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. Children younger than age one year have a history of low birth weight with growth restriction and transient intrahepatic cholestasis, hepatomegaly, diffuse fatty liver, and parenchymal cellular infiltration associated with hepatic fibrosis, variable liver dysfunction, hypoproteinemia, decreased coagulation factors, anemia, and/or hypoglycemia. NICCD is generally not severe, and clinical manifestations are often resolved by age one year with appropriate treatment, although liver failure may still occur; liver transplantation has been required in rare instances. 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 poor weight gain, growth deficiency, severe fatigue, anorexia, and impaired quality of life. Laboratory changes are dyslipidemia, recurrent hypoglycemia, increased lactate-to-pyruvate ratio, higher levels of urinary oxidative stress markers, and considerable deviation in tricarboxylic acid cycle metabolites. One or more decades later, some adults with NICCD or FTTDCD may progress and develop features of CTLN2. Presentation is sudden and usually between ages 20 and 50 years. Clinical manifestations include recurrent hyperammonemia with neuropsychiatric (aggression, irritability, restlessness, hyperactivity, delusions, nocturnal delirium) and neurologic manifestations (flapping tremors, memory loss, disorientation, drowsiness, convulsive seizures, coma). Clinical manifestations are often caused by alcohol and sugar intake, medication, and/or surgery. Complications include severe liver steatosis and pancreatitis. Affected individuals may or may not have a prior history of NICCD or FTTDCD.

DIAGNOSIS/TESTING: The diagnosis of citrin deficiency is established in an individual with characteristic biochemical analytes (increased blood or plasma concentration of ammonia, plasma or serum concentration of citrulline and arginine, plasma or serum threonine-to-serine ratio) and biallelic pathogenic variants in identified by molecular genetic testing.

MANAGEMENT

NICCD: lactose-free and medium-chain triglyceride (MCT)-enriched formula supplemented with fat-soluble vitamins. FTTDCD: protein- and lipid-rich, low-carbohydrate diet; in addition to dietary treatment, administration of sodium pyruvate and MCT oil may improve growth. CTLN2: reduced calorie/carbohydrate intake and increased protein intake lessens hypertriglyceridemia. Sodium pyruvate can increase weight and decrease frequency of hyperammonemia; arginine administration decreases blood ammonia concentration; MCT oil can decrease frequency of hyperammonemia; use of arginine, sodium pyruvate, and MCT oil may delay the need for liver transplantation; liver transplantation prevents hyperammonemic crises, corrects metabolic disturbances, and eliminates preferences for protein-rich foods. Periodic measurement of plasma concentration of ammonia and citrulline for all phenotypes associated with citrin deficiency. Assess growth and development throughout childhood; assessment of liver and pancreatic function as clinically indicated; neuropsychologic testing and quality of life assessment as clinically indicated; complete blood count and ferritin as clinically indicated. Low-protein and high-carbohydrate diets; glycerol, fructose, and glucose infusions due to risk of brain edema; alcohol. 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. If both parents are known to be heterozygous for an pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants, a 50% chance of inheriting one pathogenic variant and being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. If one parent is known to be heterozygous for an pathogenic variant and the other parent is known to have biallelic pathogenic variants, each sib of an affected individual has at conception a 50% chance of inheriting biallelic pathogenic variants and a 50% chance of inheriting one pathogenic variant. In general, sibs who inherit biallelic pathogenic variants will be affected and have clinical manifestations of citrin deficiency similar to those of the proband in the family. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.