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

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

A Case of Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency (NICCD) Confirmed by SLC25A13 Mutation

  • 손영배 (아주대학교 의과대학 의학유전학과) ;
  • 장주영 (아주대학교 의과대학 소아청소년과) ;
  • 박형두 (성균관대학교 의과대학 삼성서울병원 진단검사 의학과) ;
  • 이수연 (성균관대학교 의과대학 삼성서울병원 진단검사 의학과)
  • 발행 : 2014.12.25
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

시트룰린혈증 2형은 SLC25A13 유전자 결함으로 인한 시트린 결핍에 의한 상염색체 열성 유전질환이다. 시트룰린혈증 2형은 임상적으로 '시트린 결핍증에 의한 신생아 간내 담즙정체(NICCD)'와 '성인기 발병형 시트룰린혈증 2형'의 두 가지 형태로 나타난다. NICCD는 영아기 간내 담즙정체, 지방간, 간기능 장애, 저단백혈증과, 혈액 응고장애, 저혈당증, 성장부진 등의 증상이 나타나며 임상증상과 생화학적 검사 결과를 바탕으로 질환을 의심하에 SLC25A13 유전자 검사를 통해 확진할 수 있다. 또한 최근에는 무증상 상태에서 신생아 대사이상 선별검사를 통해 진단되기도 한다. 저자들은 신생아 대사이상 선별검사는 정상이었으나 지속되는 황달로 입원한 3개월 남아에서 SLC25A13 유전자 검사로 확진된 NICCD 1례를 경험하였기에 문헌 고찰과 함께 보고하는 바이다. 환아는 지속적 황달과 경도의 고암모니아 혈증과 간효소 수치의 상승, 직접 빌리루빈의 상승을 보이고, 혈장 아미노산 분석 결과 시트룰린과 메티오닌, 트레오닌 상승을 보였다. 시트룰린 혈증 2형 의심 하에 시행한 SLC25A13 유전자 염기서열 분석 결과, c.[852_855delTATG](p.Met285Profs*2)과 c. [1180+1G>A] 이형접합 변이가 발견되었다. 신생아 대사이상 선별검사 결과가 정상이었다고 하더라고 간내 담즙정체가 있는 영아는 NICCD를 감별진단 중 하나로 고려하여 암모니아 및 혈장 아미노산 분석을 포함하여 검사를 시행하는 것이 감별진단에 도움이 될 것으로 사료된다.

Citrullinemia type 2 (citrin deficiency) is an autosomal recessive inborn error metabolism, caused by the SLC25A13 gene mutation. Citrin deficiency is associated with two clinical phenotype; neonatal-onset type II citrullinemia (CTLN2), also known as neonatal intraphepatic cholestasis caused by citrin deficiency (NICCD) and adult-onset CTLN2. Clinical manifestations of NICCD include poor growth, intrahepatic cholestasis, liver dysfunction and increased plasma citrulline, methionine, threonine, arginine. The molecular diagnosis could be confirmed by SLC25A13 gene mutation analysis. A 3-month-old male infant with persistent jaundice was referred for evaluation. Newborn screening was normal at birth. Mild elevation of serum ammonia and AST/ALT were observed. Plasma amino acid analysis showed significantly elevated citrulline, methionine, threonine. DNA sequence analysis of the SLC25A13 gene revealed two compound heterozygous mutations, c.[852_855del]($p.Met285Profs^*2$) and [1180+1G>A]. We suggest that NICCD should be considered as one of the cause of in infants with cholestatic jaundice, although the newborn screening was normal.

키워드

참고문헌

  1. Saheki T, Nakano K, Kobayashi K, Imamura Y, Itakura Y, Sase M, et al. Analysis of the enzyme abnormality in eight cases of neonatal and infantile citrullinaemia in Japan. J Inherit Metab Dis 1985;8:155-6. https://doi.org/10.1007/BF01819306
  2. Woo HI, Park HD, Lee YW. Molecular genetics of citrullinemia types I and II. Clin Chim Acta 2014;431:1-8. https://doi.org/10.1016/j.cca.2014.01.032
  3. Saheki T, Kobayashi K, Iijima M, Horiuchi M, Begum L, Jalil MA, et al. Adult-onset type II citrullinemia and idiopathic neonatal hepatitis caused by citrin deficiency: involvement of the aspartate glutamate carrier for urea synthesis and maintenance of the urea cycle. Mol Genet Metab 2004;81 Suppl 1:S20-6. https://doi.org/10.1016/j.ymgme.2004.01.006
  4. Ohura T, Kobayashi K, Tazawa Y, Nishi I, Abukawa D, Sakamoto O, et al. Neonatal presentation of adult-onset type II citrullinemia. Hum Genet 2001;108:87-90. https://doi.org/10.1007/s004390000448
  5. Ohura T, Kobayashi K, Tazawa Y, Abukawa D, Sakamoto O, Tsuchiya S, et al. Clinical pictures of 75 patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). J Inherit Metab Dis 2007;30:139-44. https://doi.org/10.1007/s10545-007-0506-1
  6. 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.
  7. Lee BH, Jin HY, Kim GH, Choi JH, Yoo HW. Nonalcoholic fatty liver disease in 2 siblings with adult-onset type II citrullinemia. J Pediatr Gastroenterol Nutr 2010;50:682-5. https://doi.org/10.1097/MPG.0b013e3181d67fbf
  8. Ko JS, Song JH, Park SS, Seo JK. Neonatal intrahepatic cholestasis caused by citrin deficiency in Korean infants. J Korean Med Sci 2007;22:952-6. https://doi.org/10.3346/jkms.2007.22.6.952
  9. Lim HS KH, Kim SS, Kim GH, Yoo HW, Shin YL. Novel Compound Heterozygote Mutations of the SLC25A13 Gene in an Infant with Neonatalonset Type II Citrullinemia Detected by Newborn Mass Screening. Korean Soc Neonatol 2011;18:370-3. https://doi.org/10.5385/jksn.2011.18.2.370
  10. 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
  11. Tomomasa T, Kobayashi K, Kaneko H, Shimura H, Fukusato T, Tabata M, et al. Possible clinical and histologic manifestations of adult-onset type II citrullinemia in early infancy. J Pediatr 2001;138:741-3. https://doi.org/10.1067/mpd.2001.113361
  12. Kobayashi K, Sinasac DS, Iijima M, Boright AP, Begum L, Lee JR, et al. The gene mutated in adultonset type II citrullinaemia encodes a putative mitochondrial carrier protein. Nat Genet 1999;22:159-63. https://doi.org/10.1038/9667
  13. Sinasac DS, Crackower MA, Lee JR, Kobayashi K, Saheki T, Scherer SW, et al. Genomic structure of the adult-onset type II citrullinemia gene, SLC25A13, and cloning and expression of its mouse homologue. Genomics 1999;62:289-92. https://doi.org/10.1006/geno.1999.6006
  14. Sinasac DS, Moriyama M, Jalil MA, Begum L, Li MX, Iijima M, et al. Slc25a13-knockout mice harbor metabolic deficits but fail to display hallmarks of adult-onset type II citrullinemia. Mol Cell Biol 2004;24:527-36. https://doi.org/10.1128/MCB.24.2.527-536.2004
  15. Saheki T, Inoue K, Tushima A, Mutoh K, Kobayashi K. Citrin deficiency and current treatment concepts. Mol Genet Metab 2010;100 Suppl 1:S59-64. https://doi.org/10.1016/j.ymgme.2010.02.014
  16. Tamamori A, Fujimoto A, Okano Y, Kobayashi K, Saheki T, Tagami Y, et al. Effects of citrin deficiency in the perinatal period: feasibility of newborn mass screening for citrin deficiency. Pediatr Res 2004;56:608-14. https://doi.org/10.1203/01.PDR.0000139713.64264.BC
  17. Tazawa Y, Kobayashi K, Abukawa D, Nagata I, Maisawa S, Sumazaki R, et al. Clinical heterogeneity of neonatal intrahepatic cholestasis caused by citrin deficiency: case reports from 16 patients. Mol Genet Metab 2004;83:213-9. https://doi.org/10.1016/j.ymgme.2004.06.018
  18. Kasahara M, Ohwada S, Takeichi T, Kaneko H, Tomomasa T, Morikawa A, et al. Living-related liver transplantation for type II citrullinemia using a graft from heterozygote donor. Transplantation 2001;71:157-9. https://doi.org/10.1097/00007890-200101150-00027