J Korean Med Sci.  2007 Dec;22(6):952-956. 10.3346/jkms.2007.22.6.952.

Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency in Korean Infants

• Ko JS
• Song JH
• Park SS
• Seo JK

• KMID: 1785752
• DOI: http://doi.org/10.3346/jkms.2007.22.6.952

Abstract

Citrin is a liver-type mitochondrial aspartate-glutamate carrier encoded by the SLC25A13 gene, and its deficiency causes adult-onset type II citrullinemia and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). Here, the authors investigated clinical findings in Korean infants with NICCD and performed mutation analysis on the SLC25A13 gene. Of 47 patients with neonatal cholestasis, three infants had multiple aminoacidemia (involving citrulline, methionine, and arginine) and galactosemia, and thus were diagnosed as having NICCD. Two of these three showed failure to thrive. The laboratory findings showed hypoproteinemia and hyperammonemia, and liver biopsies revealed micro-macrovesicular fatty liver and cholestasis. The three patients each harbored compound heterozygous 1,638-1,660 dup/ S225X mutation, compound heterozygous 851del4/S225X mutation, and heterozygous 1,638-1,660 dup mutation, respectively. With nutritional manipulation, liver functions were normalized and catch-up growth was achieved. NICCD should be considered in the differential diagnosis of cholestatic jaundice in Korean infants.

Keyword

Cholestasis; Citrin; Citrullinemia; SLC25A13; Mutation

MeSH Terms

Amino Acids/blood
Calcium-Binding Proteins/*deficiency
Cholestasis, Intrahepatic/*etiology/genetics
Citrullinemia/genetics
Humans
Infant
Membrane Transport Proteins/genetics
Mitochondrial Proteins/genetics
Mutation
Organic Anion Transporters/*deficiency

Reference

1. Kobayashi K, Sinasac DS, Iijima M, Boright AP, Begum L, Lee JR, Yasuda T, Ikeda S, Hirano R, Terazono H, Crackower MA, Kondo I, Tsui LC, Scherer SW, Saheki T. The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Nat Genet. 1999. 22:159–163.

2. Sinasac DS, Crackower MA, Lee JR, Kobayashi K, Saheki T, Scherer SW, Tsui LC. Genomic structure of the adult-onset type II citrullinemia gene, SLC25A13, and cloning and expression of its mouse homologue. Genomics. 1999. 62:289–292.

3. Saheki T, Kobayashi K. Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD). J Hum Genet. 2002. 47:333–341.

4. Ohura T, Kobayashi K, Tazawa Y, Nishi I, Abukawa D, Sakamoto O, Iinuma K, Saheki T. Neonatal presentation of adult-onset type II citrullinemia. Hum Genet. 2001. 108:87–90.

5. Tazawa Y, Kobayashi K, Ohura T, Abukawa D, Nishinomiya F, Hosoda Y, Yamashita M, Nagata I, Kono Y, Yasuda T, Yamaguchi N, Saheki T. Infantile cholestatic jaundice associated with adult-onset type II citrullinemia. J Pediatr. 2001. 138:735–740.

6. Yamaguchi N, Kobayashi K, Yasuda T, Nishi I, Iijima M, Nakagawa M, Osame M, Kondo I, Saheki T. Screening of SLC25A13 mutations in early and late onset patients with citrin deficiency and in the Japanese population: Identification of two novel mutations and establishment of multiple DNA diagnosis methods for nine mutations. Hum Mutat. 2002. 19:122–130.

7. Tomomasa T, Kobayashi K, Kaneko H, Shimura H, Fukusato T, Tabata M, Inoue Y, Ohwada S, Kasahara M, Morishita Y, Kimura M, Saheki T, Morikawa A. Possible clinical and histologic manifestations of adult-onset type II citrullinemia in early infancy. J Pediatr. 2001. 138:741–743.

8. Kasahara M, Ohwada S, Takeichi T, Kaneko H, Tomomasa T, Morikawa A, Yonemura K, Asonuma K, Tanaka K, Kobayashi K, Saheki T, Takeyoshi I, Morishita Y. Living-related liver transplantation for type II citrullinemia using a graft from heterozygote donor. Transplantation. 2001. 71:157–159.

9. Ben-Shalom E, Kobayashi K, Shaag A, Yasuda T, Gao HZ, Saheki T, Bachmann C, Elpeleg O. Infantile citrullinemia caused by citrin deficiency with increased dibasic amino acids. Mol Genet Metab. 2002. 77:202–208.

10. Lee J, Ellaway C, Kobayashi K, Wilcken B. Citrullinemia type II: a rare cause of neonatal cholestasis detected by newborn screening. Inherit Metab Dis. 2002. 25:Suppl 1. 29.

11. Lu YB, Kobayashi K, Ushikai M, Tabata A, Iijima M, Li MX, Lei L, Kawabe K, Taura S, Yang Y, Liu T, Chiang S, Hsiao K, Lau Y, Tsui L, Lee DH, Saheki T. Frequency and distribution in East Asia of 12 mutations identified in the SLC25A13 gene of Japanese patients with citrin deficiency. J Hum Genet. 2005. 50:338–346.

12. Yasuda T, Yamaguchi N, Kobayashi K, Nishi I, Horinouchi H, Jalil MA, Li MX, Ushikai M, Iijima M, Kondo I, Saheki T. Identification of two novel mutations in the SLC25A13 gene and detection of seven mutations in 102 patients with adult-onset type II citrullinemia. Hum Genet. 2000. 107:537–545.

13. Saheki T, Nakano K, Kobayashi K, Imamura Y, Itakura Y, Sase M, Hagihara S, Matuo S. Analysis of the enzyme abnormality in eight cases of neonatal and infantile citrullinaemia in Japan. J Inherit Metab Dis. 1985. 8:155–156.

14. Saheki T, Kobayashi K, Iijima M, Horiuchi M, Begum L, Jalil MA, Li MX, Lu YB, Ushikai M, Tabata A, Moriyama M, Hsiao KJ, Yang Y. 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–S26.

15. Shigematsu Y, Hirano S, Hata I, Tanaka Y, Sudo M, Sakura N, Tajima T, Yamaguchi S. Newborn mass screening and selective screening using electrospray tandem mass spectrometry in Japan. J Chromatogr B Analyt Technol Biomed Life Sci. 2002. 776:39–48.

16. Tamamori A, Fujimoto A, Okano Y, Kobayashi K, Saheki T, Tagami Y, Takei H, Shigematsu Y, Hata I, Ozaki H, Tokuhara D, Nishimura Y, Yorifuji T, Igarashi N, Ohura T, Shimizu T, Inui K, Sakai N, Abukawa D, Miyakawa T, Matsumori M, Ban K, Kaneko H, Yamano T. Effects of citrin deficiency in the perinatal period: feasibility of newborn mass screening for citrin deficiency. Pediatr Res. 2004. 56:608–614.

17. Kobayashi K, Bang Lu Y, Xian Li M, Nishi I, Hsiao KJ, Choeh K, Yang Y, Hwu WL, Reichardt JK, Palmieri F, Okano Y, Saheki T. Screening of nine SLC25A13 mutations: their frequency in patients with citrin deficiency and high carrier rates in Asian populations. Mol Genet Metab. 2003. 80:356–359.

18. Yeh JN, Jeng YM, Chen HL, Ni YH, Hwu WL, Chang MH. Hepatic steatosis and neonatal intrahepatic cholestasis caused by citrin deficiency in Taiwanese infants. J Pediatr. 2006. 148:642–646.

19. Park HJ, Lim HJ, Jung IS, Kim YH, Kim IH, Chung IK, Kim HS, Park SH, Lee MH, Kim SJ, Lee DH. A case of adult-type citrullinemia with hyperammonemia. Korean J Gastroenterol. 2002. 39:379–385.

20. Tazawa Y, Kobayashi K, Abukawa D, Nagata I, Maisawa S, Sumazaki R, Iizuka T, Hosoda Y, Okamoto M, Murakami J, Kaji S, Tabata A, Lu YB, Sakamoto O, Matsui A, Kanzaki S, Takada G, Saheki T, Iinuma K, Ohura T. Clinical heterogeneity of neonatal intrahepatic cholestasis caused by citrin deficiency: case reports from 16 patients. Mol Genet Metab. 2004. 83:213–219.

21. Tamamori A, Okano Y, Ozaki H, Fujimoto A, Kajiwara M, Fukuda K, Kobayashi K, Saheki T, Tagami Y, Yamano T. Neonatal intrahepatic cholestasis caused by citrin deficiency: severe hepatic dysfunction in an infant requiring liver transplantation. Eur J Pediatr. 2002. 161:609–613.