The Frequency of Fabry Disease in Acute Stroke Patients with Renal Insufficiency in Sakarya Province

Year 2023, , 257 - 262, 30.12.2023

Saadet Sayan , Dilcan Kotan , Esen Çiçekli , Murat Alemdar

https://doi.org/10.18678/dtfd.1319530

Abstract

Aim: This study aimed to investigate the frequency, clinical and genetic characteristics, and therapeutic options associated with Fabry disease (FD) in individuals with acute stroke and concomitant renal insufficiency.
Material and Methods: An FD screening was performed on adult patients with renal dysfunction who were admitted to the neurology clinic due to acute stroke between 2015 and 2021. Screening was performed by a leukocyte α-galactosidase A (α-Gal A) enzyme activity assay using dried blood spot (DBS) samples from male patients. In cases where the enzyme activity was less than 2.5 nmol/ml/h, genetic analysis was performed. Female patients underwent direct genetic analysis.
Results: Renal dysfunction was detected in 39 ischemic stroke patients and 5 hemorrhagic stroke patients out of a total of 401 cases. The enzyme level was found low in only one of the male patients. The c.680G>A (p.R227Q) mutation was observed in this male patient and a female patient. In the later stages of the study, it was realized with the help of pedigree analysis that these two cases were first-degree relatives. The same mutation was also detected in 13 first-degree and 2 second-degree relatives. The frequency of FD in our study group, which included patients with cerebral and renal involvement regardless of consanguinity, was 4.54%.
Conclusion: Rapid detection of FD cases can be achieved by screening individuals presenting with multiple end-organ damages. To the best of our knowledge, this study highlights the underemphasized association between renal involvement and stroke in FD.

Keywords

fabry disease, renal insufficiency, cerebrovascular disease

Sakarya İli Akut İskemik İnme ve Kronik Renal Yetmezlikli Olgularda Fabry Hastalığı Sıklığı

Abstract

Amaç: Bu çalışmada, böbrek yetmezliği olan akut inme hastalarında Fabry Hastalığı (FH) sıklığı ile klinik ve genetik özelliklerinin ve tedavi seçeneklerinin araştırılması amaçlandı.
Gereç ve Yöntemler: 2015 ve 2021 yılları arasında nöroloji kiniğine akut inme nedeniyle yatırılan ve böbrek fonksiyon bozukluğu tespit edilen erişkin hastalarda FH taraması yapıldı. Tarama, erkek hastalardan alınan bir kuru kan lekesi (dried blood spot, DBS) örnekleri ile lökosit α-galactosidase A (α-Gal A) enzimatik aktivite değerlendirmesine ile yapıldı. Enzim aktivitesi 2,5 nmol/ml/saat'in altında tespit edilen vakalarda genetik inceleme yapıldı. Kadın hastalarda ise doğrudan genetik analiz uygulandı.
Bulgular: Toplam 401 olgudan 39 iskemik inme olgusunda ve 5 hemorajik inme olgusunda renal disfonksiyon saptandı. Erkek hastalardan sadece birinde enzim düzeyi düşük bulundu. Bu erkek hastada ve bir de kadın hastada c.680G>A (p.R227Q) mutasyonu tespit edildi. Çalışmanın ilerleyen aşamalarında pedigri analizi ile bu iki olgunun birinci derece akraba olduğu fark edildi. Aynı mutasyon 13 birinci derece ve 2 ikinci derece akrabada da tespit edildi. Akraba evliliğinden bağımsız olarak hem beyin hem de böbrek tutulumu olan hastaları içeren çalışma grubumuzda FD sıklığı %4,54 idi.
Sonuç: Çoklu uç organ hasarı olan bireylerin taranması ile FH olgularının erken tespitinde başarı sağlanabilir. Bildiğimiz kadarıyla bu çalışma, FH'da böbrek tutulumu ve inme arasında kapsamlı bir şekilde vurgulanmamış olan bu ilişkiyi vurgulamaktadır.

Keywords

fabry hastalığı, böbrek yetmezliği, serebrovasküler hastalık

References

• Barba-Romero MÁ, Rivera-Gallego A, Pintos-Morell G; Spanish FOS-Study Group. Fabry disease in Spain: description of Spanish patients and a comparison with other European countries using data from the Fabry Outcome Survey (FOS). Int J Clin Pract. 2011;65(8):903-10.
• Hsu TR, Niu DM. Fabry disease: Review and experience during newborn screening. Trends Cardiovasc Med. 2018;28(4):274-81.
• Waldek S, Patel MR, Banikazemi M, Lemay R, Lee P. Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry registry. Genet Med. 2009;11(11):790-6.
• van der Veen SJ, Hollak CEM, van Kuilenburg ABP, Langeveld M. Developments in the treatment of Fabry disease. J Inherit Metab Dis. 2020;43(5):908-21.
• Schiffmann R. Fabry disease. Pharmacol Ther. 2009;122(1):65-77.
• Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30.
• Smid BE, van der Tol L, Cecchi F, Elliott PM, Hughes DA, Linthorst GE, et al. Uncertain diagnosis of Fabry disease: consensus recommendation on diagnosis in adults with left ventricular hypertrophy and genetic variants of unknown significance. Int J Cardiol. 2014;177(2):400-8.
• Vujkovac B. Fabry disease: diagnostic methods in nephrology practice. Clin Nephrol. 2017 Supplement 1;88(13):44-7.
• Hughes DA, Nicholls K, Shankar SP, Sunder-Plassmann G, Koeller D, Nedd K, et al. Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study. J Med Genet. 2017;54(4):288-96.
• Ortiz A, Germain DP, Desnick RJ, Politei J, Mauer M, Burlina A, et al. Fabry disease revisited: Management and treatment recommendations for adult patients. Mol Genet Metab. 2018;123(4):416-27.
• Mehta A, Ricci R, Widmer U, Dehout F, Garcia de Lorenzo A, Kampmann C, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest. 2004;34(3):236-42.
• Stamova B, Tian Y, Jickling G, Bushnell C, Zhan X, Liu D, et al. The X-chromosome has a different pattern of gene expression in women compared with men with ischemic stroke. Stroke. 2012;43(2):326-34.
• Kolodny E, Fellgiebel A, Hilz MJ, Sims K, Caruso P, Phan TG, et al. Cerebrovascular involvement in Fabry disease: current status of knowledge. Stroke. 2015;46(1):302-13.
• Desnick RJ, Ioannou YA, Eng CM. α-Galactosidase A deficiency: Fabry disease. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, editors. The Online Metabolic and Molecular Bases of Inherited Disease. New York, McGraw-Hill, 2014.
• Shi Q, Chen J, Pongmoragot J, Lanthier S, Saposnik G. Prevalence of Fabry disease in stroke patients--a systematic review and meta-analysis. J Stroke Cerebrovasc Dis. 2014;23(5):985-92.
• Marquardt L, Baker R, Segal H, Burgess AI, Poole D, Hughes DA, et al. Fabry disease in unselected patients with TIA or stroke: population-based study. Eur J Neurol. 2012;19(11):1427-32.
• Tomek A, Petra R, Paulasová Schwabová J, Olšerová A, Škorňa M, Nevšímalová M, et al. National Stroke Research Network, part of Czech Clinical Research Infrastructure Network (CZECRIN) and Czech Neurological Society, Cerebrovascular Section. Nationwide screening for Fabry disease in unselected stroke patients. PLoS One. 2021;16(12):e0260601.
• Sims K, Politei J, Banikazemi M, Lee P. Stroke in Fabry disease frequently occurs before diagnosis and in the absence of other clinical events: natural history data from the Fabry Registry. Stroke. 2009;40(3):788-94.
• 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;527(1):42-7.
• Yeniçerioğlu Y, Akdam H, Dursun B, Alp A, Sağlam Eyiler F, Akın 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.
• Kleindorfer DO, Towfighi A, Chaturvedi S, Cockroft KM, Gutierrez J, Lombardi-Hill D, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2021;52(7):e364-467.
• Schiffmann R, Kopp JB, Austin HA 3rd, Sabnis S, Moore DF, Weibel T, et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA. 2001;285(21):2743-9.
• Steinicke R, Gaertner B, Grittner U, Schmidt W, Dichgans M, Heuschmann PU, et al. Kidney function and white matter disease in young stroke patients: analysis of the stroke in young Fabry patients study population. Stroke. 2012;43(9):2382-8.
• Sheng S, Wu L, Nalleballe K, Sharma R, Brown A, Ranabothu S, et al. Fabry's disease and stroke: Effectiveness of enzyme replacement therapy (ERT) in stroke prevention, a review with meta-analysis. J Clin Neurosci. 2019;65:83-6.
• Putaala J, Haapaniemi E, Gordin D, Liebkind R, Groop PH, Kaste M, et al. Factors associated with impaired kidney function and its impact on long-term outcome in young ischemic stroke. Stroke. 2011;42(9):2459-64.
• Rolfs A, Böttcher T, Zschiesche M, Morris P, Winchester B, Bauer P, et al. Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study. Lancet. 2005;366(9499):1794-6.