Pathogenesis and Management of Citrin Deficiency
Citrin deficiency (CD) is a hereditary disorder caused by SLC25A13 mutations that manifests as neonatal intrahepatic cholestasis caused by CD (NICCD), failure to thrive and dyslipidemia caused by CD (FTTDCD), and adult-onset type 2 citrullinemia (CTLN2). Citrin, an aspartate-glutamate carrier primar...
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| Published in | Internal Medicine Vol. 63; no. 14; pp. 1977 - 1986 |
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| Main Author | |
| Format | Journal Article |
| Language | English |
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Japan
The Japanese Society of Internal Medicine
15.07.2024
Japan Science and Technology Agency |
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| Online Access | Get full text |
| ISSN | 0918-2918 1349-7235 1349-7235 |
| DOI | 10.2169/internalmedicine.2595-23 |
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| Abstract | Citrin deficiency (CD) is a hereditary disorder caused by SLC25A13 mutations that manifests as neonatal intrahepatic cholestasis caused by CD (NICCD), failure to thrive and dyslipidemia caused by CD (FTTDCD), and adult-onset type 2 citrullinemia (CTLN2). Citrin, an aspartate-glutamate carrier primarily expressed in the liver, is a component of the malate-aspartate shuttle, which is essential for glycolysis. Citrin-deficient hepatocytes have primary defects in glycolysis and de novo lipogenesis and exhibit secondarily downregulated PPARα, leading to impaired β-oxidation. They are unable to utilize glucose and free fatty acids as energy sources, resulting in energy deficiencies. Medium-chain triglyceride (MCT) supplements are effective for treating CD by providing energy to hepatocytes, increasing lipogenesis, and activating the malate-citrate shuttle. However, patients with CD often exhibit growth impairment and irreversible brain and/or liver damage. To improve the quality of life and prevent irreversible damage, MCT supplementation with a diet containing minimal carbohydrates is recommended promptly after the diagnosis. |
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| AbstractList | Citrin deficiency (CD) is a hereditary disorder caused by SLC25A13 mutations that manifests as neonatal intrahepatic cholestasis caused by CD (NICCD), failure to thrive and dyslipidemia caused by CD (FTTDCD), and adult-onset type 2 citrullinemia (CTLN2). Citrin, an aspartate-glutamate carrier primarily expressed in the liver, is a component of the malate-aspartate shuttle, which is essential for glycolysis. Citrin-deficient hepatocytes have primary defects in glycolysis and de novo lipogenesis and exhibit secondarily downregulated PPARα, leading to impaired β-oxidation. They are unable to utilize glucose and free fatty acids as energy sources, resulting in energy deficiencies. Medium-chain triglyceride (MCT) supplements are effective for treating CD by providing energy to hepatocytes, increasing lipogenesis, and activating the malate-citrate shuttle. However, patients with CD often exhibit growth impairment and irreversible brain and/or liver damage. To improve the quality of life and prevent irreversible damage, MCT supplementation with a diet containing minimal carbohydrates is recommended promptly after the diagnosis.Citrin deficiency (CD) is a hereditary disorder caused by SLC25A13 mutations that manifests as neonatal intrahepatic cholestasis caused by CD (NICCD), failure to thrive and dyslipidemia caused by CD (FTTDCD), and adult-onset type 2 citrullinemia (CTLN2). Citrin, an aspartate-glutamate carrier primarily expressed in the liver, is a component of the malate-aspartate shuttle, which is essential for glycolysis. Citrin-deficient hepatocytes have primary defects in glycolysis and de novo lipogenesis and exhibit secondarily downregulated PPARα, leading to impaired β-oxidation. They are unable to utilize glucose and free fatty acids as energy sources, resulting in energy deficiencies. Medium-chain triglyceride (MCT) supplements are effective for treating CD by providing energy to hepatocytes, increasing lipogenesis, and activating the malate-citrate shuttle. However, patients with CD often exhibit growth impairment and irreversible brain and/or liver damage. To improve the quality of life and prevent irreversible damage, MCT supplementation with a diet containing minimal carbohydrates is recommended promptly after the diagnosis. Citrin deficiency (CD) is a hereditary disorder caused by SLC25A13 mutations that manifests as neonatal intrahepatic cholestasis caused by CD (NICCD), failure to thrive and dyslipidemia caused by CD (FTTDCD), and adult-onset type 2 citrullinemia (CTLN2). Citrin, an aspartate-glutamate carrier primarily expressed in the liver, is a component of the malate-aspartate shuttle, which is essential for glycolysis. Citrin-deficient hepatocytes have primary defects in glycolysis and de novo lipogenesis and exhibit secondarily downregulated PPARα, leading to impaired β-oxidation. They are unable to utilize glucose and free fatty acids as energy sources, resulting in energy deficiencies. Medium-chain triglyceride (MCT) supplements are effective for treating CD by providing energy to hepatocytes, increasing lipogenesis, and activating the malate-citrate shuttle. However, patients with CD often exhibit growth impairment and irreversible brain and/or liver damage. To improve the quality of life and prevent irreversible damage, MCT supplementation with a diet containing minimal carbohydrates is recommended promptly after the diagnosis. |
| ArticleNumber | 2595-23 |
| Author | Hayasaka, Kiyoshi |
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| Keywords | medium-chain triglycerides neonatal intrahepatic cholestasis caused by citrin deficiency citrin adult-onset type 2 citrullinemia SLC25A13 |
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| References_xml | – reference: 36. Yagi Y, Saheki T, Imamura Y, et al. The heterogeneous distribution of argininosuccinate synthetase in the liver of type II citrullinemic patients. Its specificity and possible clinical implications. Am J Clin Pathol 89: 735-741, 1998. – reference: 13. Contreras AV, Torres N, Tovar AR. PPAR-α as a key nutritional and environmental sensor for metabolic adaptation. Adv Nutr 4: 439-445, 2013. – reference: 11. Hellerstein MK. De novo lipogenesis in humans: metabolic and regulatory aspects. Eur J Clin Nutr 53: S53-S65, 1999. – reference: 3. Miyakoshi T, Takahashi T, Kato M, Watanabe M, Ito C. Abnormal citrulline metabolism of Inose-type hepatocerebral disease. Shinkei Kagaku (Bull Jpn Neurochem) 7: 88-91, 1968 (in Japanese). – reference: 2. Saheki T, Song YZ. Citrin deficiency. In: GeneReviews® [Internet]. [cited 2023 Jul 1]. Adam MP, Ardinger HH, Pagon RA, et al., Eds. University of Washington, Seattle, 2017. https://www.ncbi.nlm.nih.gov/books/NBK1181/ – reference: 7. Tavoulari S, Lacabanne D, Thangaratnarajah C, Kunji ERS. Pathogenic variants of the mitochondrial aspartate/glutamate carrier causing citrin deficiency. Trends Endocrinol Metab 33: 539-553, 2022. – reference: 32. Häberle J, Pauli S, Linnebank M, et al. Structure of the human argininosuccinate synthetase gene and an improved system for molecular diagnostics in patients with classical and mild citrullinemia. Hum Genet 110: 327-333, 2002. – reference: 34. Eguchi K, Yonezawa M, Mitsui Y, Hiramatsu Y. Developmental changes of glutamate dehydrogenase activity in rat liver mitochondria and its enhancement by branched-chain amino acids. Biol Neonate 62: 83-88, 1992. – reference: 25. Watanabe Y, Numakura C, Tahara T, et al. Diabetes mellitus exacerbates citrin deficiency via glucose toxicity. Diabetes Res Clin Pract 164: 108159, 2020. – reference: 4. Palmieri L, Pardo B, Lasorsa FM, et al. 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| SubjectTerms | adult-onset type 2 citrullinemia Brain injury Calcium-Binding Proteins - deficiency Calcium-Binding Proteins - genetics Carbohydrates Cholestasis Cholestasis, Intrahepatic - etiology Cholestasis, Intrahepatic - genetics Cholestasis, Intrahepatic - therapy citrin Citrullinemia - diagnosis Citrullinemia - genetics Citrullinemia - therapy Dietary Supplements Dyslipidemia Glycolysis Hepatocytes Hepatocytes - metabolism Humans Lipogenesis Liver medium-chain triglycerides Mitochondrial Membrane Transport Proteins - genetics Mutation neonatal intrahepatic cholestasis caused by citrin deficiency Neonates Organic Anion Transporters - deficiency Organic Anion Transporters - genetics Quality of life SLC25A13 Triglycerides - metabolism |
| Title | Pathogenesis and Management of Citrin Deficiency |
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