The therapeutic landscape of citrin deficiency

• Published in: Journal of inherited metabolic disease 2024-11, Vol.47 (6), p.1157-1174
• Main Authors: Vuković, Toni, Kuek, Li Eon, Yu, Barbara, Makris, Georgios, Häberle, Johannes
• Format: Article
• Language: English
• Subjects: Amino acids; Bioenergetics; Calcium-Binding Proteins; Carbohydrates; Cholestasis; Citrin deficiency; Citrullinemia - genetics; Citrullinemia - therapy; Food availability; Food preferences; Food selection; Gene therapy; Gluconeogenesis; Glutamic acid transporter; Glycolysis; Hepatocytes; Humans; Hyperammonemia; Immunosuppressive agents; Lipogenesis; Liver - metabolism; Liver diseases; Liver Transplantation; malate‐aspartate‐shuttle; Medical treatment; medium‐chain triglycerides; Metabolic pathways; Mitochondrial Membrane Transport Proteins - genetics; mRNA; Organic Anion Transporters - deficiency; Organic Anion Transporters - genetics; Original; Phenotypes; Pyruvic acid; SLC25A13; Sodium pyruvate; Triglycerides; Triglycerides - metabolism; Ureagenesis; Ursodeoxycholic acid
• ISSN: 0141-8955; 1573-2665; 1573-2665
• DOI: 10.1002/jimd.12768

Citrin deficiency (CD) is a recessive, liver disease caused by sequence variants in the SLC25A13 gene encoding a mitochondrial aspartate–glutamate transporter. CD manifests as different age‐dependent phenotypes and affects crucial hepatic metabolic pathways including malate–aspartate‐shuttle, glycolysis, gluconeogenesis, de novo lipogenesis and the tricarboxylic acid and urea cycles. Although the exact pathophysiology of CD remains unclear, impaired use of glucose and fatty acids as energy sources due to NADH shuttle defects and PPARα downregulation, respectively, indicates evident energy deficit in CD hepatocytes. The present review summarizes current trends on available and potential treatments for CD. Baseline recommendation for CD patients is dietary management, often already present as a self‐selected food preference, that includes protein and fat‐rich food, and avoidance of excess carbohydrates. At present, liver transplantation remains the sole curative option for severe CD cases. Our extensive literature review indicated medium‐chain triglycerides (MCT) as the most widely used CD treatment in all age groups. MCT can effectively improve symptoms across disease phenotypes by rapidly supplying energy to the liver, restoring redox balance and inducing lipogenesis. In contrast, sodium pyruvate restored glycolysis and displayed initial preclinical promise, with however limited efficacy in adult CD patients. Ursodeoxycholic acid, nitrogen scavengers and L‐arginine treatments effectively address specific pathophysiological aspects such as cholestasis and hyperammonemia and are commonly administered in combination with other drugs. Finally, future possibilities including restoring redox balance, amino acid supplementation, enhancing bioenergetics, improving ureagenesis and mRNA/DNA‐based gene therapy are also discussed.