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

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

A Case of Adult-onset Type II Citrullinemia Confirmed by Mutation of SLC25A13

SLC25A13 유전자 돌연변이로 확진된 성인형 제 2형 시트룰린혈증 1례

  • Jeung, Min Sub (Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Yang, Aram (Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Kim, Jinsup (Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Park, Hyung-Doo (Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Lee, Heon Ju (Department of Internal Medicine, Yeungnam University Medical School) ;
  • Jin, Dong-Kyu (Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Cho, Sung Yoon (Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine)
  • 정민섭 (성균관대학교 의과대학 삼성서울병원 소아청소년과) ;
  • 양아람 (성균관대학교 의과대학 삼성서울병원 소아청소년과) ;
  • 김진섭 (성균관대학교 의과대학 삼성서울병원 소아청소년과) ;
  • 박형두 (성균관대학교 의과대학 삼성서울병원 진단검사의학과) ;
  • 이헌주 (영남대학교병원 소화기내과) ;
  • 진동규 (성균관대학교 의과대학 삼성서울병원 소아청소년과) ;
  • 조성윤 (성균관대학교 의과대학 삼성서울병원 소아청소년과)
  • Published : 2016.04.25
Download PDF
⟨ Previous Next ⟩

Abstract

Adult-onset type II citrullinemia (CTLN2) is characterized by episodes of neurologic symptoms associated with hyperammonemia leading to disorientation, irritability, seizures, and coma. CTLN2 is distinct from classical citrullinemia, which is caused by a mutation of the argininosuccinic acid synthetase (ASS) gene. The serum citrulline level is elevated, while the activity of ASS in liver tissue is decreased. CTLN2 is known to have a poor prognosis if the proper treatment is not taken. We reported a female aged 37 years who developed recurrent attacks of altered consciousness, aberrant behavior, and vomiting. We initially suspected the patient had CTLN2 because of the signs of hyperammonemic encephalopathy, such as altered mentality, memory disturbance, and aberrant behaviors provoked by exercise-induced stress and excessive intravenous amino acid administration. Through her peculiar diet preferences and laboratory findings that included hyperammonemia and citrullinemia, we diagnosed the patient as CTLN2, and SLC25A13 sequencing revealed known compound heterozygous mutations (IVS11+1G>A, c.674C> A). Her parents were heterozygous carriers, and we identified that her older sister had the same mutations. The older sister had not experienced any episodes of hyperammonemia, but she had peculiar diet preferences. The patient and her sister have been well with conservative management. When considering the clinical course of CTLN2, it was meaningful that the older sister could be diagnosed early in an asymptomatic period and that preemptive treatment was employed. Through this case, CTLN2 should be considered in adults who present symptoms of hyperammonemic encephalopathy without a definite etiology. Because of its rare incidence and similar clinical features, CTLN2 is frequently misdiagnosed as hepatic encephalopathy, and it shows a poor prognosis due to the lack of early diagnosis and proper treatment. A high-carbohydrate diet, which is usually used to treat other urea cycle defects, can also exaggerate the clinical course of CTLN2, so proper metabolic screening tests and genetic studies should be performed.

성인기에 나타난 운동으로 인한 스트레스와 과량의 단백질 투여에 의한 의식 변화, 기억 장애, 행동 장애등의 고암모니아혈증성 뇌병증 소견을 토대로 저자들은 성인형 제 2형 시트룰린혈증을 의심하였다. 검사 결과에서 고암모니아혈증, 혈중 시트룰린 상승, 요중 오로트산 경도 상승을 보였으며, 이를 통해 성인형 제 2형 시트룰린혈증을 진단하였다. SLC25A13 유전자 분석 결과를 통해 환자에게서 복합 이형 접합성 돌연변이(IVS11+1G>A, c.674C>A)를 확인하였다. 환자의 가족에서도 유전자 분석 검사를 진행하였고, 아버지, 어머니, 남동생에게서 성인형 제 2형 시트룰린혈증 보인자를, 언니에게서 성인형 제 2형 시트룰린혈증 환자임을 확인하였다. 그 동안 보고된 성인형 제 2형 시트룰린혈증의 임상 경과를 고려했을 때, 증상이 없던 언니에게서 질환을 발견하고 보존적 치료를 선제적으로 시작함으로써, 신경학적 장애 없이 일상 생활을 영위하고, 추가적인 뇌 손상을 방지하기 위한 간 이식 등 장기적인 치료 계획을 수립했다는 점에서 의의가 있다. 본 환자의 증례를 통해 고암모니아혈증성 뇌병증이 발생한 성인에서, 간질환 및 뇌질환의 증거가 없으며 다른 뚜렷한 원인이 없는 경우에는, 성인형 제 2형 시트룰린혈증을 고려해야 한다는 점을 인지하였다. 빈도가 드문 질환이지만 간성 혼수로 흔히 오인되고 있으며, 조기 진단 및 적절한 치료가 이루어지지 않으면 비가역적인 신경학적 후유증이 발생할 수 있다. 또한 다른 요소 회로 대사 질환 및 간성 혼수와는 달리, 고탄수화물 식이가 질병의 경과를 인위적으로 악화시킬 수 있기에 적절한 대사 이상 검사 및 유전자 검사가 시행되어야 하겠다. 본 증례는 반복적인 고암모니아혈증성 뇌병증 소견을 보인 37세 여성과 뇌병증 소견이 없었던 언니에게서 성인형 제 2형 시트룰린혈증을 진단하고, 즉각적인 치료를 통해 심각한 신경학적 장애 없이 일상 생활을 지속하고 있는 환자들을 문헌 고찰과 함께 보고하는 바이다.

Keywords

References

  1. Kobayashi K, Sinasac DS, Iijima M, Boright AP, Begum L, Lee JR, et al. The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Nat Genet 1999;22:159-63. https://doi.org/10.1038/9667
  2. 이범희, 김유미, 김구환, 유한욱. 씨트린 결핍증에 의한 중증의 신생아 담즙 정체성 활달. 대한유전성대사질환학회지. Journal of the Korean Society of Inherited Metabolic Disease 2012;12:35-41.
  3. Kim JH, Park KW, Park CJ, Sun GH, Kim HH, Kim SY, et al. A Case of Adult Onset Type II Citrullinemia with SLC25A13 Gene Mutation. J Korean Endocr Soc DE 2006;21:542-7. https://doi.org/10.3803/jkes.2006.21.6.542
  4. Ko JS, Song JH, Park SS, Seo JK. Neonatal intrahepatic cholestasis caused by citrin deficiency in Korean infants. Journal of Korean medical science. JKMS 2007;22:952-6. https://doi.org/10.3346/jkms.2007.22.6.952
  5. Tsai CW, Yang CC, Chen HL, Hwu WL, Wu MZ, Liu KL, et al. Homozygous SLC25A13 mutation in a Taiwanese patient with adult-onset citrullinemia complicated with steatosis and hepatocellular carcinoma. J Formos Med Assoc 2006;105:852-6. https://doi.org/10.1016/S0929-6646(09)60274-6
  6. Kobayashi K, Nakata M, Terazono H, Shinsato T, Saheki T. Pancreatic secretory trypsin inhibitor gene is highly expressed in the liver of adult-onset type II citrullinemia. FEBS Lett 1995;372:69-73. https://doi.org/10.1016/0014-5793(95)00948-9
  7. Lu YB, Kobayashi K, Ushikai M, Tabata A, Iijima M, Li MX, et al. Frequency and distribution in East Asia of 12 mutations identified in the SLC25A13 gene of Japanese patients with citrin deficiency. J Hum Genet 2005;50:338-46. https://doi.org/10.1007/s10038-005-0262-8
  8. Imamura Y, Kobayashi K, Shibatou T, Aburada S, Tahara K, Kubozono O, et al. Effectiveness of carbohydrate-restricted diet and arginine granules therapy for adult-onset type II citrullinemia: a case report of siblings showing homozygous SLC25A13 mutation with and without the disease. Hepatology Research 2003;26:68-72. https://doi.org/10.1016/S1386-6346(02)00331-5
  9. Kimura N, Kubo N, Narumi S, Toyoki Y, Ishido K, Kudo D, et al. Liver transplantation versus conservative treatment for adult-onset type II citrullinemia: our experience and a review of the literature. Transplant Proc 2013;45:3432-7. https://doi.org/10.1016/j.transproceed.2013.06.016
  10. Park HJ, Lim HJ, Jung IS, Kim YH, Kim IH, Chung IK, et al. A Case of Adult-type Citrullinemia with Hyperammonemia. Korean J Gastroenterol DE 2002;39:379-85.
  11. Ko JM, Kim GH, Kim JH, Kim JY, Choi JH, Ushikai M, et al. Six cases of citrin deficiency in Korea. Int J Mol Med 2007;20:809-15.
  12. Lim HS, Kim H, Kim SS, Kim GH, Yoo HW, Shin YL. Novel Compound Heterozygote Mutations of the SLC25A13 Gene in an Infant with Neonatal-onset Type II Citrullinemia Detected by Newborn Mass Screening. J Korean Soc Neonatol DE 2011;18:370-3. https://doi.org/10.5385/jksn.2011.18.2.370
  13. Kim BS, Joo SH, Lee SH, Lee JI, Kim HC, Nam DH, et al. Auxiliary partial orthotopic liver transplantation for adult onset type II citrullinemia. J Korean Surg Soc 2011;80 Suppl 1:S51-4. https://doi.org/10.4174/jkss.2011.80.Suppl1.S51
  14. 손영배, 장주영, 박형두, 이수연. A Case of Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency (NICCD) Confirmed by SLC25A13 Mutation. 대한유전성대사질환학회지. Journal of the Korean Society of Inherited Metabolic Disease 2014;14:186-90.
  15. Lee BH, Jin HY, Kim GH, Choi JH, Yoo HW. Nonalcoholic fatty liver disease in 2 siblings with adultonset type II citrullinemia. J Pediatr Gastroenterol Nutr 2010;50:682-5. https://doi.org/10.1097/MPG.0b013e3181d67fbf
  16. Takahashi H, Kagawa T, Kobayashi K, Hirabayashi H, Yui M, Begum L, et al. A case of adult-onset type II citrullinemia--deterioration of clinical course after infusion of hyperosmotic and high sugar solutions. Med Sci Monit 2006;12:CS13-5.
  17. Terada R, Yamamoto K, Kobayashi K, Sakaguchi K, Iwasaki Y, Saheki T, et al. Adult-onset type II citrullinemia associated with idopathic hypertriglyceridemia as a preceding feature. J Gastroenterol Hepatol 2006;21:1634-5.
  18. Tazawa K, Shimojima Y, Okano T, Yazaki M, Takei Y, Shimojo H, et al. An autopsy case with adult onset type II citrullinemia showing myelopathy. J Neurol Sci 2007;253:77-80. https://doi.org/10.1016/j.jns.2006.11.014
  19. Wong YC, Au WL, Xu M, Ye J, Lim CC. Magnetic resonance spectroscopy in adult-onset citrullinemia: elevated glutamine levels in comatose patients. Arch Neurol 2007;64:1034-7. https://doi.org/10.1001/archneur.64.7.1034
  20. Mutoh K, Kurokawa K, Kobayashi K, Saheki T. Treatment of a citrin-deficient patient at the early stage of adult-onset type II citrullinaemia with arginine and sodium pyruvate. J Inherit Metab Dis 2008;31 Suppl 2:S343-7. https://doi.org/10.1007/s10545-008-0914-x
  21. Hirai I, Kimura W, Suto K, Fzjimoto H, Watanabe T, Fuse A, et al. Living donor liver transplantation for type II citrullinemia from a heterozygous donor. Hepatogastroenterology 2008;55:2211-6.
  22. Noto D, Takahashi K, Hamaguchi T, Inamura K, Nobata K, Yazaki M, et al. A case of adult onset type II citrullinemia with portal-systemic shunt. J Neurol Sci 2009;281:127-9. https://doi.org/10.1016/j.jns.2009.02.003
  23. Funabe S, Tanaka R, Urabe T, Kawasaki S, Kobayashi K, Hattori N. [A case of adult-onset type II citrullinemia with repeated nonconvulsive status epilepticus]. Rinsho Shinkeigaku 2009;49:571-5. https://doi.org/10.5692/clinicalneurol.49.571
  24. Ueda A, Okada K, Takahara T, Iwasa K, Shinagawa K, Entani A, et al. A case of adult-onset type II citrullinemia induced by hospital diet. Clin J Gastroenterol 2011;4:28-33. https://doi.org/10.1007/s12328-010-0188-3
  25. Tan HH, Chow WC, Lim KH, Wan WK, Chung AY, Cheow PC, et al. Liver transplantation in an adult with citrullinaemia type 2. J Transplant 2011;2011:176370.
  26. Yazaki M, Hineno A, Matsushima A, Ozawa K, Kishida D, Tazawa K, et al. First two cases of adultonset type II citrullinemia successfully treated by deceased-donor liver transplantation in Japan. Hepatol Res 2012;42:934-9. https://doi.org/10.1111/j.1872-034X.2012.00992.x
  27. Sakamoto S, Shinno H, Ikeda M, Miyoshi H, Nakamura Y. A patient with type II citrullinemia who developed refractory complex seizure. Gen Hosp Psychiatry 2013;35:103 e1-3.
  28. Yazaki M, Kinoshita M, Ogawa S, Fujimi S, Matsushima A, Hineno A, et al. A 73-year-old patient with adult-onset type II citrullinemia successfully treated by sodium pyruvate and arginine. Clin Neurol Neurosurg 2013;115:1542-5. https://doi.org/10.1016/j.clineuro.2012.12.027
  29. Kogure T, Kondo Y, Kakazu E, Ninomiya M, Kimura O, Kobayashi N, et al. Three cases of adult-onset type II citrullinemia treated with different therapies: Efficacy of sodium pyruvate and low-carbohydrate diet. Hepatol Res 2014;44:707-12. https://doi.org/10.1111/hepr.12170
  30. Kyo M, Mii H, Takekita Y, Tokuhara D, Yazaki M, Nakamori Y, et al. Case of adult-onset type II citrullinemia treated as schizophrenia for a long time. Psychiatry Clin Neurosci 2015;69:306-7. https://doi.org/10.1111/pcn.12253