Türkiye'nin Batı Akdeniz Bölgesindeki Hemodiyaliz Hastalarında Fabry Hastalığı Sıklığı

Öz

Amaç: Bu çalışmanın amacı, Batı Akdeniz bölgesinde hemodiyaliz uygulanan ancak böbrek yetmezliği etiyolojisi bilinmeyen veya başka nedenlere bağlanan hastaları belirlemek ve bu hastalardaki Fabry mutasyonunun prevalansını saptamaktır. Ayrıca çalışmamızda mutasyon saptanan olguların aile bireylerinde de tarama yapmayı amaçladık. Yöntemler: Türkiye'de Batı Akdeniz bölgesinde 11 farklı hemodiyaliz merkezinde hemodiyaliz tedavisi gören 18 yaş üstü 664 hasta tarandı. Erkek hastalarda ilk olarak Alfa-galaktosidaz A enzim seviyeleri test edildi ve alfa-galaktosidaz A seviyeleri < 3,3 nmol/mL/saat olan hastalarda GLA gen dizi analizi yapıldı. Kadınlarda ise GLA gen dizi analizi doğrudan yapıldı. Bulgular: Toplam 664 hasta [313 (%47.1) erkek ve 351 (%52.9) kadın] tarandı. Fabry mutasyonu sekiz kadın hastada ve bir erkek hastada pozitifti. Sonuç: Araştırmamızda hemodiyaliz tedavisi alan hastalarda Fabry hastalığı prevalansı %1,35 olarak belirlendi. Fabry hastalığının etiyolojisinde etkili olan mutasyonların yalancı alel olup olmadığı konusundaki çelişkileri ortadan kaldırmak için yeni araştırmaların yapılması, daha geniş hasta popülasyonunda prospektif tarama programlarının yapılması, genetik danışmanlık ve koruyucu hekimlik hizmetlerinin yaygınlaştırılması gerekmektedir.

Anahtar Kelimeler

• Fabry hastalığı
• Kronik böbrek hastalığı
• Hemodiyaliz

The Frequency of Fabry Disease in Hemodialysis Patients in The Western Mediterranean Region of Turkey

Öz

Aims: The aim of the present study was to identify patients with chronic kidney disease of unknown etiology or of other detected etiology among those who were undergoing hemodialysis in the Western Mediterranean region and to detect the prevalence of Fabry mutation in these patients. In addition, we aimed to screen the family members of the cases with mutations in our study. Methods: A total of 664 patients over the age of 18 who received hemodialysis treatment in 11 different hemodialysis centers in the Western Mediterranean region of Turkey were screened. Alpha-galactosidase A enzyme levels were first tested in male patients, and for patients with alpha-galactosidase A levels < 3.3 nmol/mL/h, GLA gene sequence analysis was performed. GLA gene sequence analysis was performed directly in female patients. Results: In total 664 patients [313 (47.1%) male and 351 (52.9%) female] have been scanned. Fabry mutation was positive in eight female patients and one male patient. Conclusion: According to the output of the research, the prevalence of Fabry disease among the patients who receive hemodialysis treatment determined 1.35%. In order to eliminate the conflicts upon whether the mutations which is effective on the etiology of Fabry disease are pseudo alleles it is required that new researches should be done, prospective scanning programs in a wider patient population and genetic consultancy and preventive medicine services should become more prevalent.

Anahtar Kelimeler

• Fabry disease
• Chronic kidney disease
• Hemodialysis

Kaynakça

1. Referans1. El-Abassi R, Singhal D, England JD. Fabry's disease. J Neurol Sci. 2014 Sep 15;344(1-2):5-19.
2. Referans2. Bishop DF, Kornreich R, Desnick RJ. Structural organization of the human alpha-galactosidase A gene: further evidence for the absence of a 3' untranslated region. Proc Natl Acad Sci U S A. 1988 Jun; 85(11):3903-7.
3. Referans3. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999 Jan 20;281(3):249-54.
4. Referans4. Masson C, Cisse I, Simon V, Insalaco P, Audran M. Fabry disease. Joint Bone Spine. 2004 Sep;71(5):381-3.
5. Referans5. Rozenfeld P, Feriozzi S. Contribution of inflammatory pathways to Fabry disease pathogenesis. Mol Genet Metab. 2017 Nov;122(3):19-27.
6. Referans6. Drawz P, Rahman M. Chronic kidney disease. Ann Intern Med. 2015 Jun 2;162(11):ITC1-16.
7. Referans7. Desnick RJ, Ioannou YA, Eng CM. a-Galactosidase A deficiency: Fabry disease. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, editors. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill; 1995. p. 2741-84.
8. Referans8. Kuhn H, Kohler E, Hort W, Frenzel H. Concealed myocardial storage disease (Fabry’s disease): pitfalls in the diagnosis of hypertrophic nonobstructive cardiomyopathy. Circulation 1982;66(Suppl. II), 117.

9. Referans9. Nakao S, Kodama C, Takenaka T, Tanaka A, Yasumoto Y, Yoshida A, Kanzaki T, Enriquez AL, Eng CM, Tanaka H, Tei C, Desnick RJ. Fabry disease: Detection of undiagnosed hemodialysis patients and identification of a “renal variant” phenotype. Kidney Int. 2003 Sep;64(3):801-7.
10. Referans10. Maier EM, Osterrieder S, Whybra C, Ries M, Gal A, Beck M, Roscher AA, Muntau AC. Disease manifestations and X inactivation in heterozygous females with Fabry disease. Acta Paediatr Suppl. 2006 Apr;95(451):30-8.
11. Referans11. 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(4):249-255.
12. Referans12. Suleymanlar G. Hemodialysis. In; Suleymanlar G, Ates K, Seyahi N editors. Registry Of The Nephrology, Dialysis And Transplantation In Turkey. Ankara: Miki Press; 2019; p 10.
13. Referans13. Gundogdu A, Kotan D, Alemdar M. The Frequency of Fabry Disease among Young Cryptogenic Stroke Patients in the City of Sakarya. J Stroke Cerebrovasc Dis. 2017 Jun;26(6):1334-1340.
14. Referans14. Barman HA, Özcan S, Atıcı A, Özgökçe C, Öztürk A, Kafalı AE, Çakar NE, Tavşanlı ME, Küçük M, Şahin I, Okuyan E. Ratio of Fabry disease in patients with idiopathic left ventricular hypertrophy: A single-center study in Turkey. Anatol J Cardiol. 2020 Jan;23(2):79-85.
15. Referans15. Boscaro F, Pieraccini G, Marca Gl, Bartolucci G, Luceri C, Luceri F, Moneti G. Rapid quantitation of globotriaosylceramide in human plasma and urine:a potential application for monitoring enzyme replacement therapy in Andreson-Fabry disease. Rapid Commun Mass Spectrom. 2002;16(16):1507-14.
16. Referans16. Winchester B, Young E. Biochemical and genetic diagnosis of Fabry disease. In. Mehta A, Beck M, Sunder-Plassmann G, eds. Fabry Disease: Perspectives from 5 Years of FOS. Oxford: Oxford Pharma Genesis 2006.
17. Referans17. Stark S, Fong B, Fletcher J, Fietz M. Screening For Fabry Disease Using Dried Blood Spots. In: Abstracts for the 38th Human Genetics Society of Australasia Annual Scientific Meeting Adelaide, South Australia: Twin Research and Human Genetics, Volume 17, Issue 4, August 2014, pp. 322 - 346
18. Referans18. Oqvist B, Brenner BM, Oliveira JP, Ortiz A, Schaefer R, Svarstad E, Wanner C, Zhang K, Warnock DG. Nephropathy in Fabry disease: the importance of early diagnosis and testing in high-risk populations. Nephrol Dial Transplant. 2009 Jun;24(6):1736-43.
19. Referans19. Lidove O, Joly D, Barbey F, Bekri S, Alexandra JF, Peigne V, Jaussaud R, Papo T. Clinical results of enzyme replacement therapy in Fabry disease: a comprehensive review of literature. Int J Clin Pract. 2007 Feb;61(2):293-302.
20. Referans20. Veen SJ, Hollak CEM, Kuilenburg ABP, Langeveld M. Developments in the Treatment of Fabry Disease. J Inherit Metab Dis. 2020 Sep;43(5):908-921.
21. Referans21. Bülbül SF, Dursun O, Dursun ZE. Physicians, Who are Working in Kırıkkale, Awareness of Fabry Disease and Inherited Metabolic Diseases. J LSD 2012; 4(1): 1-8.
22. Referans22. Okur I, Ezgu F, Biberoglu G, Tumer L, Erten Y, Isitman M, Eminoglu FT, Hasanoglu A. Screening for Fabry Disease in Patients Undergoing Dialysis for Chronic Renal Failure in Turkey: Identification of New Case With Novel Mutation. Gene. 2013 Sep 15;527(1):42-7.
23. Referans23. Sayilar EI, Ayar Y, Yavuz M. Prevalence of Fabry disease among Turkish dialysis patients: Data from hemodialysis centers in Bursa province. Clin Nephrol. 2016 Mar;85(3):165-72.
24. Referans24. Yalın SF, Eren N, Sinangil A, Yilmaz VT, Tatar E, Ucar AR, Sevinc M, Can Ö, Gurkan A, Arik N, Alisir Ecder S, Uyar M, Yasar M, Gulcicek S, Mese M, Dheir H, Cakir U, Köksal Cevher Ş, Turkmen K, Guven B, Guven Taymez D, Erkalma Senates B, Ecder T, Kocak H, Uslu A, Demir E, Basturk T, Ogutmen MB, Kinalp C, Dursun B, Bicik Bahcebasi Z, Sipahi S, Dede F, Oruc M, Caliskan Y, Genc A, Yelken B, Altıparmak MR, Turkmen A, Seyahi N. Fabry Disease Prevalence in Renal Replacement Therapy in Turkey. Nephron. 2019;142(1):26-33.
25. Referans25. Turkmen K, Guçlu A, Sahin G, Kocyigit I, Demirtas L, Erdur FM, Sengül E, Ozkan O, Emre H, Turgut F, Unal H, Karaman M, Acıkel C, Esen H, Balli E, Bıtırgen G, Tonbul HZ, Yılmaz MI, Ortiz A. The Prevalence of Fabry Disease in Patients with Chronic Kidney Disease in Turkey: The TURKFAB Study. Kidney Blood Press Res. 2016;41(6):1016-1024.
26. Referans26. Saito O, Kusano E, Akimoto T, Asano Y, Kitagawa T, Suzuki K, Ishige N, Akiba T, Saito A, Ishimura E, Hattori M, Hishida A, Guili C, Maruyama H, Kobayashi M, Ohashi T, Matsuda I, Eto Y. Prevalence of Fabry disease in dialysis patients: Japan Fabry disease screening study (J-FAST). Clin Exp Nephrol. 2016 Apr;20(2):284-93.
27. Referans27. Capuano I, Garofalo C, Buonanno P, Pinelli M, Risi TD, Feriozzi S, Riccio E, Pisani A. Identifying Fabry Patients in Dialysis Population: Prevalence of GLA Mutations by Renal Clinic Screening, 1995-2019. J Nephrol. 2020 Jun;33(3):569-581.
28. Referans28. Silva CAB, Barreto FC, Reis MAD, Junior JAM, Cruz CMS. Targeted Screening of Fabry Disease in Male Hemodialysis Patients in Brazil Highlights Importance of Family Screening. Nephron. 2016;134(4):221-230.
29. Referans29. Froissart R, Guffon N, Vanier MT, Desnick RJ, Maire I. Fabry disease: D313Y is an alphagalactosidase A sequence variant that causes pseudodeficient activity in plasma. Mol Genet Metab. 2003 Nov;80(3):307-14.
30. Referans30. Niemann M, Rolfs A, Giese A, Mascher H, Breunig F, Ertl G, Wanner C, Weidemann F. Lyso-Gb3 indicates that the alpha-galactosidase A mutation D313Y is not clinically relevant for Fabry disease. JIMD Rep. 2013;7:99-102.
31. Referans31. Hasholt L, Ballegaard M, Bundgaard H, Christiansen M, Law I, Lund AM, Norremolle A, Krogh Rasmussen A, Ravn K, Tumer Z, Wibrand F, Feldt-Rasmussen U. The D313Y Variant in the GLA Gene - No Evidence of a Pathogenic Role in Fabry Disease. Scand J Clin Lab Invest. 2017 Dec;77(8):617-621.
32. Referans32. Ortiz A, Germain DP, Desnick RJ, Politei J, Mauer M, Burlina A, Eng C, Hopkin RJ, Laney D, Linhart A, Waldek S, Wallace E, Weidemann F, Wilcox WR. Fabry disease revisited: Management and treatment recommendations for adult patients. Mol Genet Metab. 2018 Apr;123(4):416-427.
33. Referans33. Colon C, Ortolano S, Alvarez JV, Lopez-Suarez OE, Couce ML, Fernández-Lorenzo JR. Newborn screening for Fabry disease in the north-west of Spain. Eur J Pediatr. 2017 Aug;176(8):1075-1081.
34. Referans34. Moulin Md, Koehn AF, Golsari A, Dulz S, Atiskova Y, Patten M, Münch J, Avanesov M, Ullrich K, Muschol N. The mutation p.D313Y is associated with organ manifestation in Fabry disease. Clin Genet. 2017 Nov;92(5):528-533.
35. Referans35. Tol Lvd, Smid BE, Poorthuis BJ, Biegstraaten M, Deprez RH, Linthorst GE, Hollak CE. A systematic review on screening for Fabry disease: prevalence of individuals with genetic variants of unknown significance. J Med Genet. 2014 Jan;51(1):1-9.
36. Referans36. Yeniçerioğlu Y, Akdam H, Dursun B, Alp A, Eyiler FS, Akın D, Gün Y, Hüddam B, Batmazoğlu M, Gibyeli Genek D, Pirinççi S, Ersoy İR, Üzüm A, Soypaçacı Z, Tanrısev M, Çolak H, Demiral Sezer S, Bozkurt G, Akyıldız UO, Akyüz Ünsal Aİ, Ünübol M, Uslu M, Eryılmaz U, Günel C, Meteoğlu İ, Yavaşoğlu İ, Ünsal A, Akar H, Okyay P. Screening Fabry's Disease in Chronic Kidney Disease Patients Not on Dialysis: A Multicenter Study. Ren Fail. 2017 Nov;39(1):104-111.
37. Referans37. Linthorst GE, Vedder AC, Aerts JM, Hollak CE. Screening for Fabry disease using whole blood spots fails to identify one-third of female carriers. Clin Chim Acta. 2005 Mar;353(1-2):201-3.
38. Referans38. Lin CJ, Chien YH, Lai TS, Shih HM, Chen YC, Pan CF, Chen HH, Hwu WL, Wu CJ. 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(5):1636-1645.
39. Referans39. Uçar S.K, Sozmen E, Duman S, Başçi A, Çoker M. Alpha-galactosidase A Activity Levels in Turkish Male Hemodialysis Patients. Ther Apher Dial. 2012 Dec;16(6):560-5.
40. Referans40. Shabbeer J, Yasuda M, Luca E, Desnick RJ. Fabry disease: 45 novel mutations in the a-galactosidase A gene causing the classical phenotype. Mol Genet Metab. 2002 May;76(1):23-30.