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

The Korea Society of Inherited Metabolic Disease (대한유전성대사질환학회)
권호 표지

Chronic Hereditary Tyrosinemia Type I with Novel Mutation in FAH Gene

FAH gene novel mutation을 가진 만성형 Hereditary tyrosinemia 1형

  • Yang, Sungmin (Department of Pediatrics, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine) ;
  • Choi, Hyo Won (Department of Pediatrics, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine) ;
  • Kang, Yun Koo (Department of Pediatrics, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine) ;
  • Lee, Jin-Sung (Division of Clinical Genetics, Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine) ;
  • Namgoong, Mee Kyung (Department of Pediatrics, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine)
  • 양성민 (연세대학교 원주의과대학 소아청소년과) ;
  • 최효원 (연세대학교 원주의과대학 소아청소년과) ;
  • 강윤구 (연세대학교 원주의과대학 소아청소년과) ;
  • 이진성 (연세대학교 의과대학 소아청소년과) ;
  • 남궁미경 (연세대학교 원주의과대학 소아청소년과)
  • Published : 2020.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

A 22-month-old girl who had taken iron supplements due to iron deficiency anemia, presented bloody mucoid stool for one month. She had a bruise at the right periorbital area due to minor trauma and hepatosplenomegaly. Laboratory studies showed anemia, thrombocytopenia, elevated alkaline phosphatase (ALP), hypophosphatemia, decreased haptoglobin, hypocomplementemia, negative direct/indirect Coomb's test, normal vitamin D3 level and high PTHi. Wrist x-ray showed no signs of rickets. The abdominal ultrasound showed only accessory spleen. Tandem mass spectrometry was normal. During follow up, bloody stool regressed after seven days of withdrawal of iron supplement and cow milk, and the total CO2 level had been within 15-20 mEq/L with normal anion gap. NGS (next generation sequencing) panel test for evaluation of renal tubular acidosis showed negative results. After low dose steroid and vitamin D supplements under the impression of hypocomplementemic vasculitis, thrombocytopenia, C3/C4, decreased haptoglobin, and elevated ALP level became normal. At 57 months of age, laboratory findings showed elevated liver enzyme, ALP and gamma-glutamyl transferase again. And liver cirrhosis with splenomegaly and diffuse renal disease were reported with abdomen CT scan. Liver biopsy reported macro- and micronodular cirrhosis. Urine organic acid profile showed elevated succinylacetone level. Whole exome sequencing revealed novel compound heterozygous mutations (NM_00137.2:c.107T>C, NM_00137, 2:c.614T>C) in FAH gene and confirmed by Sanger sequencing. Consequently, the patient was diagnosed as chronic hereditary tyrosinemia type I. She started low phenylalanine/tyrosine diet and nitisinone treatment. Our case had presented symptoms very slowly, which is the first case of chronic tyrosinemia type I in South Korea.

HT-1은 FAH의 돌연변이에 의한 FAH의 결함으로 타이로신 대사의 중간산물인 FAA, SA가 간세포, 신세뇨관 세포에 축적되어 증상을 일으키는 대사이상 질환의 일종이다. 생후 6개월 내에 증상이 발현되는 급성형의 경우 간기능 저하에 따른 간부전, 응고장애, Fanconi 증후군, FAA 축적에 의한 델타-아미노레부릭산 탈수효소의 기능 저하에 의한 포르피린증 유사 증상이 발생한다. 증상이 생후 12개월 이후 발현되는 만성형의 경우 간경화, 간세포암종, 저인산혈증 구루병, 인지기능 저하와 같은 증상이 발생할 수 있다. 본 증례는 생후 20개월 경 간비장비대, 내반슬, 대상산증으로 대사이상질환 감별을 위하여 시행한 탠덤매스 분석에서 특이 소견이 보고되지 않았으나, 57개월에 시행한 복부 초음파 검사에서 간경화, 소변 유기산 분석에서 SA 상승, NGS에서 FAH 돌연변이 c.107T>C (p.Ile 36Thr), c.614T>C (pPhe205Ser)가 확인되어 HT-1이 진단된 증례로, 환아는 현재까지 NTBC 및 단백제한식이를 유지하며 특이 합병증 없이 외래 추적관찰 중이다. HT-1은 혈장 타이로신 농도가 증가하지 않는 경우도 있으며, 만성형의 경우 임상양상이 생후 12개월 이후에 나타나므로 탠덤매스 검사에서 음성 소견이 보고되어도 임상적으로 의심되는 경우 소변 유기산 분석과 같은 추가적 검사가 필요하다. 또한 기존의 탠덤매스 분석을 통하여는 HT-1이 진단되지 않는 경우가 있을 수 있어, 신생아 선별검사에서 혈장 타이로신 농도뿐 아니라 SA 농도도 추가로 확인하는 것의 비용 편익에 대한 추가적 연구가 필요하다.

Keywords

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.
  2. Pohorecka M, Biernacka M, Jakubowska-Winecka A, Biernacki M, Kusmierska K, Kowalik A, et al. Behavioral and intellectual functioning in patients with tyrosinemia type I. Pediatr Endocrinol Diabetes Metab 2012;18:96-100.
  3. van Spronsen FJ, Thomasse Y, Smit GP, Leonard JV, Clayton PT, Fidler V, et al. Hereditary tyrosinemia type I: a new clinical classification with difference in prognosis on dietary treatment. Hepatology 1994;20:1187-91. https://doi.org/10.1002/hep.1840200513
  4. Hahn SH, Pai KS, Lee KB, Park KH, Kim OH, Hong CH, et al. Acute Tyrosinemia Type 1 in a 5 Month Old Korean Boy. J Korean Pediatr Soc 1996;39:866-72.
  5. Kim KT, Kim YM, Park SE, Nam SO, Park JH. Two Cases of Acute Form of Tyrosinemia Type I. J Korean Pediatr Soc 2002;45:131-6.
  6. Cho JH, Shim KJ, Kim SK, Shin SH, Lee KH, Yun HS. A Case of Tyrosinemia Type 1 with Cytomegalovirus Infection. Clin Exp Pediatr 2004;47:111-4.
  7. 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.
  8. 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. Ann Clin Lab Sci 2014;44:317-23.
  9. Poudrier J, Lettre F, Scriver CR, Larochelle J, Tanguay RM. Different Clinical Forms of Hereditary Tyrosinemia (Type I) in Patients with Identical Genotypes. Molecular Genetics and Metabolism 1998;64:119-25. https://doi.org/10.1006/mgme.1998.2695
  10. Weinberg AG, Mize CE, Worthen HG. The occurrence of hepatoma in the chronic form of hereditary tyrosinemia. The Journal of Pediatrics 1976;88:434-8. https://doi.org/10.1016/S0022-3476(76)80259-4
  11. Ozcan HN, Karcaaltincaba M, Pektas E, Sivri HS, Oguz B, Dursun A, et al. Imaging liver nodules in tyrosinemia type-1: A retrospective review of 16 cases in a tertiary pediatric hospital. European Journal of Radiology 2019;116:41-6. https://doi.org/10.1016/j.ejrad.2019.04.016
  12. Mitchell G, Larochelle J, Lambert M, Michaud J, Grenier A, Ogier H, et al. Neurologic crises in hereditary tyrosinemia. N Engl J Med 1990;322:432-7. https://doi.org/10.1056/NEJM199002153220704
  13. 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
  14. Couce ML, Sanchez-Pintos P, Aldamiz-Echevarria L, Vitoria I, Navas V, Martin-Hernandez E, et al. Evolution of tyrosinemia type 1 disease in patients treated with nitisinone in Spain. Medicine (Baltimore) 2019;98:e17303. https://doi.org/10.1097/md.0000000000017303
  15. 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. Paediatr Drugs 2019;21:413-26. https://doi.org/10.1007/s40272-019-00364-4
  16. van Vliet D, van Dam E, van Rijn M, Derks TG, Venema-Liefaard G, Hitzert MM, et al. Infants with Tyrosinemia Type 1: Should phenylalanine be supplemented? JIMD Rep 2015;18:117-24. https://doi.org/10.1007/8904_2014_358
  17. Hickey RD, Nicolas CT, Allen K, Mao S, Elgilani F, Glorioso J, et al. Autologous Gene and Cell Therapy Provides Safe and Long-Term Curative Therapy in A Large Pig Model of Hereditary Tyrosinemia Type 1. Cell Transplant 2019;28:79-88. https://doi.org/10.1177/0963689718814188
  18. Kaiser RA, Nicolas CT, Allen KL, Chilton JA, Du Z, Hickey RD, et al. Hepatotoxicity and Toxicology of In Vivo Lentiviral Vector Administration in Healthy and Liver-Injury Mouse Models. Hum Gene Ther Clin Dev 2019;30:57-66.
  19. Thompson WS, Mondal G, Vanlith CJ, Kaiser RA, Lillegard JB. The future of gene-targeted therapy for hereditary tyrosinemia type 1 as a lead indication among the inborn errors of metabolism. Expert Opinion on Orphan Drugs 2020;8:245-56. https://doi.org/10.1080/21678707.2020.1791082
  20. Yazici H, Er E, Canda E, Habif S, Ucar S, Coker M. Clinical Features of 29 Patients with Hereditary Tyrosinemia I in Western Turkey. The Journal of Pediatric Research 2018;5.
  21. Mitchell O, Feldman DM, Diakow M, Sigal SH. The pathophysiology of thrombocytopenia in chronic liver disease. Hepatic medicine : evidence and research 2016;8:39-50.
  22. Baumann M, Witzke O, Canbay A, Patschan S, Treichel U, Gerken G, et al. Serum C3 complement concentrations correlate with liver function in patients with liver cirrhosis. Hepatogastroenterology 2004;51:1451-3.
  23. Ministry of Health and Welfare. Maternal and child health service 2020. 2020. p. 192.
  24. Jun SH, Do Seo J, Lee K, Song J. Measurement of Succinylacetone Using HPLC-Tandem Mass Spectrometry and Establishment of a Cut-off Value. Journal of Laboratory Medicine and Quality Assurance 2018;40:149-54. https://doi.org/10.15263/jlmqa.2018.40.3.149
  25. Metz TF, Mechtler TP, Merk M, Gottschalk A, Lukacin R, Herkner KR, et al. Evaluation of a novel, commercially available mass spectrometry kit for newborn screening including succinylacetone without hydrazine. Clinica Chimica Acta 2012;413:1259-64. https://doi.org/10.1016/j.cca.2012.04.007
  26. la Marca G, Malvagia S, Pasquini E, Cavicchi C, Morrone A, Ciani F, et al. Newborn Screening for Tyrosinemia Type I: Further Evidence that Succinylacetone Determination on Blood Spot Is Essential. JIMD Rep 2011;1:107-9. https://doi.org/10.1007/8904_2011_24