SLC25A13 gene

Also known as: Citrin deficiency; Cholestasis, neonatal intrahepatic, caused by citrin deficiency (NICCD); Citrullinemia, type II, neonatal-onset, with or without failure to thrive and dyslipidemia (FTTDCD); CTLN2


1. The disease:

Citrin deficiency can manifest in newborns or infants as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), in older children as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and in adults as recurrent hyperammonemia with neuropsychiatric symptoms in citrullinemia type II (CTLN2). It is like a clinical spectrum. Often citrin deficiency is characterized by strong preference for protein-rich and/or lipid-rich foods and aversion to carbohydrate-rich foods. Lack of early signs or symptoms does not exclude the diagnosis.

2. The Symptoms:

  • NICCD: Children younger than one year of age have a history of low birth weight with growth restriction and transient intrahepatic cholestasis, hepatomegaly, diffuse fatty liver, hepatic fibrosis, variable liver dysfunction, hypoproteinemia, decreased coagulation factors, hemolytic anemia, and/or hypoglycemia. NICCD is generally not severe and symptoms often resolve by age one year with appropriate treatment, although liver transplantation has been required in rare instances.
  • FTTDCD: Beyond age one year, many children with citrin deficiency develop a protein-rich and/or lipid-rich food preference and aversion to carbohydrate-rich foods. Clinical abnormalities may include growth restriction, hypoglycemia, pancreatitis, severe fatigue, anorexia, and impaired quality of life. Laboratory changes are dyslipidemia, increased lactate-to-pyruvate ratio, higher levels of urinary oxidative stress markers, and considerable deviation in tricarboxylic acid (TCA) cycle metabolites. One or more decades later, some individuals with NICCD or FTTDCD develop CTLN2.
  • CTLN2: Presentation is sudden and usually between ages 20 and 50 years. Manifestations are recurrent hyperammonemia with neuropsychiatric symptoms including nocturnal delirium, aggression, irritability, hyperactivity, delusions, disorientation, restlessness, drowsiness, loss of memory, flapping tremor, convulsive seizures, and coma. Symptoms are often provoked by alcohol and sugar intake, medication, and/or surgery. Affected individuals may or may not have a prior history of NICCD or FTTDCD.

3. Actions to take in case of early diagnosis:

  • Infants with a positive genetic test (having 2 pathogenic variants or 2 copies of a single pathogenic variant in the gene SLC25A13) should continue breastfeeding and avoid baby formulas. Early treatment is essential in preventing chronic symptoms.
  • Biochemical correlation is essential for confirming diagnosis with plasma quantitative amino acids, ammonia levels and urinary organic acids. Biochemical NBS with tandem mass spectrometry can also help (high citrulline, but some cases can be missed).
  • CTLN2 is a lifelong disease that requires lifetime management and regular follow-up with a metabolic physician and dietician, a part from a multidisciplinary approach to care.
  • NICCD: Supplement diet with fat-soluble vitamins and use of lactose-free and medium-chain triglyceride MCT-enriched formula. FTTDCD: In addition to dietary treatment, administration of sodium pyruvate may improve growth. CTLN2: Liver transplantation prevents hyperammonemic crises, corrects metabolic disturbances, and eliminates preferences for protein-rich foods; arginine administration decreases blood ammonia concentration and reduced calorie/carbohydrate intake; increased protein intake lessens hypertriglyceridemia. Use of arginine, sodium pyruvate, and MCT oil may delay the need for liver transplantation.
  • Agents/circumstances to avoidLow-protein high-carbohydrate diets; glycerol and fructose infusions for brain edema; alcohol; acetaminophen and rabeprozole.
  • Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.

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