Citrin deficiency

Citrin deficiency is a rare inherited metabolic disorder caused by mutations in the SLC25A13 gene, which encodes citrin, a mitochondrial aspartate-glutamate carrier predominantly expressed in the liver. Citrin plays a critical role in the urea cycle, gluconeogenesis, and the malate-aspartate shuttle. The disease has two major clinical presentations that can occur at different ages. In infancy, it manifests as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), characterized by prolonged jaundice, cholestasis, hepatomegaly, fatty liver, elevated liver enzymes, citrullinemia, and failure to thrive. NICCD typically resolves by one year of age with dietary management. A second presentation, adult-onset type II citrullinemia (CTLN2), can emerge in adolescence or adulthood with recurrent episodes of hyperammonemia, neuropsychiatric symptoms including confusion, disorientation, abnormal behavior, seizures, and potentially fatal encephalopathy. Some patients experience a milder intermediate phenotype called failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) during childhood. Citrin deficiency primarily affects the liver and central nervous system. Patients characteristically develop a strong preference for protein-rich and lipid-rich foods and an aversion to carbohydrate-rich foods, which is considered a compensatory dietary behavior. Excessive carbohydrate intake can precipitate hyperammonemic crises in affected individuals. Treatment for NICCD includes dietary management with medium-chain triglyceride (MCT)-enriched formulas and avoidance of excessive carbohydrate intake. For CTLN2, liver transplantation is the definitive treatment and may be life-saving in patients with recurrent hyperammonemic episodes unresponsive to medical management. Pharmacological interventions such as sodium pyruvate and arginine supplementation may also be used. The disease is most prevalent in East Asian populations, particularly in Japan, where carrier frequency is estimated at approximately 1 in 65.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

Common questions about Citrin deficiency