Journal of The Korean Society of Inherited Metabolic disease (대한유전성대사질환학회지)

The Korea Society of Inherited Metabolic Disease (대한유전성대사질환학회)
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Case Report on NTBC Treatment of Type 1 Tyrosinemia Diagnosed through Newborn Screening

신생아 선별검사를 통해 진단된 1형 타이로신혈증의 NTBC 치료 사례 보고

  • Ji Eun Jeong (Department of Pediatrics, Seoul National University College of Medicine) ;
  • Hwa Young Kim (Department of Pediatrics, Seoul National University College of Medicine) ;
  • Jung Min Ko (Department of Pediatrics, Seoul National University College of Medicine)
  • 정지은 (서울대학교 의과대학 소아청소년과학교실) ;
  • 김화영 (서울대학교 의과대학 소아청소년과학교실) ;
  • 고정민 (서울대학교 의과대학 소아청소년과학교실)
  • Published : 2023.12.31
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Abstract

Hereditary tyrosinemia type 1 (HT-1) is a metabolic disorder caused by biallelic pathogenic variants in the fumarylacetoacetate hydrolase (FAH) gene, which impairs the function of the FAH enzyme, resulting in the accumulation of tyrosine's toxic metabolites in hepatocytes and renal tubular cells. As a consequence, individuals with HT-1 exhibit symptomatic manifestations. Rapid diagnosis and treatment of HT-1 can prevent short-term death and long-term complications. A 15-day-old boy presented to the outpatient department with elevated levels of tyrosine on his newborn screening tests conducted at the age of 3 and 10 days, respectively. Further blood tests revealed increased levels of alpha-fetoprotein and amino acids including tyrosine and threonine. Urine organic acid tests indicated a significant elevation in tyrosine metabolites, as well as the presence of succinylacetone (SA), which led to the diagnosis of HT-1. Two pathogenic and likely pathogenic variants of FAH compatible with HT-1 were also detected. He began a tyrosine-restricted diet at one month old and received nitisinone (NTBC) at two months old. With continued treatment, the patient's initially elevated AFP level, detection of SA in the urine, and mild hepatomegaly showed improvement. During four years and seven months of treatment, there were no exceptional complications apart from an increase in tyrosine levels and a delay in speech. We report a case of tyrosinemia type 1 detected through newborn screening, treated with dietary restriction and NTBC, with a good prognosis.

HT-1은 FAH 유전자의 돌연변이에 의해 타이로신 대사의 중간산물이 축적되어 발생하는 유전성 대사 질환이다. 치료하지 않으면 치명적인 결과를 초래할 수 있으며, 간 기능 및 신세뇨관 기능 장애와 더불어 Fanconi 증후군, 포르피린증과 유사한 증상, 지능지수 감소, 인지기능 저하 등을 초래할 수 있다. 국내에서는 탠덤매스 스크리닝을 이용한 신생아 대사이상 선별검사를 통한 조기 진단과 함께 NTBC 약물 치료의 도입으로 치료 성적이 향상되었다. 본 증례는 생후 1개월에 급성 HT-1으로 진단 후 4년 7개월째 NTBC 치료 중인 증례로, 환아는 현재까지 단백 제한식이와 NTBC 복용을 유지하면서 언어지연 외에 특별한 합병증 없이 추적 관찰 중이다. NTBC의 복용이 간 및 신장 기능의 보존과 신경학적 예후에 미치는 영향에 대해서는 장기적인 추적 연구가 필요하다.

Keywords

References

  1. Morrow G, Tanguay RM. Biochemical and Clinical Aspects of Hereditary Tyrosinemia Type 1. Adv Exp Med Biol 2017;959:9-21.  https://doi.org/10.1007/978-3-319-55780-9_2
  2. St-Louis M, Tanguay RM. Mutations in the fumarylacetoacetate hydrolase gene causing hereditary tyrosinemia type I: overview. Hum Mutat 1997;9:291-9.  https://doi.org/10.1002/(SICI)1098-1004(1997)9:4<291::AID-HUMU1>3.0.CO;2-9
  3. Russo PA, Mitchell GA, Tanguay RM. Tyrosinemia: a review. Pediatr Dev Pathol 2001;4:212-21.  https://doi.org/10.1007/s100240010146
  4. 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. 
  5. 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;12:48. 
  6. Masurel-Paulet A, Poggi-Bach J, Rolland MO, Bernard O, Guffon N, Dobbelaere D, et al. NTBC treatment in tyrosinaemia type I: long-term outcome in French patients. J Inherit Metab Dis 2008;31:81-7.  https://doi.org/10.1007/s10545-008-0793-1
  7. Kang HY, Kim SZ, Song WJ, Chang MY. Hereditary Tyrosinemia Type I. Journal of The Korean Society of Inherited Metabolic disease 2004;4:13-7. 
  8. Park HD, Lee DH, Choi TY, Lee YK, Kim JW, Ki CS, et al. Clinical, biochemical, and genetic analysis of a Korean neonate with hereditary tyrosinemia type 1. Clin Chem Lab Med 2009;47:930-3. 
  9. Sohn YB, Lee HS, Lee JH, Hwang JS. A Case with Tyrosinemia Type I Detected by Neonatal Screening Test. Journal of The Korean Society of Inherited Metabolic Disease 2012;12:99-103. 
  10. Yang S, Choi HW, Kang YK, Lee JS, Namgoong MK. Chronic Hereditary Tyrosinemia Type I with Novel Mutation in FAH Gene. Journal of The Korean Society of Inherited Metabolic Disease 2020;20:55-62. 
  11. Choi HJ, Bang HI, Ki CS, Lee SY, Kim JW, Song J, et al. Two novel FAH gene mutations in a patient with hereditary tyrosinemia type I. Annals of Clinical & Laboratory Science 2014;44:317-23. 
  12. Imtiaz F, Rashed MS, Al-Mubarak B, Allam R, El-Karaksy H, Al-Hassnan Z, et al. Identification of mutations causing hereditary tyrosinemia type I in patients of Middle Eastern origin. Molecular Genetics and Metabolism 2011;104:688-90.  https://doi.org/10.1016/j.ymgme.2011.06.019
  13. Grompe M. The pathophysiology and treatment of hereditary tyrosinemia type 1. Semin Liver Dis 2001;21:563-71  https://doi.org/10.1055/s-2001-19035
  14. King LS, Trahms C, Scott CR. Tyrosinemia Type I. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. 2006 [Updated 2017]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1515/. 
  15. National Center for Biotechnology Information. FAH [gene] [Internet]. the United States: National Library of Medicine; [cited 2023 November 30]. Available from: https://www.ncbi.nlm.nih.gov/clinvar/?term=FAH%5Bgene%5D&redir=gene. 
  16. Angileri F, Bergeron A, Morrow G, Lettre F, Gray G, Hutchin T, et al. Geographical and ethnic distribution of mutations of the fumarylacetoacetate hydrolase gene in hereditary tyrosinemia type 1. JIMD Reports 2015;19:43-58. 
  17. van Ginkel WG, Rodenburg IL, Harding CO, Hollak CE, Heiner-Fokkema MR, van Spronsen FJ. Long-term outcomes and practical considerations in the pharmacological management of tyrosinemia type 1. Pediatric Drugs 2019;21:413-26. https://doi.org/10.1007/s40272-019-00364-4