Cardiol. 2002;40(9):1668-1674. doi:10.1016/s0735-1097(02)02380-x
• Shah JS, Elliott PM. Fabry disease and the heart: an overview of the natural history and the effect of enzyme replacement therapy. Acta Paediatr Suppl. 2005;94(447):11-10. doi:10.1111/j.1651-2227.2005.tb02103.x
• MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet. 2001;38(11):750-760. doi:10.1136/jmg. 38.11.750
• Ortiz A, Oliveira JP, Waldek S, et al. Nephropathy in males and females with Fabry disease: cross-sectional description of patients before treatment with enzyme replacement therapy. Nephrol Dial Transplant. 2008;23(5):1600-1607. doi:10.1093/ndt/gfm848
• Mehta A, Ricci R, Widmer U, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry outcome survey. Eur J Clin Invest. 2004;34(3):236-242. doi:10.1111/j.1365-2362.2004.01309.x
• Alroy J, Sabnis S, Kopp JB. Renal pathology in Fabry disease. J Am Soc Nephrol. 2002;13(Suppl 2):S134-S138.
• Cammarata G, Fatuzzo P, Rodolico MS, et al. High variability of Fabry disease manifestations in an extended Italian family. Biomed Res Int. 2015;2015:504784. doi:10.1155/2015/504784
• Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30. doi:10.1186/1750-1172-5-30
• 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
• Swinford NA, Prall SP, Gopalan S, et al. Increased homozygosity due to endogamy results in fitness consequences in a human population. Proc Natl Acad Sci U S A. 2023;120(43):e2309552120. doi:10.1073/pnas.2309552120
• Heyne HO, Karjalainen J, Karczewski KJ, et al. Mono- and biallelic variant effects on disease at biobank scale. Nature. 2023;613(7944):519-525. doi:10.1038/s41586-022-05420-7
• Akbayram S, Sari N, Akgün C, et al. The frequency of consanguineous marriage in eastern Turkey. Genet Couns. 2009;20(3):207-214.
• Tunçbílek E, Koc I. Consanguineous marriage in Turkey and its impact on fertility and mortality. Ann Hum Genet. 1994;58(4):321-329. doi:10. 1111/j.1469-1809.1994.tb00729.x
• Yalın SF, Eren N, Sinangil A, et al. Fabry disease prevalence in renal replacement therapy in Turkey. Nephron. 2019;142(1):26-33. doi:10.1159/ 000496620
• Okur I, Ezgu F, Biberoglu G, 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;527(1):42-47. doi:10.1016/j.gene.2013.05.050
• Kalkan Uçar S, Sozmen E, Duman S, Başçi A, Çoker M. Alpha-galactosidase A activity levels in Turkish male hemodialysis patients. Ther Apher Dial. 2012;16(6):560-565. doi:10.1111/j.1744-9987.2012. 01092.x
• Serin EN, Ataş Ü, Çetinkaya R, Sarı F. The Frequency of Fabry disease in hemodialysis patients in the Western Mediterranean region of Turkiye. Akdeniz Tıp Dergisi. 2024;10(1):92-99. doi:10.53394/akd.1136791
• Chamoles NA, Blanco M, Gaggioli D. Fabry disease: enzymatic diagnosis in dried blood spots on filter paper. Clin Chim Acta. 2001;308(1-2):195-196. doi:10.1016/s0009-8981(01)00478-8
• Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for molecular pathology. Genet Med. 2015;17(5):405-424. doi:10.1038/gim.2015.30
• Genome Aggregation Database [Available from:. https://gnomad.broadinstitute.org]
• ClinVar [Available from:https://www.ncbi.nlm.nih.gov/clinvar/]
• Flanagan SE, Patch AM, Ellard S. Using SIFT and PolyPhen to predict loss-of-function and gain-of-function mutations. Genet Test Mol Biomarkers. 2010;14(4):533-537. doi:10.1089/gtmb.2010.0036
• Kotanko P, Kramar R, Devrnja D, et al. Results of a nationwide screening for Anderson-Fabry disease among dialysis patients. J Am Soc Nephrol. 2004;15(5):1323-1329. doi:10.1097/01.asn.0000124671.61963.1e
• Merta M, Reiterova J, Ledvinova J, et al. A nationwide blood spot screening study for Fabry disease in the Czech Republic haemodialysis patient population. Nephrol Dial Transplant. 2007;22(1):179-186. doi:10.1093/ndt/gfl528
• Doi K, Noiri E, Ishizu T, et al. High-throughput screening identified disease-causing mutants and functional variants of α-galactosidase A gene in Japanese male hemodialysis patients. J Hum Genet. 2012;57(9):575-579. doi:10.1038/jhg.2012.68
• Maruyama H, Takata T, Tsubata Y, et al. Screening of male dialysis patients for Fabry disease by plasma globotriaosylsphingosine. Clin J Am Soc Nephrol. 2013;8(4):629-636. doi:10.2215/CJN.08780812
• Herrera J, Miranda CS. Prevalence of Fabry’s disease within hemodialysis patients in Spain. Clin Nephrol. 2014;81(2):112-120. doi:10. 5414/CN108053
• Szpiech ZA, Xu J, Pemberton TJ, et al. Long runs of homozygosity are enriched for deleterious variation. Am J Hum Genet. 2013;93(1):90-102. doi:10.1016/j.ajhg.2013.05.003
• Xiao Q, Lauschke VM. The prevalence, genetic complexity and population-specific founder effects of human autosomal recessive disorders. NPJ Genom Med. 2021;6(1):41. doi:10.1038/s41525-021-00203-x
• Tomek A, Petra R, Paulasová Schwabová J, et al. Nationwide screening for Fabry disease in unselected stroke patients. PLoS One. 2021;16(12):e0260601. doi:10.1371/journal.pone.0260601
• Izhar R, Borriello M, La Russa A, et al. Fabry disease in women: genetic basis, available biomarkers, and clinical manifestations. Genes (Basel). 2023;15(1):37. doi:10.3390/genes15010037
• 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
• Wanner C, Arad M, Baron R, et al. European expert consensus statement on therapeutic goals in Fabry disease. Mol Genet Metab. 2018;124(3):189-203. doi:10.1016/j.ymgme.2018.06.004