Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)

Condition: Adult‑onset type II citrullinemia
Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The prevalence of adult‑onset type II citrullinemia (CTLN2) in Japan is 1 in 100,000-230,000. Until recently, citrin deficiency was thought to be restricted to Japan; however it is now recognized to be pan ethic with individuals in Israel, Pakistan, the United States, the United Kingdom, China, and the Czech Republic.
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Clinical Features
(Signs / symptoms)
Citrin deficiency can manifest in newborns as neonatal intrahepatic cholestasis caused by
citrin deficiency (NICCD) characterized by cholestasis and variable hepatic dysfunction with some children developing liver cirrhosis. Citrin deficiency can also manifest in older children as growth retardation and abnormalities of serum lipid concentrations characterized as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD). CTLN2 can manifest in children or adults as recurrent hyperammonemia with neuropsychiatric symptoms.
CTLN2 is associated with decreased activity of argininosuccinate synthase activity and protein in the liver but normal levels in other tissues such as the kidney, brain, and fibroblasts. Manifestations of CTLN2 are sudden and may resemble those of encephalopathy or urea cycle disorders and are often provoked by alcohol and surgery intake, medication and/or surgery. Symptoms may include nocturnal delirium, aggression, irritability, hyperactivity, delusions, disorientation, restlessness, drowsiness, loss of memory, flapping tremor, convulsive seizures, and coma due to hyperammonemia. Death may result from brain edema. Complications occurring in more than 10% of individuals include: pancreatitis, hyperlipidemia, fatty liver, and hepatoma. Intrahepatic cholestasis may occur in rare cases; however these individuals may have had signs of NICCD in early childhood.
CTLN2 patients are often characterized by fondness for protein-rich and/or lipid-rich foods and aversion to carbohydrate-rich foods. Most individuals are thin with a BMI lower than 20 in 90% and below 17 in 40% of individuals.
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Natural History
(Important subgroups & survival / recovery)
Symptoms of NICCD are generally not severe and symptoms often resolve by age one with appropriate treatment including vitamin supplementation and modified formula; however, in some rare cases infants succumb to infection and liver cirrhosis and others require liver transplantation. Onset of FTDCD is typically around age one to two years. One or more decades later, some individuals with NICCD or FTTDCD may develop CTLN2; however individuals with CTLN2 may or may not have a prior history of NICCD or FTTDCD. The proportion of persons with NICCD or FTTDCD that evolves into CTLN2 is unknown. Historically, the time between NICCD and CTLN2 has been considered a silent, apparently healthy phase. However, laboratory and clinical abnormalities have been identified during this time and characterized as FTTDCD.
Onset of CTLN2 is sudden, with a mean age of onset of 34.4 years with a range of 11-79 years. The male to female ratio of CTLN is 2.4 to 1; the reasons for unequal expression of the phenotype is unknown. Some patients may present with nonalcoholic hepatic steatosis or may develop hepatic fibrosis or hepatocellular carcinoma. In some cases, rapid progression can lead to brain edema and death within a few years of onset if liver transplantation is not possible.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extent of disease and needs of an individual diagnosed with a phenotype of CTLN2 individuals should undergo an investigation of the carbohydrate, protein, and lipid composition of their diet and a medical genetics consultation. (Tier 4)
To prevent hyperammonemia a diet rich in protein and lipids and low in carbohydrates is recommended. A low-protein/high-caloric (high carbohydrate) diet is harmful for individuals with CTLN2. A high carbohydrate diet may increase NADH production, disturb urea synthesis, and stimulate the citrate-malate shuttle, resulting in hyperammonemia, fatty liver, and hypertriglyceridemia. (Tier 3)
Arginine and sodium pyruvate administration may be effective in preventing hyperammonemic crises (by reducing blood ammonia concentrations) and fatty liver, thereby delaying the need for liver transplantation. (Tier 4)
To date the most successful therapy for symptomatic patients has been liver transplantation which prevents episodic hyperammonemic crises, corrects the metabolic disturbances, and eliminates preferences for protein rich foods. Nearly all individuals with CTLN2 required liver transplantation in the past; however the introduction of arginine and sodium pyruvate has altered the situation. (Tier 3)
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No evidence was identified on the effectiveness of dietary treatment prior to the onset of symptoms of CTLN2.
A review of CTLN2 case reports identified 77 cases with a mean age of onset was 34.1 years (range 12-60 years). 21 patients were treated with liver transplantation and all showed good prognosis with a survival rate of 100%. 56 patients received conservative treatment (without liver transplantation) and 29 died within a few years of onset (48% survival rate). Survival of patients treated with conservative medical treatment improved to 76.5% when limited to patients treated after 2003 compared to 39.5% survival prior to 2002. This improvement was attributed to the identification of the SLC25A13 gene as the cause of CTLN2 and development of more effective conservative therapy (arginine with carbohydrate-restricted diet). In addition, recent case reports have found that arginine and sodium pyruvate administration combined with a carbohydrate-restricted diet may be effective therapy for CTLN2. (Tier 5)
Increases in plasma citrulline concentration and serum pancreatic secretory trypsin inhibitor (PSTI) suggest onset of CTLN2 and should prompt initiation of treatment. It is recommended that the following be measured every several months:
- Plasma ammonia concentration (especially in the evening or 2 hours after feeding)
- Plasma citrulline concentration
- Serum PSTI concentration. (Tier 3)
Family Management
It is appropriate to clarify the genetic status of at risk asymptomatic sibs of a proband for citrin deficiency so that appropriate dietary management of infants (discontinuation of breast feeding and introduction of lactose free and/or MCT-enriched formulas) can be instituted before symptoms occur. Because asymptomatic or presymptomatic individuals with citrin deficiency do not always show biochemical abnormalities, definitive diagnosis of at risk relatives such as sibs would depend heavily on the molecular genetic findings in SLC25A13 in the index case. If both SLC25A13 pathogenic variants in the index case have been identified, molecular genetic testing can be used reliably. If only one SLC25A13 pathogenic variant is ascertained in the index case, it may not be feasible to definitively exclude the diagnosis in at risk relatives who have the one identified pathogenic variant. In such cases, serial clinical and biochemical assessment will be needed over time to confirm or rule out the diagnosis. (Tier 4)
Circumstances to Avoid
Severe brain edema treated with glycerol-containing osmotic agents (the conventional treatment for hyperammonemia and brain edema) has resulted in continued deterioration and is contraindicated in those with CTLN2. Degradation of large amounts of glycerol and fructose generates NADH in the liver cytosol, which may disturb liver function and produce toxic substances. Infusion of high concentration glucose may also exacerbate hyperammonemia. Mannitol infusion appears to be safer. A retrospective study of 3 patients with CTLN2 treated for brain edema at one institute and an additional 11 patients previously reported found that all 12 patients treated with 10% glycerol (with or without 20% mannitol) died due to rapidly deteriorating encephalopathy and brain edema while the 2 patients who received only 20% D-mannitol recovered with the disappearance of brain edema. (Tier 3)
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Drinking alcohol can trigger the onset of CTLN2 because alcohol dehydrogenase (ADH) generates NADH in the cytosol of the liver. (Tier 4)
Acetaminophen and rabeprozole may trigger CTLN2. (Tier 3)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Recessive
Prevalence of Genetic Mutations
In Japan, the frequency of homozygotes or compound heterozygotes for SLC25A13 pathogenic variants is calculated to be 1:17,000-21,000. Carrier or heterozygote rates have been estimated as 1:65-1:67. The estimated frequency in Korea is 1 in 50,000 and 1 in 17,000 in China with an estimated carrier frequency of 1:65 in China and 1:112 in Korea. (Tier 3)
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Relative Risk
(Include any high risk racial or ethnic subgroups)
No information on the penetrance of developing CTLN2 was identified.
While the male-to-female ration of NICCD is roughly equal (73:80) the unequal male-to-female ratio of CTLN2 (2.4:1) suggests that among individuals with biallelic SLC25A13 variants, females are more resistant to the CTLN2 phenotype than males. (Tier 3)
Occasionally a parent of a child with NICCD may have two SLC25A13 pathogenic variants without severe symptoms of CTLN2, a finding in two of 48 fathers and one of 54 mothers tested in 163 Japanese families with NICCD. (Tier 3)
One study of Japanese patients found that 17 of 19 patients (89%) with genetically confirmed CTLN2 had hepatic steatosis. Four patients (21%) had been diagnosed with nonalcoholic fatty liver disease before the appearance of neuropsychologic symptoms. (Tier 3)
No information on relative risk was identified.
No significant correlation between SLC25A13 pathogenic variant types and decreased level of hepatic enzyme ASS activity/protein or age of onset in individuals with CTLN2 is observed. (Tier 3)
4. What is the Nature of the Intervention?
Nature of Intervention
Identified interventions include liver transplantation and/or dietary therapy, ongoing blood monitoring, and avoidance of possible triggers (e.g., medications and alcohol).
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
More than 30% of individuals with CTLN2 have been misdiagnosed initially as having epileptic seizures and/or a psychological disorder (e.g., depression, schizophrenia); others may be diagnosed as having diseases such as hepatoma, pancreatitis, and hyperlipidemia. (Tier 4)

Final Consensus Scores
Outcome / Intervention Pair
Nature of the
Hepatic encephalopathy / Dietary modification with arginine and sodium pyruvate supplementation
3 1
Liver failure / Liver transplantation
1. This dietary modification was considered less burdensome than PKU etc
To see the scoring key, please go to:
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Citrullinemia, type ii, adult-onset; ctln2. MIM: 603471: 2016 Nov 10. World Wide Web URL:
2. K Kobayashi, T Saheki, YZ Song. Citrin deficiency. 2005 Sep 16 [Updated 2014 Jul 31]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from:
3. Kimura N, Kubo N, Narumi S, Toyoki Y, Ishido K, Kudo D, Umehara M, Yakoshi Y, Hakamada K. Liver transplantation versus conservative treatment for adult-onset type ii citrullinemia: our experience and a review of the literature. Transplant Proc. (2013) 45(9):3432-7.
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