General description

Citrin deficiency is an autosomal recessive metabolic disorder caused by mutations in the SLC25A13 gene, which encodes citrin, a protein involved in maintaining the balance of NADH between the cytoplasm and mitochondria. This condition presents distinct clinical stages, including neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) in infancy and adult-onset type II citrullinemia (CTLN2) later in life.

NICCD manifests in neonates as transient jaundice and intrahepatic cholestasis, which often resolves spontaneously. However, a small number of individuals progress to develop CTLN2 in adulthood, typically after 20–30 years of a compensatory phase during which metabolic disturbances remain subclinical. During this phase, patients often exhibit unique dietary preferences, avoiding carbohydrates while favoring high-protein and high-fat foods, particularly soy-based products like tofu and peanuts. This adaptation appears to help mitigate metabolic imbalances caused by excessive cytoplasmic NADH accumulation. Alcohol consumption is generally avoided, as it can act as a trigger for metabolic decompensation.

CTLN2 is characterized by severe hyperammonemia, leading to encephalopathy with symptoms such as altered consciousness, disorientation, and psychiatric disturbances. The condition arises from impaired activity of argininosuccinate synthetase (ASS), a key enzyme in the urea cycle, due to citrin deficiency. This disruption results in elevated ammonia and citrulline levels, along with fatty liver. While initially thought to predominantly affect young males, CTLN2 has been reported in patients as old as their 70s. Environmental or lifestyle changes, such as the loss of dietary habits established during the compensatory phase, are hypothesized to precipitate metabolic crises and the onset of CTLN2 symptoms.