Citrullinemia type 2 (CTLN2) is caused by mutations in the SLC25A13 gene. The disease is inherited in an autosomal recessive manner. It may manifest in form of early-onset cholestasis or as adult-onset recurrent encephalopathy. Spontaneous resolution is the most likely outcome in case of neonatal-onset disease, but this form of CTLN2 may also progress to liver failure. Adult-onset CTLN2 is related to recurrent hyperammonemic crises. They may be life-threatening. Affected individuals usually require liver transplantation.
Both neonatal-onset and adult-onset forms of CTLN2 have been described, but there is no definite clinical presentation associated with either one. In fact, some patients may experience minor complaints only, while others fall into coma or succumb to liver failure. CTLN2 patients may present as follows:
It is important to note that homozygosity for pathogenic mutations does not necessarily result in clinical disease .
Newborn screens are an important tool to diagnose CTLN2 in neonates before the onset of clinical symptoms. Abnormal serum amino acid profiles should raise suspicion as to a potential metabolic disease, and CTLN2 patients have been reported to have hypercitrullinemia, hypermethioninemia, and hyperphenylalaninemia. Additionally, serum concentrations of arginine, lysine, threonine, and tyrosine may be augmented. Further studies may reveal hypoproteinemia and decreased levels of coagulation factors, findings that indicate an impairment of protein biosynthesis and liver function. Hepatic transaminases may be elevated. Due to cholestasis, serum bile acid leveles are usually increased. Hypoglycemia and hypergalactosemia have also been reported as possible features of neonatal-onset CTLN2  .
Adults suffering from CTLN2 are usually examined due to an encephalopathic episode. Such an episode is triggered by hyperammonemia, a condition easily verified by measuring serum ammonia levels. Further metabolic anomalies detected in case of adult-onset CTLN2 resemble those described for the neonatal form of the disease.
Blood sample analyses and coagulation studies should be repeated periodically independent of the patient's age in order to anticipate any possible deterioration, progression to liver failure or life-threatening hyperammonemia.
It is important to consider that metabolic profiles of CTLN2 patients differ considerably . Therefore, they may only serve as a first hint on the underlying disease. It is highly recommendable to confirm the suspected diagnosis by means of genetic analyses. Sequencing of the SLC25A13 gene allows for the identification of the causal mutation and can be achieved applying simple and rapid genetic tests .
Infants suffering from CTLN2 are to be kept on a protein-rich, lipid-rich, low-carbohydrate diet . With regards to those presenting with prolonged cholestasis, bile acids may be supplemented to facilitate the digestion and subsequent absorption of lipophilic food components. Ursodeoxycholic acid may be applied to this end . Medium-chain triglyceride-enriched formulas have been recommended to support CTLN2 therapy in such cases and fat-soluble vitamins may be supplemented, too . It is to be kept in mind that an impairment of liver function may give rise to a coagulopathy, and that this condition may be exacerbated by vitamin K deficiency. Further dietary restrictions may be necessary depending on the metabolic anomalies detected in individual cases, e.g, lactose-free formulas are to be fed to prevent hypergalactosemia.
As for those suffering from failure to thrive and dyslipidemia caused by citrin deficiency, dietary adjustments similar to those described for affected neonates should be made. Additional administration of sodium pyruvate may improve growth .
Adult CTLN2 patients often require liver transplantation . To bridge the gap until a transplant becomes available, arginine and sodium pyruvate may be given. These patients should also keep to a low-carbohydrate diet. In isolated cases, adult patients could be maintained on such therapy alone and did not require liver transplantation .
As can be seen, management of CTLN2 differs from that of other urea cycle disorders. Patients are not to be treated with a low-protein diet and metabolic decompensation cannot be corrected administering high amounts of carbohydrates like dextrose  .
Neonatal-onset CTLN2 usually resolves spontaneously within the first year of life. However, disease progression to liver failure requiring liver transplantation in infancy may also occur . Isolated case reports exist about patients who fell ill within the neonatal period or in infancy, and who developed recurrent encephalopathy due to citrin deficiency later on .
Adult-onset CTLN2 is associated with a dismal prognosis. Affected individuals are to be referred for consideration of liver transplantation as soon as possible .
CTLN2 patients are homozygous or compound heterozygous for mutations in the SLC25A13 gene. This gene encodes for member 13 of the solute carrier family 25, an aspartate-glutamate carrier. This carrier localizes to mitochondria and is expressed in different cell types, but the expression of isoform 2 is largely restricted to hepatocytes. This isoform is also called citrin.
The SLC25A13 gene is located on the long arm of chromosome 7. Distinct SLC25A13 mutations have been related to the disease. In detail, 11 mutations account for 95% of the mutant alleles in Japanese patients, who make up the majority of CTLN2 patients . Genotype-phenotype relations have not yet been established .
For a long time, CTLN2 has been thought to almost exclusively affect people of East Asian ancestry. And while Japanese patients still account for the vast majority of CTLN2 patients, the disease has also been described in individuals pertaining to other ethnic groups   . Both genders may be affected. Those suffering from neonatal-onset CTLN2 manifest first symptoms within a few months of life. The patient's age at the appearance of adult-onset CTLN2 varies largely and ranges from adolescence to senility .
In Japan, the incidence of neonatal-onset CTLN2 has been estimated to 1 in 34,000 . The frequency of homozygosity for SLC25A13 mutations is presumably higher, though: For Japan, it has been estimated to 1 in 19,000, for China to 1 in 17,000 or 25,000, for Taiwan to 1 in 38,000, and for Korea to 1 in 10,000 or 50,000  . The disease' incidence is assumed to be significantly lower in non-Asian countries.
SLC25A13 encodes for an aspartate-glutamate carrier mediating the exchange of aspartate for glutamate and a proton across the inner mitochondrial membrane. This carrier is involved in a variety of metabolic processes, e.g., carbohydrate, protein, and nucleotide metabolism, and the urea cycle. Therefore, CTLN2 may be classified as an urea cycle disorder. However, CTLN2 als interferes with gluconeogenesis, glycolysis, galactose metabolism, protein biosynthesis and nucleotide production, and thus, the consequences of citrin deficiency go beyond those of an urea cylce disorder. While patients may develop hyperammonemia in the course of the disease - particularly those suffering from adult-onset CTLN2 -, it is no exclusion criterion. Indeed, hyperammonemia is rarely presented in case of neonatal-onset disease .
Newborn screens should be carried out to detect metabolic anomalies and, in case of positive results, those should prompt further tests to determine their cause  . However, CTLN2 may also go unnoticed in newborn screens . Affected families are therefore recommended to seek genetic counseling. In the first place, genetic analyses need to be carried out on samples obtained from an affected family member to identify the underlying SLC25A13 mutation. Targeted analyses can then be performed to identify carriers and asymptomatic homozygotes who may or may not develop the disease at a later point in time. In fact, dietary adjustments may be sufficient to prevent the onset of symptoms in as-of-yet asymptomatic homozygotes . Prenatal diagnosis is feasible.
CTLN2 is a metabolic disorder resulting from mutations in the SLC25A13 gene. This gene encodes for an aspartate-glutamate carrier whose isoform 2 is also called citrin. Therefore, CTLN2 is also referred to as citrin deficiency. The clinical presentation of CTLN2 is heterogeneous and ranges from neonatal-onset cholestatic liver disease to adult-onset encephalopathy. The following terms refer to distinct forms of CTLN2 :
The intermediate phenotype, failure to thrive and dyslipidemia caused by citrin deficiency, has only recently been defined and is thus not considered in elder literature  . Some authors reserve the term CTLN2 to refer to the adult-onset form of the disease .
Citrullinemia type 2 (CTLN2) is a metabolic disorder inherited in an autosomal recessive manner, i.e., only individuals who inherit defective alleles from both their parents will develop the disease. Even though CTLN2 is a hereditary disease, it is not generally apparent at birth:
As has been mentioned above, the disease is hereditary. It is caused by mutations in the SLC25A13 gene and it is diagnosed upon the identification of such mutations. CTLN2 is usually suspected if preceding biochemical analyses reveal certain metabolic anomalies, e.g., increased serum levels of citrulline or ammonia. Because metabolic anomalies detected in CTLN2 patients may resemble those expected in case of other diseases, it is important to inform the treating physician about all symptoms observed. Seemingly negligible details such as food preferences may be important to distinguish between CTLN2 and other disorders like citrullinemia type 1.