Clinical characteristics: 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). Often citrin deficiency is characterized by strong preference for protein-rich and/or lipid-rich foods and aversion to carbohydrate-rich foods.
Diagnosis/testing: The diagnosis of citrin deficiency is established in an individual with characteristic biochemical findings (in general, increased blood or plasma concentration of ammonia, plasma or serum concentration of citrulline and arginine, plasma or serum threonine-to-serine ratio, and serum concentration of pancreatic secretory trypsin inhibitor) and identification of biallelic pathogenic variants in SLC25A13.
Management: Treatment of manifestations: 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. Prevention of primary manifestations: Lipid and protein-rich low-carbohydrate diet. Surveillance: Periodic measurement of plasma concentration of ammonia and citrulline, and serum concentration of PSTI for all phenotypes associated with citrin deficiency. Follow up of children who have had NICCD for the laboratory and physical findings of FTTDCD. Agents/circumstances to avoid: Low-protein high-carbohydrate diets; glycerol and fructose infusions for brain edema; alcohol; acetaminophen and rabeprozole. Evaluation of relatives at risk: It is appropriate to identify affected sibs of a proband so that appropriate dietary management can be instituted before symptoms occur.
Genetic counseling: Citrin deficiency is inherited in an autosomal recessive manner. When both parents are carriers of an SLC25A13 pathogenic variant, each sib of an affected individual has, at conception, a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. When one parent is a carrier and the other parent has two SLC25A13 pathogenic variants, each sib of an affected individual has, at conception, a 50% chance of being affected and a 50% chance of being an asymptomatic carrier. Testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the SLC25A13 pathogenic variants in the family are known.
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