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  • Updated 08.04.2019
  • Released 03.30.1995
  • Expires For CME 08.04.2022

Citrullinemias types 1 and 2


This article includes discussion of citrullinemia types 1 and 2, classic citrullinemia, citrullinemia type 1 (CTLN1), argininosuccinate synthetase 1 deficiency, citrullinuria, neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), citrullinemia type 2 (CTLN2), 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). 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 because 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 2006; 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).

Key points

• Citrullinemia type 1 is a rare urea cycle disorder that causes hyperammonemia, neurologic sequelae, and intellectual disability.

• Disease manifestations most often occur within the first days of life (early onset ≤ 28 days) and less commonly after the neonatal period (late onset > 28 days).

• Therapy is based on principles of acute and long-term management involving diet and antihyperammonemic pharmacotherapy.

• Neurologic outcome depends primarily on noninterventional parameters, eg, intrinsic disease severity (reflected by onset type and initial peak plasma ammonium concentration during first metabolic decompensation). The impact of interventional parameters, eg, diagnostic and therapeutic interventions, on clinical outcome remains to be elucidated.

• Citrullinemia type 2 is common in East Asians and usually presents in adults with hyperammonemia and neuropsychiatric disease. It may also cause neonatal/infantile cholestatic liver disease without hyperammonemia, which is mostly transient.

Historical note and terminology

Citrullinemia was first reported in 1962 (69). 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 1 deficiency" to denote its enzyme defect. Heterogeneity is seen clinically, biochemically, as well as 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).

Until the development of modern methods of pharmacologic therapy, the disease course was uniformly lethal. Citrullinemia type 1 is genetically heterogeneous, and there has been a variety of different clinical phenotypes in patients with partial residual activity of the defective enzyme.

Citrullinemia type 2 occurs frequently in China and Japan. It 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, but the most common presentation is 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 (52). Multiple case reports established an epidemiological link between citrin deficiency and hepatocellular carcinoma; however, the underlying pathophysiology is not well understood (19).

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