Citrullinemias types 1 and 2

Roland Posset MD (Dr. Posset of the University Center for Child and Adolescent Medicine in Heidelberg has no relevant financial relationships to disclose.)
Georg F Hoffmann MD (Dr. Hoffmann of the University Center for Child and Adolescent Medicine in Heidelberg has no relevant financial relationships to disclose.)
Barry Wolf MD PhD, editor. (Dr. Wolf of Henry Ford Hospital has no relevant financial relationships to disclose.)
Originally released March 30, 1995; last updated June 7, 2016; expires June 7, 2019

This article includes discussion of citrullinemia types 1 and 2, classic citrullinemia, citrullinemia type 1 (CTLN1), argininosuccinate synthetase deficiency, citrullinuria, neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), citrullinemia type 2, and citrin deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


Citrullinemia is a term for 2 different inherited defects of the urea cycle: deficiency of the enzyme argininosuccinate synthetase (classic citrullinemia, citrullinemia type 1, or CTLN1) or of the deficient amino acid transporter citrin (citrullinemia type 2 or CTLN2).

Image: Urea cycle defects causing citrullinemia
Citrullinemia type 1 can present at any age with acute neonatal- or early-onset (28 days or earlier) hyperammonemic coma or late-onset (later than 28 days) disease manifestation. Citrullinemia type 2 is common in East Asians and usually presents in adults with hyperammonemia and neuropsychiatric disease. It may also cause neonatal or infantile cholestatic liver disease without hyperammonemia, which is usually transient. However, some patients may have a progressive course with continued failure to thrive and dyslipidemia, and a few may develop chronic or fatal liver disease.

Markedly elevated plasma citrulline is the hallmark of these disorders. Diagnosis is established by enzymatic or mutation analysis. Treatment of citrullinemia type 1 consists of a protein-restricted diet, ammonia scavenger drugs, and L-arginine supplementation. Liver transplantation cures recurrent hyperammonemic episodes, but will not restore irreversible neurologic sequelae. Effective treatment of citrullinemia type 2 is very different as patients with citrullinemia type 2 do better on a high-protein and low-carbohydrate diet.

Currently, international networks for rare metabolic diseases (UCDC, E-IMD, JUCDC) aim to more completely describe the initial and evolving clinical phenotype of urea cycle disorders such as citrullinemia type 1 and type 2. Furthermore, they want to determine if the natural disease course can be favorably modulated by diagnostic and therapeutic interventions. These networks collect systematic data to improve clinical knowledge, develop guidelines, and provide patients and professionals with reliable data on disease manifestations and complications as well as long-term outcomes of urea cycle disorders. These networks include the Urea Cycle Disorders Consortium (UCDC), established in 2003; the European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD), established in 2011; and the Japanese Urea Cycle Disorders Consortium (JUCDC), established in 2012 (Summar et al 2014).

Historical note and terminology

Citrullinemia was first reported in 1962 (McMurray et al 1962). Its name derives from the marked elevation of L-citrulline in blood of affected individuals. This disorder has also been called "citrullinuria" because of the increased excretion of L-citrulline in urine and "argininosuccinic acid (argininosuccinate) synthetase deficiency" to denote its enzyme defect. Heterogeneity is seen clinically, biochemically, and at the molecular level.

Citrullinemia type 1 is similar to all urea cycle disorders and presents mostly with severe neonatal onset (with very little to no residual enzyme activity in all organs) or as a late-onset form (with reduced enzyme activity in all organs). The aim of newborn screening programs is primarily to allow a good clinical outcome for babies by early diagnosis of treatable disorders (Wilcken 2008). Nevertheless, studies from the E-IMD consortium showed that newborn screening for citrullinemia type 1 is rarely performed in Europe. If newborn screening for citrullinemia type 1 was performed, results of the testing were often not available before the diagnosis was made by selective metabolic investigation for early-onset patients with argininosuccinate synthetase deficiency. Overall, newborn screening helps to identify late-onset urea cycle disorder patients, but is not as useful for early-onset patients. More data are required from a larger and more age-advanced sample to evaluate the long-term benefits of newborn screening for urea cycle disorders (Posset et al 2016). Screening programs have also identified a considerable portion of individuals with mild citrullinemia type 1 and significant residual activities who apparently have virtually no risk for metabolic disease and need no treatment (Lindner et al 2011); we lack extensive scientific evidence if phenotypic mild citrullinemia type 1 patients need continuous dietary or medical treatment (Häberle et al 2002). The key to answering this question might be a systematic follow-up of mild phenotypes, probably representing non-disease (Lindner et al 2011).

Citrullinemia type 2 presents in newborns with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). In older children, citrullinemia type 2 presents with failure to thrive and dyslipidemia and in adults usually between the second and fourth decade of life as recurrent hyperammonemia with neuropsychiatric symptoms. In the latter, onset of symptoms can be rapidly precipitated by medications, surgery, and alcohol consumption (Kobayashi et al 2014). Multiple case reports established an epidemiological link between citrin deficiency and hepatocellular carcinoma; however, the underlying pathophysiology is not well understood (Chanprasert and Scaglia 2015). Citrullinemia type 2 occurs frequently in China and Japan (where 2 mutations account for around 70% of mutant alleles) and is caused by mutations in a calcium-dependent mitochondrial membrane protein named citrin (Kobayashi et al 1999). This inner mitochondrial membrane transporter has been shown to transport aspartate and glutamate (Palmieri et al 2001).

Image: Urea cycle defects causing citrullinemia

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