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

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

요소회로대사 질환 환자들의 장기적인 임상 경과에 대한 단일 기관 경험

Long-term Clinical Consequences in Patients with Urea Cycle Disorders in Korea: A Single-center Experience

  • 이준 (부산대학교 어린이병원 소아청소년과) ;
  • 김민지 (부산대학교 어린이병원 소아청소년과) ;
  • 유석동 (부산대학교 어린이병원 소아청소년과) ;
  • 윤주영 (부산대학교 어린이병원 소아청소년과) ;
  • 김유미 (세종충남대학교병원 소아청소년과) ;
  • 전종근 (부산대학교 어린이병원 소아청소년과)
  • Lee, Jun (Division of Medical Genetics and Metabolism, Department of Pediatrics, Pusan National University Children's Hospital) ;
  • Kim, Min-ji (Division of Medical Genetics and Metabolism, Department of Pediatrics, Pusan National University Children's Hospital) ;
  • Yoo, Sukdong (Division of Medical Genetics and Metabolism, Department of Pediatrics, Pusan National University Children's Hospital) ;
  • Yoon, Ju Young (Division of Medical Genetics and Metabolism, Department of Pediatrics, Pusan National University Children's Hospital) ;
  • Kim, Yoo-Mi (Department of Pediatrics, Chungnam National University Sejong Hospital) ;
  • Cheon, Chong Kun (Division of Medical Genetics and Metabolism, Department of Pediatrics, Pusan National University Children's Hospital)
  • 발행 : 2021.12.31
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초록

목적: 요소회로대사 질환은 선천성 대사이상질환으로, 요소 회로 각 단계의 특정 효소의 결핍에 따라 다양한 질환과 임상적 증상이 나타난다. 본 연구의 목적은 요소회로대사 질환의 다양한 종류에 따른 장기적 임상 경과를 조사하는 것이다. 방법: 부산대학교 어린이병원에 등록된 22명의 요소회로대사 질환 환자들의 임상적 양상과 생화학적, 유전학적 검사 결과들을 포함한 의무기록을 후향적으로 조사하였다. 결과: 본 연구에서 진단된 요소회로대사 질환은, OTCD 10명(45.5%), ASSD 6명(27.3%), CPS1D 3명, HHHS 2명 ARG1D 1명으로 확인되었다. 진단 시 평균연령은 32.7±66.2개월(범위 0.1-228.0개월) 이었다. 요소회로대사 질환 환자 8명(36.4%)에서 성장 장애가 동반되었다. 또한 요소회로대사 질환 환자11명(50%)에서는 신경학적 후유증이 관찰되었다. 분자유전학적 분석 결과 새로운 돌연변이 14개를 포함해 37개의 서로 다른 돌연변이 유형(과오돌연변이 14개, 넌센스 6개, 결실변이 6개, 스플라이싱변이 6개, 결실삽입변이 3개, 삽입변이 1개, 중복변이 1개)이 확인됐다. 진행성 성장 장애와 나쁜 신경학적 결과는 혈장 이소루이신과 루이신 농도와 각각 관련이 있었다. 결론: 단백의 제한과 같은 조치나 과다한 질소를 제거하는 약제의 복용에도 불구하고, 요소회로대사 질환의 예후는 아직까지 만족스럽지 못하다. 가지사슬아미노산의 보충이 요소회로대사 질환 환자들의 성장부전과, 대사성 위기 또는 신경학적 예후에 효과를 보일지에 관해서는 전향적인 추가 연구가 필요하겠다.

Purpose: Urea cycle disorder (UCD) is an inherited inborn error of metabolism, acting on each step of urea cycle that cause various phenotypes. The purpose of the study was to investigate the long-term clinical consequences in different groups of UCD to characterize it. Methods: Twenty-two patients with UCD genetically confirmed were enrolled at Pusan National University Children's hospital and reviewed clinical features, biochemical and genetic features retrospectively. Results: UCD diagnosed in the present study included ornithine transcarbamylase deficiency (OTCD) (n=10, 45.5%), argininosuccinate synthase 1 deficiency (ASSD) (n=6, 27.3%), carbamoyl-phosphate synthetase 1 deficiency (CPS1D) (n=3, 13.6%), hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHHS) (n=2, 9.1%), and arginase-1 deficiency (ARG1D) (n=1, 4.5%). The age at the diagnosis was 32.7±66.2 months old (range 0.1 to 228.0 months). Eight (36.4%) patients with UCD displayed short stature. Neurologic sequelae were observed in eleven (50%) patients with UCD. Molecular analysis identified 37 different mutation types (14 missense, 6 nonsense, 6 deletion, 6 splicing, 3 delins, 1 insertion, and 1 duplication) including 14 novel variants. Progressive growth impairment and poor neurological outcomes were associated with plasma isoleucine and leucine concentrations, respectively. Conclusion: Although combinations of treatments such as nutritional restriction of proteins and use of alternative pathways for discarding excessive nitrogen are extensively employed, the prognosis of UCD remains unsatisfactory. Prospective clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth or neurological outcomes and decrease metabolic crisis episodes in patients with UCD.

키워드

과제정보

The authors thank the patients and their families for participating in this study.

참고문헌

  1. Summar ML, Mew NA. Inborn errors of metabolism with hyperammonemia: urea cycle defects and related disorders. Pediatric Clinics 2018;65:231-46.
  2. Rossignol F, Mew NA, Meltzer MR, Gropman AL. Urea cycle disorders. Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease: Elsevier, 2020:827-48.
  3. Haberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis 2012;7:32. https://doi.org/10.1186/1750-1172-7-32
  4. Haberle J, Burlina A, Chakrapani A, Dixon M, Karall D, Lindner M, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: first revision. J Inherit Metab Dis 2019;42:1192-230. https://doi.org/10.1002/jimd.12100
  5. Adam S, Almeida MF, Assoun M, Baruteau J, Bernabei SM, Bigot S, et al. Dietary management of urea cycle disorders: European practice. Mol Genet Metab 2013;110:439-45. https://doi.org/10.1016/j.ymgme.2013.09.003
  6. Posset R, Garcia-Cazorla A, Valayannopoulos V, Teles EL, Dionisi-Vici C, Brassier A, et al. Age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders. J Inherit Metab Dis 2016;39:661-72. https://doi.org/10.1007/s10545-016-9938-9
  7. Adam S, Champion H, Daly A, Dawson S, Dixon M, Dunlop C, et al. Dietary management of urea cycle disorders: UK practice. J Hum Nutr Diet 2012;25:398-404. https://doi.org/10.1111/j.1365-277X.2012.01259.x
  8. Molema F, Gleich F, Burgard P, van der Ploeg AT, Summar ML, Chapman KA, et al. Decreased plasma l-arginine levels in organic acidurias (MMA and PA) and decreased plasma branched-chain amino acid levels in urea cycle disorders as a potential cause of growth retardation: Options for treatment. Mol Genet Metab 2019;126:397-405. https://doi.org/10.1016/j.ymgme.2019.02.003
  9. Posset R, Garbade SF, Gleich F, Gropman AL, de Lonlay P, Hoffmann GF, et al. Long-term effects of medical management on growth and weight in individuals with urea cycle disorders. Scientific Reports 2020;10:1-13. https://doi.org/10.1038/s41598-019-56847-4
  10. Harris RA, Joshi M, Jeoung NH, Obayashi M. Overview of the molecular and biochemical basis of branched-chain amino acid catabolism. J Nutr 2005;135:1527S-30S. https://doi.org/10.1093/jn/135.6.1527S
  11. Cole JT, Mitala CM, Kundu S, Verma A, Elkind JA, Nissim I, et al. Dietary branched chain amino acids ameliorate injury-induced cognitive impairment. Proc Natl Acad Sci U S A 2010;107:366-71. https://doi.org/10.1073/pnas.0910280107
  12. Shih YT, Huang TN, Hu HT, Yen TL, Hsueh YP. Vcp Overexpression and Leucine Supplementation Increase Protein Synthesis and Improve Fear Memory and Social Interaction of Nf1 Mutant Mice. Cell Rep 2020;31:107835. https://doi.org/10.1016/j.celrep.2020.107835