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Citrin Deficiency

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Human Pathobiochemistry

Abstract

Citrin deficiency arises from biallelic mutations in SLC25A13 gene, and can manifest in newborns or infants as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), in older children as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and in adults as adult-onset citrullinemia type II (CTLN2). The diagnosis of citrin deficiency is based on characteristic biochemical findings and identification of biallelic pathogenic variants in SLC25A13 gene. Lactose-free and medium-chain triglycerides (MCT)-enriched formula and fat-soluble vitamins yield satisfactory outcomes in most NICCD cases. For FTTDCD, besides dietary treatment, sodium pyruvate may improve growth. For CTLN2, liver transplantation is effective, but arginine, sodium pyruvate, and MCT oil may delay the need for liver transplantation.

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Abbreviations

4-HPL:

 4-Hydroxyphenyllactate

4-HPPV:

 4-Hydroxyphenylpyruvate

ABC:

 ATP-binding cassette

ABCG5/8:

ATP-binding cassette, subfamily G, member 5/8

AFP:

α-Fetoprotein

Ag:

Antigen

AGC:

Aspartate-glutamate carrier

ALP:

Alkaline phosphatase

ALT:

Alanine aminotransferase

ASS:

Argininosuccinate synthetase

AST:

Aspartate aminotransferase

BSEP:

Bile salt export pump

CMV:

Cytomegalovirus

CTLN1:

Argininosuccinate synthetase deficiency or classical citrullinemia

CTLN2:

Adult-onset type II citrullinemia

FTTDCD:

Failure to thrive and dyslipidemia caused by citrin deficiency

GC-MS:

Gas chromatography-mass spectrometry

GGT:

γ-Glutamyltransferase

MCFA:

Medium-chain fatty acid

MCT:

Medium-chain triglyceride

MRD3:

Multidrug-resistant protein 3

MS-MS:

Tandem mass spectrometry

NICCD:

Neonatal intrahepatic cholestasis caused by citrin deficiency

ORF:

Open reading frame

TBA:

Total bile acids

Tbil/Dbil:

Total bilirubin/direct bilirubin

References

  • Fukushima K, Yazaki M, Nakamura M et al (2010) Conventional diet therapy for hyperammonemia is risky in the treatment of hepatic encephalopathy associated with citrin deficiency. Intern Med 49:1–20

    Article  Google Scholar 

  • Hayasaka K, Numakura C, Toyota K et al (2014) Medium-chain triglyceride supplementation under a low-carbohydrate formula is a promising therapy for adult-onset type II citrullinemia. Mol Genet Metab Rep 1:42–50

    Article  CAS  Google Scholar 

  • Ikeda S, Yazaki M, Takei Y et al (2001) Type II (adult onset) citrullinemia: clinical pictures and the therapeutic effect of liver transplantation. J Neurol Neurosug Psychiatr 71:663–670

    Article  CAS  Google Scholar 

  • Imamura Y, Kobayashi K, Shibatou T et al (2003) Effectiveness of carbohydrate-restrictive 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. Hepatol Res 26:68–72

    Article  Google Scholar 

  • Kikuchi A, Arai-Ichinoi N, Sakamoto O et al (2012) Simple and rapid genetic testing for citrin deficiency by. Screening 11 prevalent mutations in SLC25A13. Mol Genet Metab 105:553–558

    Article  CAS  Google Scholar 

  • Kobayashi K, Sinasac DS, Iijima M et al (1999) The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Nat Genet 22:159–163

    Article  CAS  Google Scholar 

  • Kobayashi K, Saheki T, Song YZ (2014) Citrin deficiency. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP (eds) Gene reviews [Internet]. University of Washington, Seattle; 1993–2005 Sept 16

    Google Scholar 

  • Komatsu M, Yazaki M, Tanaka N et al (2008) Citrin deficiency as a cause of chronic liver disorder mimicking non-alcoholic fatty liver disease. J Hepatol 49:810–820

    Article  CAS  Google Scholar 

  • Komatsu M, Kimura T, Yazaki M et al (2015) Steatogenesis in adult-onset type II citrullinemia is associated with down-regulation of PPARα. Biochim Biophys Acta 1852:473–481

    Article  CAS  Google Scholar 

  • Lin WX, Zeng HS, Zhang ZH et al (2016) Molecular diagnosis of pediatric patients with citrin deficiency in China: SLC25A13 mutation spectrum and the geographic distribution. Sci Rep 6:29732

    Article  Google Scholar 

  • Moriyama M, Li MX, Kobayashi K et al (2006) Pyruvate ameliorates the defect in ureogenesis from ammonia in citrin-deficient mice. J Hepatol 44:930–938

    Article  CAS  Google Scholar 

  • Mutoh K, Kurokawa K, Kobayashi K, Saheki T (2008) 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 31(Suppl 2):S343–S347

    Article  Google Scholar 

  • Nakamura M, Yazaki M, Kobayashi Y et al (2011) The characteristics of food intake in patients with type II citrullinemia. J Nutr Sci Vitaminol 57:239–245

    Article  CAS  Google Scholar 

  • Palmieri L, Pardo B, Lasorsa FM et al (2001) Citrin and aralar 1 are Ca2+-stimulated aspartate/glutamate transporters in mitochondria. EMBO J 20:5060–5069

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Saheki T, Kobayashi K, Terashi M et al (2008) Reduced carbohydrate intake in citrin-deficient subjects. J Inherit Metab Dis 31:386–394

    Article  CAS  Google Scholar 

  • Soeda J, Yazaki M, Nakata T et al (2008) Primary liver carcinoma exhibiting dual hepatocellular-biliary epithelial differentiations associated with citrin deficiency: a case report and review of the literature. J Clin Gastroenterol 42:855–860

    Article  Google Scholar 

  • Tanaka M, Nishigaki Y, Fuku N et al (2007) Therapeutic potential of pyruvate therapy for mitochondrial diseases. Mitochondrion 7:399–401

    Article  CAS  Google Scholar 

  • Thangaratnarajah C, Ruprecht JJ, Kunji ER (2014) Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers. Nat Commun 5:5491

    Article  CAS  Google Scholar 

  • Yazaki M, Takei Y, Kobayashi K et al (2005) Risk of worsened encephalopathy after intravenous glycerol therapy in patients with adult-onset type II citrullinemia (CTLN2). Intern Med 44:188–195

    Article  CAS  Google Scholar 

  • Yazaki M, Kinoshita M, Ogawa S et al (2013) A 73-year-old patient with adult-onset type II citrullinemia successfully treated by sodium pyruvate and arginine. Clin Neurol Neurosurg 115:1542–1545

    Article  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China

    Yuan-Zong Song

  2. Institute for Biomedical Sciences, Shinshu University, Matsumoto, Japan

    Masahide Yazaki

  3. Department of Clinical Laboratory Medicines, Shinshu University School of Health Sciences, Matsumoto, Japan

    Masahide Yazaki

  4. Department of Hygiene and Health Promotion Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

    Takeyori Saheki

Authors
  1. Yuan-Zong Song
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  2. Masahide Yazaki
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  3. Takeyori Saheki
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Editor information

Editors and Affiliations

  1. Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan

    Toshitaka Oohashi

  2. Department of Pediatrics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan

    Hirokazu Tsukahara

  3. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Francesco Ramirez

  4. Department of Biology College of Arts and Sciences, California Lutheran University, Thousand Oaks, CA, USA

    Chad L. Barber

  5. Department of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan

    Fumio Otsuka

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© 2019 Springer Nature Singapore Pte Ltd.

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Song, YZ., Yazaki, M., Saheki, T. (2019). Citrin Deficiency. In: Oohashi, T., Tsukahara, H., Ramirez, F., Barber, C., Otsuka, F. (eds) Human Pathobiochemistry. Springer, Singapore. https://doi.org/10.1007/978-981-13-2977-7_1

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