Pathogenesis and pathophysiology of citrullinemia

• Published in: Japanese Journal of Clinical Chemistry Vol. 36; no. 1; pp. 40 - 48
• Main Authors: Kobayashi, Keiko, Saheki, Takeyori
• Format: Journal Article
• Language: Japanese
• Published: Japan Society of Clinical Chemistry 2007; 一般社団法人 日本臨床化学会
• Subjects: citrin; citrullinemia; CTLN1; CTLN2; hyperammonemia; mitochondrial aspartate glutamate carrier; NICCD; アスパラギン酸・グルタミン酸ミトコンドリア膜輸送体; シトリン; 高アンモニア血症
• ISSN: 0370-5633; 2187-4077
• DOI: 10.14921/jscc1971b.36.1_40

Citrulline is generally a non-proteineous amino acid and an intermediate for arginine and urea syntheses. Citrullinemia is caused by a deficiency of argininosuccinate synthetase (ASS) and a deficiency of mitochondrial aspartate glutamate carrier (AGC). We discovered SLC25A13 as the causative gene of adult-onset type II citrullinemia (CTLN2), which encodes citrin, and established a disease entity of citrin deficiency. Citrin deficiency results in not only CTLN2 but also neonatal cholestatic hepatitis (NICCD). NICCD patients suffer from a variety of symptoms such as citrullinemia, prolonged jaundice, hypoglycemia, galactosemia and hypoproteinemia. Citrin, as the liver-type AGC, playsa role not only in urea, protein and nucleotide biosynthetic pathways by transporting aspartate from mitochondria to cytosol, but also in aerobic glycolysis by transporting NADH reducing equivalent from cytosol to mitochondria as a member of malate aspartate shuttle, which is probably the reason why citrin deficiency patients suffer from a variety of symptoms. The most critical point so far we have known concerning the therapy is that carbohydrate intake or administration may deteriorate the symptoms.