Herediter Tirozinemi Tip 1’in Klinik Özellikleri, Genetik Spektrumu ve Sonuçları: Güneydoğu Anadolu Bölgesinden Çok Merkezli Çalışma

Year 2025, Volume: 26 Issue: 1, 33 - 41, 20.03.2025

Emine Göksoy , Ergül Bozacı , Berrak Bilginer Gürbüz

https://doi.org/10.69601/meandrosmdj.1614784

Abstract

Giriş: Herediter Tirozinemi Tip 1 (HT1), fumarilasetoasetat hidrolaz eksikliğine bağlı gelişen metabolik bir hastalık olup karaciğer ve böbrek hasarı ile karakterizedir. Bu çalışma, yüksek akraba evliliği oranlarına sahip Güneydoğu Anadolu bölgesindeki HT1 hastalarının klinik prezentasyonu, tanısı ve sonuçları hakkında bilgi birikimimizi genişletmeyi amaçlamaktadır.
Gereç ve Yöntemler: Bu retrospektif, çok merkezli çalışmaya, Ocak 2018-Mart 2021 tarihleri arasında Güneydoğu Anadolu’daki üç metabolizma merkezinde takip edilen 20 HT1 hastası dahil edildi. Hastaların demografik, klinik, laboratuvar ve genetik verileri retrospektif olarak değerlendirildi. Semptomların başlangıcına göre hastalar akut, subakut ve kronik formlara ayrıldı. İstatistiksel analizler tanımlayıcı ve çıkarımsal yöntemlerle yapıldı.
Bulgular: Çalışmaya dahil edilen 20 hastanın tamamının (9K/11E) ebeveynleri arasında akrabalık vardı. Tanı yaşı ortalama 10,53±12,54 ay, tanıda gecikme süresi ortalama 2,96±4,42 ay olarak hesaplandı. En sık görülen form akut HT1 (%55) olup, bunu kronik (%25) ve subakut (%20) form izledi. Hepatomegali (%40) en yaygın bulguydu. Kronik HT1 hastalarının %80’inde tübülopati saptandı. Tanı anında vakaların %60’ında α-fetoprotein düzeyleri artmıştı. Üç hastada hepatoselüler karsinom gelişti ve iki hasta bu nedenle hayatını kaybetti. Genetik analizlerde en sık gözlenen mutasyon c.554-1G>T (%27) idi.
Sonuç: Bu çalışma, ülkemizde HT1’e yönelik yenidoğan tarama programı bulunmamasına bağlı geç tanı nedeniyle hastalığın yönetimindeki zorlukları ve klinik yükünü vurgulamaktadır. Çalışmalar erken nitisinon tedavisinin sonuçları iyileştirdiğini gösterse de, hepatosellüler karsinom gibi komplikasyonlar için uzun vadeli takip gereklidir. HT1 ile ilişkili morbidite ve mortaliteyi azaltmak için yenidoğan tarama programlarının yaygınlaştırılması gerekmektedir.

Keywords

Herediter tirozinemi tip 1, hepatoselüler karsinom, nitisinon

Clinical Features, Genetic Spectrum, and Outcome of Hereditary Tyrosinemia Type 1: A Multicenter Study from Southeastern Türkiye

Abstract

Introduction: Hereditary Tyrosinemia Type 1 (HT1) is a metabolic disorder due to fumarylacetoacetate hydrolase deficiency, which can lead to liver and kidney damage. This study aims to expand our knowledge of the clinical presentation, diagnosis, and outcome of HT1 patients from southeastern Türkiye, a region characterized by high consanguinity rates.
Materials and Methods: This retrospective multicenter study included 20 HT1 patients from three metabolic centers in southeastern Türkiye between January 2018 and March 2021. Demographic, clinical, laboratory, and genetic data were retrieved. According to the beginning of the symptoms, patients were divided into acute, subacute, and chronic forms. The statistical analyses consisted of descriptive and inferential methods.
Results: The parents of all 20 cases (9F/11M) were consanguineous. The mean diagnostic age was 10.5312.54 months, with an average diagnostic delay of 2.964.42 months. The most common forms were acute HT1 (55%), followed by chronic (25%) and subacute (20%) forms. Common findings were hepatomegaly (40%) and hypotonia/intellectual disability (40%). Tubulopathy was frequent in chronic HT1 (80%). Increased α-fetoprotein levels were found in 60% of the cases at the diagnosis. Hepatocellular carcinoma developed in three patients. Two died of the disease. Genetic studies showed that the most common mutation was IVS6-1G>T (27%).
Conclusion: The study highlights the clinical burden and the challenge in managing HT1 in Türkiye, attributed to late diagnosis resulting from absence of newborn screening. Early initiation of NTBC significantly improves the outcome, but long-term follow-up for complications like hepatocellular carcinoma is imperative. Newborn screening programs need to be extended reduce morbidity and mortality associated with HT1.

Keywords

hereditary tyrosinemia type 1, hepatocellular carcinoma, FAH gene, Nitisinon

References

• 1. Chinsky JM, Singh R, Ficicioglu C, van Karnebeek CDM, Grompe M, Mitchell G, et al. Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations. Genet Med. 2017;19(12):1380–95.
• 2. Stinton C, Geppert J, Freeman K, Clarke A, Johnson S, Fraser H, et al. Newborn screening for Tyrosinemia type 1 using succinylacetone – a systematic review of test accuracy. Orphanet J Rare Dis. 2017;12(1):48.
• 3. Holme E, Lindstedt S. Tyrosinaemia type I and NTBC (2‐(2‐nitro‐4‐trifluoromethylbenzoyl)‐1,3‐cyclohexanedione). J Inherit Metab Dis. 1998;21(5):507–17.
• 4. Morrow G, Tanguay RM. Biochemical and clinical aspects of hereditary tyrosinemia type 1. Adv Exp Med Biol. 2017;959:9–21.
• 5. Aktuglu-Zeybek AC, Kiykim E, Cansever MS. Hereditary tyrosinemia type 1 in Turkey. Adv Exp Med Biol. 2017;959:157–72.
• 6. van Ginkel WG, Rodenburg IL, Harding CO, Hollak CEM, Heiner-Fokkema MR, van Spronsen FJ. Long-Term Outcomes and Practical Considerations in the Pharmacological Management of Tyrosinemia Type 1. Pediatric Drugs. 2019;21(6):413–26.
• 7. Bilginer Gürbüz B, Aykan H, Çiki K, Karagöz T, Sivri S, Dursun A, et al. Cardiomyopathy in patients with type 1 tyrosinemia, and the effect of nitisinone treatment on cardiomyopathy. Cukurova Med J. 2021 Dec 30;46(4):1419–25.
• 8. van Ginkel WG, Pennings JP, van Spronsen FJ. Liver cancer in tyrosinemia type 1. Adv Exp Med Biol. 2017;959:101–9.
• 9. van Spronsen FJ, Thomasse Y, Smit GP, Leonard J V, Clayton PT, Fidler V, et al. Hereditary tyrosinemia type I: a new clinical classification with difference in prognosis on dietary treatment. Hepatology. 1994;20(5):1187–91.
• 10. Wu JT, Book L, Sudar K. Serum Alpha Fetoprotein (AFP) Levels in Normal Infants. Pediatr Res. 1981;15(1):50–2.
• 11. Hacettepe Universitesi Nufus Etutleri Enstitusu. Türkiye Nufus ve Saglık Arastirmasi. Hacettepe Universitesi Nufus Etutleri Enstitusu, T.C. Cumhurbaskanligi ve TUBITAK. Turkiye: Ankara; 2018: 47-48.
• 12. Ozalp I, Coskun T, Tokol S, Demircin G, Monch E. Inherited Metabolic Disorders in Turkey. J. Inher. Metab. Dis. 1990;13
• 13. Dweikat I, Qawasmi N, Najeeb A, Radwan M. Phenotype, genotype, and outcome of 25 Palestinian patients with hereditary tyrosinemia type 1. Metabol Open. 2021;9:100-83.
• 14. Khan SA, Fakih M, Taufiq N, Ahmerin A, Bangash A, Iqbal Malik M. Clinical Spectrum of Hereditary Tyrosinemia Type 1 in a Cohort of Pakistani Children. Clin Med Insights Pediatr. 2024;18.
• 15. Couce ML, Dalmau J, Del Toro M, Pintos-Morell G, Aldámiz-Echevarría L. Tyrosinemia type 1 in Spain: Mutational analysis, treatment and long-term outcome. Pediatr Int. 2011;53(6):985–9.
• 16. Yazıcı H, Er E, Canda E, Habif S, Kalkan Uçar S, Çoker M. Clinical Features of 29 Patients with Hereditary Tyrosinemia I in Western Turkey. J Pediatr Res. 2018;21:1–6.
• 17. Hajji H, Imbard A, Spraul A, Taibi L, Barbier V, Habes D, et al. Initial presentation, management and follow-up data of 33 treated patients with hereditary tyrosinemia type 1 in the absence of newborn screening. Mol Genet Metab Rep. 2022;8;33:100933
• 18. Bendadi F, De Koning TJ, Visser G, Prinsen HCMT, De Sain MGM, Verhoeven-Duif N, et al. Impaired cognitive functioning in patients with tyrosinemia type 1 receiving nitisinone. J of Pediatr. 2014;164(2):398–401.
• 19. Hillgartner MA, Coker SB, Koenig AE, Moore ME, Barnby E, MacGregor GG. Tyrosinemia type I and not treatment with NTBC causes slower learning and altered behavior in mice. J Inherit Metab Dis. 2016;6;39(5):673–82.
• 20. Önenli Mungan N, Yıldızdaş D, Kör D, Horoz ÖÖ, İncecik F, Öktem M, et al. Tyrosinemia type 1 and irreversible neurologic crisis after one month discontinuation of nitisone. Metab Brain Dis. 2016;31(5):1181–3.
• 21. Dursun A, Özgül RK, Sivri S, Tokatlı A, Güzel A, Mesci L, et al. Mutation spectrum of fumarylacetoacetase gene and clinical aspects of tyrosinemia type I disease. J Inherit Metab Dis. 2011;1:17–21.
• 22. Baumann U, Preece MA, Green A, Kelly DA, Mckiernan PJ. Hyperinsulinism in tyrosinaemia type I. J Inherit Metab Dis. 2005;28:131-135.
• 23. Nasir S, Raza M, Siddiqui SI, Saleem A, Abbas A. Hereditary Tyrosinemia Compounded With Hyperinsulinemic Hypoglycemia: Challenging Diagnosis of a Rare Case. Cureus. 2020;12:e11541.
• 24. Sethuram S, Sperling MA, Gujral J, Romero CJ. Neonatal hyperinsulinism in transient and classical forms of tyrosinemia. Orphanet J Rare Dis. 2021;1:16(1).
• 25. Rokaitė R, Čibirkaitė A, Zeleckytė V, Lazdinytė G, Dženkaitis M. A Lithuanian Case of Tyrosinemia Type 1 with a Literature Review: A Rare Cause of Acute Liver Failure in Childhood. Medicina (Lithuania). 2024;60(1):1–9.
• 26. Gokay S, Ustkoyuncu PS, Kardas F, Kendirci M. The outcome of seven patients with hereditary tyrosinemia type 1. J Pediatr Endocrinol Metab. 2016;29(10):1151–7.
• 27. Ates I, Stuart C, Rathbone T, Barzi M, He G, Major AM, et al. Ex vivo gene editing and cell therapy for hereditary tyrosinemia type 1. Hepatol Commun. 2024;8(5):e0424