Journal of Inherited Metabolic Disease

, Volume 31, Issue 3, pp 386–394 | Cite as

Reduced carbohydrate intake in citrin-deficient subjects

  • T. Saheki
  • K. Kobayashi
  • M. Terashi
  • T. Ohura
  • Y. Yanagawa
  • Y. Okano
  • T. Hattori
  • H. Fujimoto
  • K. Mutoh
  • Z. Kizaki
  • A. Inui
Original Article


Citrin is the liver-type aspartate-glutamate carrier that resides within the inner mitochondrial membrane. Citrin deficiency (due to homozygous or compound heterozygous mutations in the gene SLC25A13) causes both adult-onset type II citrullinaemia (CTLN2) and neonatal intrahepatic cholestasis (NICCD). Clinically, CTLN2 is characterized by hyperammonaemia and citrullinaemia, whereas NICCD has a much more varied and transient presentation that can include multiple aminoacidaemias, hypoproteinaemia, galactosaemia, hypoglycaemia, and jaundice. Personal histories from CTLN2 patients have repeatedly described an aversion to carbohydrate-rich foods, and clinical observations of dietary and therapeutic outcomes have suggested that their unusual food preferences may be directly related to their pathophysiology. In the present study, we monitored the food intake of 18 Japanese citrin-deficient subjects whose ages ranged from 1 to 33 years, comparing them against published values for the general Japanese population. Our survey confirmed a marked decrease in carbohydrate intake, which accounts for a smaller proportion of carbohydrates contributing to the total energy intake (PFC ratio) as well as a shift towards a lower centile distribution for carbohydrate intake relative to age- and sex-matched controls. These results strongly support an avoidance of carbohydrate-rich foods by citrin-deficient patients that may lead to worsening of symptoms.


Carbohydrate Intake Urea Synthesis General Japanese Population SLC25A13 Mutation Citrullinemia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Akaboshi I, Endo F, Matsuda I, Saheki T (1983) Kinetic analysis of argininosuccinate synthetase in a variant form of citrullinaemia. J Inherit Metab Dis 6: 36–39.CrossRefPubMedGoogle Scholar
  2. Awrich AE, Stackhouse WJ, Cantrell JE, Patterson JH, Rudman D (1975) Hyperdibasicaminoaciduria, hyperammonemia, and growth retardation: treatment with arginine, lysine, and citrulline. J Pediatr 87: 731–738.CrossRefPubMedGoogle Scholar
  3. Begum L, Jalil MA, Kobayashi K, et al (2002) Expression of three mitochondrial solute carriers, citrin, aralar1 and ornithine transporter, in relation to urea cycle in mice. Biochim Biophys Acta 1574: 283–292.PubMedGoogle Scholar
  4. Blouet C, Mariotti F, Azzout-Marniche D, et al (2006) The reduced energy intake of rats fed a high-protein low-carbohydrate diet explains the lower fat deposition, but macronutrient substitution accounts for the improved glycemic control. J Nutr 136: 1849–1854.PubMedGoogle Scholar
  5. del Arco A, Satrustegui J (1998) Molecular cloning of Aralar, a new member of the mitochondrial carrier superfamily that binds calcium and is present in human muscle and brain. J Biol Chem 273: 23327–23334.CrossRefPubMedGoogle Scholar
  6. Dimmock D, Kobayashi K, Iijima M, et al (2007) Citrin deficiency: a novel cause of failure to thrive that responds to a high protein, low carbohydrate diet. Pediatrics 119: 773–777.CrossRefGoogle Scholar
  7. Doi M, Yamaoka I, Nakayama M, et al (2005) Isoleucine, a blood glucose-lowering amino acid, increases glucose uptake in rat skeletal muscle in the absence of increases in AMP-activated protein kinase activity. J Nutr 135: 2103–2108.PubMedGoogle Scholar
  8. Gannon MC, Nuttall JA, Nuttall FQ (2002) Oral arginine does not stimulate an increase in insulin concentration but delays glucose disposal. Am J Clin Nutr 76: 1016–1022.PubMedGoogle Scholar
  9. Gulliford MC, Bicknell EJ, Scarpello JH (1989) Differential effect of protein and fat ingestion on blood glucose responses to high- and low-glycemic-index carbohydrates in noninsulin-dependent diabetic subjects. Am J Clin Nutr 50: 773–777.PubMedGoogle Scholar
  10. Hachisu M, Oda Y, Goto M, et al (2005) Citrin deficiency presenting with ketotic hypoglycaemia and hepatomegaly in childhood. Eur J Pediatr 164: 109–110.CrossRefPubMedGoogle Scholar
  11. Hagiwara N, Sekijima Y, Takei Y, et al (2003) Hepatocellular carcinoma in a case of adult-onset type II citrullinemia. Intern Med 42: 978–982.CrossRefPubMedGoogle Scholar
  12. Hue L, Maisin L, Rider MH (1988) Palmitate inhibits liver glycolysis. Involvement of fructose 2,6-bisphosphate in the glucose/fatty acid cycle. Biochem J 251: 541–545.PubMedGoogle Scholar
  13. Hwu WL, Kobayashi K, Hu YH, et al (2001) A Chinese adult onset type II citrullinaemia patient with 851del4/1638ins23 mutations in the SLC25A13 gene. J Med Genet 38: E23.CrossRefPubMedGoogle Scholar
  14. Iijima M, Jalil A, Begum L, et al (2001) Pathogenesis of adult-onset type II citrullinemia caused by deficiency of citrin, a mitochondrial solute carrier protein: tissue and subcellular localization of citrin. Adv Enzyme Regul 41: 325–342.CrossRefPubMedGoogle Scholar
  15. Ikeda S, Yazaki M, Takei Y, et al (2001) Type II (adult onset) citrullinaemia: clinical pictures and the therapeutic effect ofliver transplantation. J Neurol Neurosurg Psychiatry 71: 663–670.CrossRefPubMedGoogle Scholar
  16. Imamura Y, Kobayashi K, Shibatou T, et al (2003) 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. Hepatol Res 26: 68–72.CrossRefPubMedGoogle Scholar
  17. Ishikawa F, Nakamuta M, Kato M, et al (2000) Reversibility of serum NH3 level in a case of sudden onset and rapidly progressive case of type 2 citrullinemia. Intern Med 39: 925–929.CrossRefPubMedGoogle Scholar
  18. Ito T, Shiraki K, Sekoguchi K, et al (2000) Hepatocellular carcinoma associated with adult-type citrullinemia. Dig Dis Sci 45: 2203–2206.CrossRefPubMedGoogle Scholar
  19. Kobayashi K, Saheki T (2004) Molecular basis of citrin deficiency. Seikagaku 76: 1543–1559 [in Japanese].PubMedGoogle Scholar
  20. Kobayashi K, Saheki T (2005/2006) Citrin deficiency. GeneReviews. GeneTests. University of Washington, Seattle: Medical Genetics Information Resource. (accessed 26/01/08).
  21. 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.CrossRefPubMedGoogle Scholar
  22. Liu YQ, Uyeda K (1996) A mechanism for fatty acid inhibition of glucose utilization in liver. Role of xylulose 5-P. J Biol Chem 271: 8824–8830.CrossRefPubMedGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. Nishitani S, Matsumura T, Fujitani S, et al (2002) Leucine promotes glucose uptake in skeletal muscles of rats. Biochem Biophys Res Commun 299: 693–696.CrossRefPubMedGoogle Scholar
  25. Ohura T, Kobayashi K, Tazawa Y, et al (2001) Neonatal presentation of adult-onset type II citrullinemia. Hum Genet 108: 87–90.CrossRefPubMedGoogle Scholar
  26. Ohura T, Kobayashi K, Abukawa D, et al (2003) A novel inborn error of metabolism detected by elevated methionine and/or galactose in newborn screening: neonatal intrahepatic cholestasis caused by citrin deficiency. Eur J Pediatr 162: 317–322.PubMedGoogle Scholar
  27. Palmieri L, Pardo B, Lasorsa FM, et al (2001) Citrin and aralar1 are Ca2+-stimulated aspartate/glutamate transporters in mitochondria. EMBO J 20: 5060–5069.CrossRefPubMedGoogle Scholar
  28. Plecko B, Erwa W, Wermuth B (1998) Partial N-acetylglutamate synthetase deficiency in a 13-year-old girl: diagnosis and response to treatment with N-carbamylglutamate. Eur J Pediatr 157: 996–998.CrossRefPubMedGoogle Scholar
  29. Sadava D, Depper M, Gilbert M, Bernard B, McCabe ER (1987) Development of enzymes of glycerol metabolism in human fetal liver. Biol Neonate 52: 26–32.PubMedCrossRefGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar
  31. Saheki T, Kobayashi K, Inoue I (1987) Hereditary disorders of the urea cycle in man: biochemical and molecular approaches. Rev Physiol Biochem Pharmacol 108: 21–68.PubMedCrossRefGoogle Scholar
  32. Saheki T, Kobayashi K, Iijima M, et al (2004) 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 81: S20–26.CrossRefPubMedGoogle Scholar
  33. Saheki T, Kobayashi K, Iijima M, et al (2005) Metabolic derangements in deficiency of citrin, a liver-type mitochondrial aspartate-glutamate carrier. Hepatol Res 33: 181–184.CrossRefPubMedGoogle Scholar
  34. Saheki T, Iijima M, Li MX, et al (2007) Citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mice recapitulate features of human citrin deficiency. J Biol Chem 282: 25041–25052.CrossRefPubMedGoogle Scholar
  35. Sinasac DS, Moriyama M, Jalil MA, et al (2004) Slc25a13-knockout mice harbor metabolic deficits but fail to display hallmarks of adult-onset type II citrullinemia. Mol Cell Biol 24: 527–536.CrossRefPubMedGoogle Scholar
  36. Takahashi H, Kagawa T, Kobayashi K, et al (2006) A case of adult-onset type II citrullinemia—deterioration of clinical course after infusion of hyperosmotic and high sugar solutions. Med Sci Monit 12: CS13–15.PubMedGoogle Scholar
  37. Tamakawa S, Nakamura H, Katano T, et al (1994) Hyperalimentation therapy produces a comatose state in a patient with citrullinemia. J Jpn Soc Intensive Care Med 1: 37–41 [in Japanese].Google Scholar
  38. Tamamori A, Okano Y, Ozaki H, et al (2002) Neonatal intrahepatic cholestasis caused by citrin deficiency: severe hepatic dysfunction in an infant requiring liver transplantation. Eur J Pediatr 161: 609–613.CrossRefPubMedGoogle Scholar
  39. Tamamori A, Fujimoto A, Okano, Y, et al (2004) Effects of citrin deficiency in the perinatal period: feasibility of newborn massscreening for citrin deficiency. Pediatr Res 56: 608–614.CrossRefPubMedGoogle Scholar
  40. Tazawa Y, Kobayashi K, Ohura T, et al (2001) Infantile cholestatic jaundice associated with adult-onset type II citrullinemia. J Pediatr 138: 735–740.CrossRefPubMedGoogle Scholar
  41. Tazawa Y, Kobayashi K, Abukawa D, et al (2004) Clinical heterogeneity of neonatal intrahepatic cholestasis caused by citrin deficiency: case reports from 16 patients. Mol Genet Metab 83: 213–219.CrossRefPubMedGoogle Scholar
  42. Terada R, Yamamoto K, Kobayashi K, et al (2006) Adult-onset type II citrullinemia associated with idopathic hypertriglyceridemia asa preceding feature. J Gastroenterol Hepatol 21: 1634–1635.CrossRefPubMedGoogle Scholar
  43. Tokuhara D, Iijima M, Tamamori A, et al (2007) Novel diagnostic approach to citrin deficiency: analysis of citrin protein in lymphocytes. Mol Genet Metab 90: 30–36.CrossRefPubMedGoogle Scholar
  44. Tsujii T, Morita T, Matsuyama Y, et al (1976) Sibling cases of chronic recurrent hepatocerebral disease with hypercitrullinemia. Gastroenterol Jap 11: 328–340.Google Scholar
  45. Waki M, Mutoh K, Murata K, Uemoto S, Kobayashi K (2004) Severe hyperlipidemia in a patient with adult-onset type II citrullinemia, associated with decreased lipoprotein lipase protein and dysgenesis of the corpus callosum. The Lipid 15: 266–270 [in Japanese].Google Scholar
  46. Yajima Y, Hirasawa T, Saheki T (1982) Diurnal fluctuation of blood ammonia levels in adult-type citrullinemia. Tohoku J Exp Med 137: 213–220.CrossRefPubMedGoogle Scholar
  47. Yamaguchi N, Kobayashi K, Yasuda T, et al (2002) 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 19: 122–130.CrossRefPubMedGoogle Scholar
  48. Yazaki M, Takei Y, Kobayashi K, Saheki T, Ikeda S (2005) Risk of worsened encephalopathy after intravenous glycerol therapy in patients with adult-onset type II citrullinemia (CTLN2). Intern Med 44: 188–195.CrossRefPubMedGoogle Scholar
  49. Zhang Y, Guo K, LeBlanc RE, et al (2007) Increasing dietary leucine intake reduces diet-induced obesity and improves glucose and cholesterol metabolism in mice via multimechanisms. Diabetes 56: 1647–1654.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • T. Saheki
    • 1
    • 9
  • K. Kobayashi
    • 1
  • M. Terashi
    • 1
  • T. Ohura
    • 2
  • Y. Yanagawa
    • 3
  • Y. Okano
    • 4
  • T. Hattori
    • 5
  • H. Fujimoto
    • 5
  • K. Mutoh
    • 6
  • Z. Kizaki
    • 7
  • A. Inui
    • 8
  1. 1.Department of Molecular Metabolism and Biochemical GeneticsKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan
  2. 2.Department of PediatricsTohoku University School of MedicineSendaiJapan
  3. 3.Nutrition Management RoomTohoku University HospitalSendaiJapan
  4. 4.Department of PediatricsOsaka City University Graduate School of MedicineOsakaJapan
  5. 5.Osaka City University HospitalOsakaJapan
  6. 6.Department of PediatricsShimada Municipal HospitalShimadaJapan
  7. 7.Department of PediatricsKyoto First Red-Cross HospitalKyotoJapan
  8. 8.Division of Hepatology & Gastroenterology Children’s Center for Health & DevelopmentYokohama Tobu HospitalYokohamaJapan
  9. 9.Institute for Health SciencesTokushima Bunri UniversityTokushimaJapan

Personalised recommendations