Citrin, encoded by SLC25A13, constitutes the
malate-
aspartate shuttle, the main
NADH-shuttle in the liver.
Citrin deficiency causes neonatal
intrahepatic cholestasis (
NICCD) and adult-onset type II
citrullinemia (CTLN2).
Citrin deficiency is predicted to impair hepatic glycolysis and de novo lipogenesis, resulting in hepatic energy deficit. Secondary decrease in hepatic
argininosuccinate synthetase (ASS1) expression has been considered a cause of
hyperammonemia in CTLN2. We previously reported that medium-chain
triglyceride (MCT) supplement
therapy with a low-
carbohydrate formula was effective in CTLN2 to prevent a relapse of hyperammonemic
encephalopathy. We present the
therapy for six CTLN2 patients. All the patients' general condition steadily improved and five patients with hyperammonemic
encephalopathy recovered from unconsciousness in a few days. Before the treatment, plasma
glutamine levels did not increase over the normal range and rather decreased to lower than the normal range in some patients. The treatment promptly decreased the blood
ammonia level, which was accompanied by a decrease in plasma
citrulline levels and an increase in plasma
glutamine levels. These findings indicated that
hyperammonemia was not only caused by the impairment of ureagenesis at ASS1 step, but was also associated with an impairment of
glutamine synthetase (GS)
ammonia-detoxification system in the hepatocytes. There was no decrease in the GS expressing hepatocytes. MCT supplement with a low-
carbohydrate formula can supply the energy and/or substrates for ASS1 and GS, and enhance
ammonia detoxification in hepatocytes. Histological improvement in the hepatic steatosis and ASS1-expression was also observed in a patient after long-term treatment.