NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Citrullinemia Type I

Synonyms: Argininosuccinate Synthetase Deficiency; ASS Deficiency; Argininosuccinic Acid Synthetase Deficiency; CTLN1; Citrullinemia, Classic

, MD and , MD.

Author Information
, MD
Clinical Lecturer
University of Michigan
Ann Arbor, Michigan
, MD
Active Emeritus Professor of Pediatrics
Director, Biochemical Genetics Laboratory
University of Michigan
Ann Arbor, Michigan

Initial Posting: ; Last Update: January 23, 2014.

Summary

Disease characteristics. Citrullinemia type I (CTLN1) presents as a clinical spectrum that includes an acute neonatal form (the "classic" form), a milder late-onset form, a form without symptoms or hyperammonemia, and a form in which women have onset of severe symptoms during pregnancy or post partum. Distinction between the clinical forms is based on clinical findings and is not clear-cut.

Infants with the acute neonatal form appear normal at birth. Shortly thereafter, they develop hyperammonemia and become progressively lethargic, feed poorly, often vomit, and may develop signs of increased intracranial pressure (ICP). Without prompt intervention, hyperammonemia and the accumulation of other toxic metabolites (e.g., glutamine) result in ICP, increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death. Children with the severe form who are treated promptly may survive for an indeterminate period of time, but usually with significant neurologic deficits.

The late-onset form may be milder than that seen in the acute neonatal form, for unknown reasons. The episodes of hyperammonemia are similar to those seen in the acute neonatal form, but the initial neurologic findings may be more subtle because of the older age of the affected individuals.

Diagnosis/testing. Citrullinemia type I results from deficiency of the enzyme argininosuccinate synthase (ASS), the third step in the urea cycle, in which citrulline is condensed with aspartate to form argininosuccinic acid. Untreated individuals with the severe form of citrullinemia type I have hyperammonemia (plasma ammonia concentration 1000-3000 µmol/L). Plasma quantitative amino acid analysis shows absence of argininosuccinic acid and concentration of citrulline usually greater than 1000 µmol/L (normal: <50 µmol/L). Argininosuccinate synthase enzyme activity, measured in fibroblasts, liver, and in all tissues in which ASS is expressed, is decreased. ASS1 is the only gene in which mutation is known to cause citrullinemia type I.

Management. Treatment of manifestations:

  • Acute management of hyperammonemia involves rapidly lowering plasma ammonia concentration using pharmacologic nitrogen scavenger therapy (sodium benzoate, sodium phenylacetate and arginine) or hemodialysis, if scavenger therapy fails; reversal of catabolism via intravenous glucose infusion and intralipids or protein-free enteral nutrition, if tolerated; and control of intracranial pressure.
  • Chronic management involves lifelong dietary management to maintain plasma ammonia concentration lower than100 µmol/L and near-normal plasma glutamine concentration; oral administration of sodium phenylbutyrate or glycerol phenylbutyrate and; L-carnitine to prevent systemic hypocarnitinemia. Liver transplantation has been reported.

Prevention of secondary complications: Medical attention during intercurrent infections to prevent hyperammonemia.

Surveillance: Routine follow up in a metabolic clinic; monitoring for hyperammonemia and secondary deficiency of essential amino acids; monitoring older individuals for signs of impending hyperammonia (i.e., mood changes, headache, lethargy, nausea, vomiting, refusal to feed, ankle clonus) and elevated plasma glutamine concentration.

Agents/circumstances to avoid: Excess protein intake; exposure to communicable diseases.

Evaluation of relatives at risk: Sibs should be evaluated immediately after birth and placed on a protein-restricted diet until the diagnostic evaluation is complete.

Genetic counseling. Citrullinemia type I is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the disease-causing mutations in the family are known.

Diagnosis

Clinical Diagnosis

Citrullinemia type I (CTLN1) results from deficiency of the enzyme argininosuccinate synthase, the third step in the urea cycle, in which citrulline is condensed with aspartate to form arginosuccinic acid (see Urea Cycle Disorders Overview Figure 1).

Classic neonatal-onset CTLN1 is suspected in infants who have been on a full protein diet and who present in the first week of life with:

  • Hyperammonemia resulting in increasing lethargy, somnolence, refusal to feed, vomiting, and tachypnea or stroke. Initial plasma ammonia concentration in the severe form may be 1000-3000 µmol/L (normal: 40-50 µmol/L).
  • Increased intracranial pressure (secondary to hyperammonemia) resulting in increased neuromuscular tone, spasticity, and ankle clonus.

Milder, adult-onset citrullinemia type I is suspected in individuals with recurrent lethargy and somnolence; intellectual disability; and chronic or recurrent hyperammonemia. In these forms, a lower plasma concentration may be seen than in the classic form (adult upper limit of normal: <35 µmol/L).

Testing

Plasma quantitative amino acid analysis

  • Citrulline. Usually greater than 1000 µmol/L (normal: <50 µmol/L)
  • Argininosuccinic acid. Absent
  • Arginine and ornithine. Low to normal range; see Urea Cycle Disorders Overview Figure 3.
  • Lysine, glutamine, and alanine. Increased; these are surrogate markers of hyperammonemia.

Urinary organic acids. Normal, except orotic acid may be detected as part of urinary organic acid analysis by gas chromatography/mass spectrometry; however, the sensitivity depends on the extraction method.

Argininosuccinate synthase (ASS) enzyme activity. Incorporation of radiolabeled citrulline into argininosuccinic acid is measured in cultured fibroblasts. ASS activity is also determined by a method based on the conversion of radiolabeled (14C)-aspartate to (14C)-argininosuccinate [Gao et al 2003]:

  • The normal enzyme activity in fibroblasts is 0.8-3.8 nmol/min/mg protein, but this is specific to tissue, method, and laboratory.
  • Cultured chorionic villus cells or cultured amniocytes from the fetus may be used for prenatal diagnosis.

Newborn screening. As of this writing, all states include CTLN1 in their newborn screening programs. Elevated citrulline is detected in dried blood spots on newborn screen by tandem mass spectroscopy (MS/MS). Citrullinemia is confirmed by plasma amino acid analysis that demonstrates the findings described above. Other conditions that may result in elevated citrulline on NBS are argininosuccinic acidemia, citrullinemia II (citrin deficiency), and pyruvate carboxylase deficiency.

Molecular Genetic Testing

Gene. ASS1 is the only gene in which mutations are known to cause citrullinemia type I.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Citrullinemia Type I

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
ASS1Sequence analysis 4Sequence variants 596% 6, 7
Deletion/duplication analysis 8(Multi)exonic or whole-gene deletionsUnknown 9
Linkage analysisIntragenic dinucleotide repeatInformative in 60%-70%

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. In Japan, a small number of mutations account for the majority of cases of CTLN1; however, a large number of mutations are found in individuals of European origin

6. In 80 individuals evaluated, both abnormal alleles were identified in 75 (94%), one abnormal allele in four (5%), and no abnormal alleles in one (1%).

7. Sequencing of genomic DNA from a variety of cells or cDNA from cultured fibroblasts detected 154 of 160 (96%) abnormal alleles [Häberle, personal communication].

8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

9. Exonic and multiexonic deletions were reported by Engel et al [2009].

Testing Strategy

To confirm/establish the diagnosis in a symptomatic proband

  • The finding of elevated plasma ammonia concentration (>150; may range to ≥2000-3000 µmol/L) and plasma citrulline concentration (usually >1000 µmol/L) establishes the diagnosis of CTLN1. Note: Following the work up described in Urea Cycle Disorders Overview leads to the diagnosis of citrullinemia type 1 when present (see Urea Cycle Disorders Overview Figure 3).
  • Molecular genetic testing (sequence analysis of ASS1 followed by deletion/duplication analysis if neither or only one mutation is identified) may be helpful when the phenotype is unclear or biochemical values are borderline; it is especially helpful in distinguishing CTLN1 in its mild form from citrin deficiency.

    Note: (1) Determining the prognosis prospectively can be difficult in some individuals who fit the biochemical phenotype but may or may not have serious clinical illness. (2) Enzyme assay is not widely used because the clinical presentation and relatively specific pattern of metabolites found in affected individuals are sufficient to establish the diagnosis.

Clinical Description

Natural History

Citrullinemia type I (CTLN1) presents as a spectrum that includes a neonatal acute form (the "classic" form), a milder late-onset form, a form in which women have onset of symptoms at pregnancy or post partum, and a form without symptoms or hyperammonemia.

In the acute neonatal form, the infant appears normal at birth. After an interval of one to a few days, the infant becomes progressively more lethargic, feeds poorly, may vomit, and may develop signs of increased intracranial pressure [Brusilow & Horwich 2014]. Fifty-six percent of infants with classic citrullinemia type I are symptomatic by age four days and 67% by age one week [Bachmann 2003a].

Recently, two infants with classic CTLN1 with ammonia concentrations in the range of 400-500 µmol/L presented at age two and three months with cerebral infarcts [Choi et al 2006].

Children diagnosed and referred for appropriate treatment (see Management) survive for an indeterminate period of time, usually with significant neurologic deficits. All children with a peak plasma ammonia concentration greater than 480 µmol/L or an initial plasma ammonia concentration greater than 300 µmol/L have cognitive impairment [Bachmann 2003b]. The longest survival of an untreated infant with classic citrullinemia type I is 17 days.

In the late-onset form, the clinical course may be similar to or milder than that seen in the acute neonatal form, but for unknown reasons commences later in life. When episodes of hyperammonemia occur, they are similar to those seen in the acute neonatal form, but the neurologic findings may be more subtle because of the older age of the affected individuals. These can include intense headache, scotomas, migraine-like episodes, ataxia, slurred speech, lethargy, and somnolence. Individuals with hyperammonemia also display respiratory alkalosis and tachypnea [Brusilow & Horwich 2014]. Without prompt intervention, increased intracranial pressure occurs, with increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death.

Liver failure is being increasingly recognized as a primary presentation of CTLN1, contradicting established dogma of CNS symptoms as the primary findings. Two examples include:

  • A woman age 25 years who presented with two episodes of acute liver failure, and who was ultimately shown to have CTLN1 by metabolite testing and molecular genetic testing [Salek et al 2010]
  • A female age 15 months with CTLN1 who "...presented with encephalopathy and seizures with hyperammonemia requiring emergency treatment. Although there was a rapid resolution of her hyperammonemia, she developed fulminant liver failure. The severe increase of transaminases (aspartate aminotransferase and alanine aminotransferase levels peaking at 19,794 UI/L and 19,938 UI/L, respectively) and concurrent disturbances in her hepatic synthetic functions led to the consideration of a liver transplantation…" [Faghfoury et al 2011].

Possible long-term complications. An individual with classic citrullinemia treated with chronic protein restriction and scavenger therapy (see Treatment of Manifestations) developed progressive hypertrophic cardiomyopathy and bilateral cataracts, diagnosed at 23 and 27 years of age, respectively [Brunetti-Pierri et al 2012]. No additional individuals with classic CTLN1 have been identified with similar findings. As such, the necessity for cardiac and ophthalmologic surveillance remains controversial until more affected individuals have been studied.

Pregnancy. A healthy woman with untreated CTLN1 underwent two successful pregnancies [Potter et al 2004]; however, women with onset of severe symptoms during pregnancy or in the postpartum period have been reported [Gao et al 2003, Ruitenbeek et al 2003].

  • Three women not known to have citrullinemia presented in hyperammonemic coma shortly after delivery; one died and two survived without neurologic sequelae [Häberle et al 2009].
  • CTLN1 has been implicated in postpartum psychosis [Häberle et al 2010].

Individuals remaining asymptomatic up to at least age ten years have been reported; it seems possible that they may remain asymptomatic lifelong [Häberle et al 2002, Häberle et al 2003].

Neuroimaging. CT scan of infants with citrullinemia type I demonstrates cerebral atrophy, particularly in the cingulate gyrus, the insula, and the temporal lobes, as well as general cortical hypo-attenuation (i.e., the cortex appears darker than in unaffected individuals) [Albayram et al 2002].

Brain MRI findings in classic citrullinemia include restricted diffusion and T2 signal hyperintensities in the basal ganglia, thalami, and subcortical white matter of the bilateral temporal, parietal, and occipital cortex [Majoie et al 2004, Bireley et al 2012]. Multicystic encephalomalacia and cerebral atrophy have been seen as early as age three to four months in an individual with classic CTLN1 [Lee et al 2013].

Genotype-Phenotype Correlations

Although certain mutations are identified with some phenotypes, the phenotype cannot be predicted in all instances [Engel et al 2009].

Nomenclature

The preferred terms for argininosuccinic acid synthetase deficiency are "citrullinemia type I" and "classic citrullinemia," which are used to avoid confusion with the genetically distinct disease, citrullinemia type II, also known as citrin deficiency.

Prevalence

Citrullinemia type I occurs in 1:57,000 births and represented 74 (13.6%) of 545 individuals with urea cycle disorders referred to the Johns Hopkins Hospital from 1974 to 1994 [Brusilow & Horwich 2014].

Newborn screening programs found CTLN1 in the following:

  • In Korea: two in 44,300 newborns [Yoon et al 2003]
  • In New England: one in 200,000 newborns [Marsden 2003]
  • In Taiwan: five (2 severe and 3 mild) in a pilot program of 592,717 newborns; overall incidence 1:118,543 [Niu et al 2010]
  • In Austria: 1:77,811 among 622,489 newborns [Kasper et al 2010]

Differential Diagnosis

Citrullinemia type II (CTLN2) is caused by citrin deficiency resulting from mutations in SLC25A13, which encodes the mitochondrial solute carrier protein, citrin. In citrin deficiency aspartate and glutamate fail to shuttle to and from the mitochondrion, leading to a mild hyperammonemia and citrullinemia. Mutation in SLC25A13 also leads to intrahepatic cholestasis in the neonate [Saheki & Kobayashi 2002]. The clinical course in adults with citrullinemia type II is milder than that of CTLN1, possibly distinguishing it from milder late-onset citrullinemia type I. It is not known why CTLN2 is milder and later in onset than CTLN1; distinguishing between the two disorders is difficult. The prevalence of citrullinemia type II has not been reported.

It is critical to distinguish hyperammonemia caused by a defect in the urea cycle from the secondary hyperammonemia caused by an organic acidemia (see Organic Acidemias Overview), which may cause inhibition of N-acetylglutamate synthase (see Urea Cycle Disorders Overview Figure 2).

Dihydrolipoamide dehydrogenase (DLD) deficiency has also recently been reported to display increased citrulline, ammonia and glutamine [Haviv et al 2013].

Classic citrullinemia type I shares the phenotype of the typical acute neonatal hyperammonemia displayed by other defects in the first four steps in the urea cycle pathway. The mild phenotype shares a later onset with other disorders such as late-onset ornithine transcarbamylase (OTC) deficiency. Urea Cycle Disorders Overview Figure 3 shows a diagnostic strategy to identify which steps in the urea cycle are defective in an individual with hyperammonemia.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with citrullinemia type I (CTLN1), the following evaluations are recommended:

  • Measurement of: concentration of plasma ammonia, amino acids, and electrolytes; blood gases; urinary organic acids; and urinary orotic acid
  • Assessment of intracranial pressure and overall neurologic status
  • Medical genetics consultation

Treatment of Manifestations

As soon as a diagnosis of CTLN1 is made, acute (if needed) and chronic management should be initiated per established treatment guidelines [Batshaw et al 2001, Summar 2001, Urea Cycle Disorders Conference Group 2001]. See Image ACMGACT.jpg, Image ACMGalg.jpg.

Acute Management of Hyperammonemia

Hallmarks of therapy include rapid lowering of the plasma ammonia concentration, reversal of catabolism, and avoidance and/or treatment of increased intracranial pressure.

Rapidly decreasing plasma ammonia concentration. When hyperammonemia is diagnosed or suspected, all protein intake should be withheld for a maximum of 24-48 hours. This time frame allows for the plasma ammonia concentration to be lowered via nitrogen scavenger therapy and/or dialysis (see below) and avoids an essential amino acid deficiency that would promote a catabolic state.

  • Pharmacologic nitrogen scavenger therapy (sodium benzoate, sodium phenylacetate and arginine) should be given intravenously as soon as hyperammonemia is diagnosed in an individual known to have CTLN1. (For information pertaining to the mechanism of action of this treatment, see Scavenger Therapy.)
    • Priming infusion (to be given continuously over 90 minutes):
      • Sodium benzoate: 250 mg/kg or 5.5 g/m2
      • Sodium phenylacetate: 250 mg/kg or 5.5 g/m2
      • 10% arginine HCl: 600 mg/kg or 12.0 g/m2
    • Sustaining infusion (to be given continuously over 24 hours):
      • Sodium benzoate: 250 mg/kg or 5.5 g/m2
      • Sodium phenylacetate: 250 mg/kg or 5.5 g/m2
      • 10% arginine HCl: 600 mg/kg or 12.0 g/m2
    • Note: Repeat boluses are not recommended unless the individual is receiving dialysis (see following).
  • Dialysis is the most effective means of reducing plasma ammonia rapidly. Failure to control ammonia with scavenger therapy requires the emergency use of dialysis.
    • Hemodialysis is the preferred method of dialysis and exceeds both peritoneal dialysis and hemofiltration in the rate of ammonia clearance.
    • Scavenger therapy should be continued while dialysis is being performed.
    • Note: Exchange transfusions have no place in hyperammonemic treatment.

Reversal of catabolism. An anabolic state should be promoted through the provision of IV glucose (and insulin in the event of hyperglycemia) and intralipids.

  • Complete protein restriction should be limited to 24-48 hours to avoid a catabolic state.
  • In small infants, 40 kcal/100 mL given as D10W can be significant in averting catabolism. As soon as possible, osmolar load permitting, the individual should receive total parenteral nutrition (TPN) providing 0.25 g/kg/day of protein and 50 kcal/kg/day, advancing (as plasma ammonia concentration allows) to 1.0-1.5 g/kg/day of protein and 100-120 kcal/kg/day. Standard TPN solutions of dextrose, aminosol, and intralipid are used.

Control of intracranial pressure. It is critical to monitor fluid balance, intake and output, and body weight.

  • The affected individual should be maintained on the dry side of fluid balance: approximately 85 mL/kg of body weight per day in infants and appropriate corresponding fluid restriction in children and adults.
  • Increased intracranial pressure is manifested by tension in the fontanel, acute enlargement of the liver, edema, and worsening neurologic signs including fisting, scissoring, ankle clonus, and coma. Cerebral edema and ischemia may be documented by MRI.

Chronic Management

Chronic therapy for those with CTLN1 consists of lifelong protein restriction, medications (nitrogen scavenger therapy and carnitine), and liver transplantation based on the degree of metabolic control achieved with dietary modification and medication therapy.

Protein restriction. Lifelong dietary management is necessary and requires the services of a metabolic nutritionist.

Nitrogen scavenger therapy

  • When the affected individual is able to tolerate solid food, the oral medication sodium phenylbutyrate (Buphenyl®, Ammonaps®), at a dose of 450-600 mg/kg/day divided into three doses, and arginine-free base of 400 and 700 mg/kg/day are begun. As children grow, doses change to 9.9-13 g/m2/day of sodium phenylbutyrate and 8.8-15.4 g/m2/day of arginine. For details of management, the reader is referred to Brusilow & Horwich [2014].
  • Glycerol phenylbutyrate (Ravicti®) is a more palatable option that was FDA approved in February, 2013. The initial dosage for phenylbutyrate naïve affected individuals is 4.5-11.2 mL/m2/day (5-12.4 g/m2/day). If the individual is transitioning from sodium phenylbutyrate to glycerol phenylbutyrate, the daily dose of glycerol phenylbutyrate (mL) = daily dose of sodium phenylbutyrate (g) x 0.86.
  • Success of therapy is defined by a plasma ammonia concentration lower than 100 µmol/L and near-normal plasma glutamine concentration. Plasma arginine concentration may be up to 250% above upper normal limit for age.
  • Treatment with L-carnitine has been advocated as auxiliary treatment to prevent systemic hypocarnitinemia, which may result from therapy with acylating agents.

Liver transplantation for treatment of urea cycle disorders has been reported by several groups. Of sixteen individuals undergoing liver transplantation, 14 lived 11 months to six years post transplantation; their neurologic outcomes correlated closely with their pre-transplantation neurologic status. Few problems with long-term health were related to the liver transplantation itself and quality of life was much improved [Whitington et al 1998].

A successful living related-donor liver transplantation (240 g) from mother to six-year-old daughter has been reported. The allopurinol challenge test was normalized in this child, who previously had very brittle control with four to six hyperammonemic episodes per year [Ito et al 2003]. A living related-donor liver transplantation from mother to son resulted in continued elevation in plasma concentration of citrulline (200-400µmol/L). The mother, a heterozygote, had 28% residual ASS 1 enzyme activity [Ando et al 2003].

Liver transplantation of four individuals with CTLN1 between the ages of six and 64 months showed better developmental outcomes when the transplant was performed at earlier ages [Kim et al 2013].

A larger series of successful auxiliary partial liver transplants has been reported in CTLN type II [Yazaki et al 2004].

Prevention of Primary Manifestations

Prevention of hyperammonemia is achieved through lifelong protein restriction, nitrogen scavenger therapy, and possible liver transplantation based on metabolic control (see Treatment of Manifestations).

Prevention of Secondary Complications

Intercurrent infections (particularly some viral exanthems) may induce a catabolic state. Affected individuals must be observed carefully during such episodes and medical attention sought to prevent hyperammonemia.

Surveillance

Appropriate monitoring of concentration of plasma amino acids to identify deficiency of essential amino acids as well as impending hyperammonemia is indicated.

Routine follow up in a metabolic clinic with a qualified metabolic nutritionist and clinical biochemical geneticist is required.

Monitoring for early warning signs of impending hyperammonic episodes including mood changes, headache, lethargy, nausea, vomiting, refusal to feed, ankle clonus, and elevated plasma concentration of glutamine and other surrogate markers is warranted in older individuals. Plasma glutamine concentration may rise 48 hours in advance of increases in plasma ammonia concentration in such individuals [Brusilow & Horwich 2014].

Agents/Circumstances to Avoid

Avoid the following:

  • Excess protein intake
  • Obvious exposure to communicable diseases

Evaluation of Relatives at Risk

Because the long-term outlook for individuals with citrullinemia type I depends on initial and peak plasma ammonia concentration, it is important that at-risk sibs are identified as soon as possible. Current practice dictates either in utero diagnosis (which permits appropriate oral therapy beginning with first feeds) or measurement of plasma concentrations of ammonia and citrulline on day one of life. Elevation of either above acceptable levels (ammonia >100 µmol/L or plasma citrulline >~100 µmol/L) is sufficient evidence to initiate treatment.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Because women with onset of severe symptoms during pregnancy or in the postpartum period have been reported, scrupulous attention needs to be paid to diet and medication during these periods.

Therapies Under Investigation

Gene therapy has been suggested; success has not been achieved to date.

Phase I and Phase II clinical trials to assess the safety and efficacy of human hepatocyte transplantation as either an alternative to liver transplantation or as a temporizing measure for individuals with CTLN1awaiting transplantation is underway.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Ketoacids of essential amino acids were an early form of auxiliary waste nitrogen disposal enhancement, now replaced by the agents described in Treatment of Manifestations.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Citrullinemia type I (CTNL1) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) have no symptoms of the urea cycle defect phenotype. One case of a heterozygote who developed cirrhosis has been reported [Güçer et al 2004].
  • Sibs should be evaluated immediately after birth and placed on a protein-restricted diet until the diagnostic evaluation is complete (see Management).

Offspring of a proband. The offspring of an individual with citrullinemia type I are obligate heterozygotes (carriers) for a disease-causing mutation in ASS1.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing is possible by molecular genetic test methods if both disease-causing mutations have been identified in the family.

Note: Linkage analysis can be considered for carrier testing if neither or only one mutation has been identified in an affected family member.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at 25% risk is possible. Methods of prenatal diagnosis:

  • Argininosuccinate synthase enzyme activity is measured in uncultured fetal tissue obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or cultured amniocytes obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation.

    Note: (1) Improvement in diagnostic accuracy using the ratio of citrulline to ornithine and arginine concentrations in amniotic fluid has been reported [Chadefaux-Vekemans et al 2002]. (2) Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
  • Molecular genetic testing is possible for families in which both mutations have been identified in the family [Hong et al 2000, Hayakawa et al 2003].

    Note: In certain instances, linkage analysis may be considered to improve prenatal testing accuracy if neither or only one mutation has been identified in an affected family member. Linkage must be established in the family before prenatal testing can be performed.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • National Urea Cycle Disorders Foundation
    75 South Grand Avenue
    Pasadena CA 91105
    Phone: 800-386-8233 (toll-free); 626-578-0833
    Fax: 626-578-0823
    Email: info@nucdf.org
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk
  • Save Babies Through Screening Foundation, Inc.
    P. O. Box 42197
    Cincinnati OH 45242
    Phone: 888-454-3383
    Email: email@savebabies.org
  • European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD)
  • Urea Cycle Disorder International Patient Registry
    Phone: 626-578-0833
    Fax: 626-578-0823
    Email: coordinator@ucdparegistry.org
  • Urea Cycle Disorders Consortium Registry
    Children's National Medical Center
    Phone: 202-306-6489
    Email: jseminar@childrensnational.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Citrullinemia Type I: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
ASS19q34​.11Argininosuccinate synthaseASS1 @ LOVDASS1

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Citrullinemia Type I (View All in OMIM)

215700CITRULLINEMIA, CLASSIC
603470ARGININOSUCCINATE SYNTHETASE 1; ASS1

Gene structure. ASS1 comprises 16 exons; the primary transcript is 1239 bp. Transcription starts at the 5' end of exon 3. For a detailed summary of gene and protein information, see Table A, Gene Symbol

Benign allelic variants. In the homozygous state, mutations p.Trp179Arg, c.1168G>A, and p.Gly362Val are associated with mild or no clinical symptoms, as is heterozygosity for c.[323G>T]+[970+5G>A] [Häberle et al 2002]. At least 14 ASS1 pseudogenes are known.

Pathogenic allelic variants. See Table 2. Engel et al [2009] defined 87 ASS1 mutations from all available ethnicities; 27 were previously undescribed. They were found to occur in most exons and several intervening sequences leading to abnormal mRNA splicing. Seven mutations are associated with severe disease; three of them (p.Arg304Trp, c.421-2A>G, and p.Gly390Arg) account for the majority of citrullinemia type I [Gao et al 2003]. See Table A.

Table 2. Selected ASS1 Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.257G>Ap.Arg86His 2NM_000050​.4
NP_000041​.2
c.323G>T 3p.Arg108Leu 3
c.421-2A>G
(IVS6-2A>G)
--
c.535T>C 3p.Trp179Arg 2, 3
c.794G>Ap.Arg265His 2
c.910C>Tp.Arg304Trp
c.970+5G>A 3
(IVS13+5G>A)
--
c.1085G>T 3p.Gly362Val 2, 3
c.1168G>A 3p.Gly390Arg

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Associated with late-onset citrullinemia type I; see Genotype-Phenotype Correlations.

3. Variants associated with no clinical or mild clinical symptoms; see Table A.

Normal gene product. The translational product, argininosuccinate synthase, is a homotetramer of 186 kd. It catalyzes an essential reaction in the biosynthesis of urea, causing the condensation of citrulline and aspartate to argininosuccinic acid in the cytosol, and requiring 1 mol of ATP.

Abnormal gene product. The argininosuccinate synthase enzyme is inactive or absent. Mutant ASS with abnormal KM (Michaelis constant) or very low ASS protein detected by ELISA using anti-ASS antibody (low CRIM: cross-reacting immunologic materials) has been found.

References

Published Guidelines / Consensus Statements

  1. Urea Cycle Disorders Conference Group. Consensus statement from a conference for the management of patients with urea cycle disorders. Available online. 2001. Accessed 8-14-14. [PubMed: 11148543]

Literature Cited

  1. Albayram S, Murphy KJ, Gailloud P, Moghekar A, Brunberg JA. CT findings in the infantile form of citrullinemia. AJNR Am J Neuroradiol. 2002;23:334–6. [PubMed: 11847065]
  2. Ando T, Fuchinoue S, Shiraga H, Ito K, Shimoe T, Wada N, Kobayashi K, Saeki T, Teraoka S. Living-related liver transplantation for citrullinemia: different features and clinical problems between classical types (CTLN1) and adult-onset type (CTLN2) citrullinemia. Japan J Transplant. 2003;38:143–7.
  3. Bachmann C. Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation. Eur J Pediatr. 2003a;162:410–6. [PubMed: 12684900]
  4. Bachmann C. Long-term outcome of patients with urea cycle disorders and the question of neonatal screening. Eur J Pediatr. 2003b;162 Suppl 1:S29–33. [PubMed: 14634803]
  5. Batshaw ML, MacArthur RB, Tuchman M. Alternative pathway therapy for urea cycle disorders: Twenty years later. J Pediatr. 2001;138:S46–S55. [PubMed: 11148549]
  6. Bireley WR, Van Hove JL, Gallagher RC, Fenton LZ. Urea cycle disorders: brain MRI and neurological outcome. Pediatr Radiol. 2012;42:455–62. [PubMed: 21989980]
  7. Brunetti-Pierri N, Lamance KM, Lewis RA, Craigen WJ. 30-year follow-up of a patient with classic citrullinemia. Mol Genet Metab. 2012;106:248–50. [PubMed: 22494546]
  8. Brusilow SW, Horwich AL. Urea cycle enzymes. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Available online. 2014. Accessed 8-14-14.
  9. Chadefaux-Vekemans B, Rabier D, Chabli A, Blanc A, Aupetit J, Bardet J, Kamoun P. Improving the prenatal diagnosis of citrullinemia using citrulline/ornithine+arginine ratio in amniotic fluid. Prenat Diagn. 2002;22:456–8. [PubMed: 12116302]
  10. Choi JH, Kim H, Yoo HW. Two cases of citrullinaemia presenting with stroke. J Inherit Metab Dis. 2006;29:182–3. [PubMed: 16601887]
  11. Engel K, Höhne W, Häberle J. Mutations and polymorphisms in the human argininosuccinate synthetase (ASS1) gene. Hum Mutat. 2009;30:300–7. [PubMed: 19006241]
  12. Faghfoury H, Baruteau J, de Baulny HO, Häberle J, Schulze A. Transient fulminant liver failure as an initial presentation in citrullinemia type I. Mol Genet Metab. 2011;102:413–7. [PubMed: 21227727]
  13. Gao HZ, Kobayashi K, Tabata A, Tsuge H, Iijima M, Yasuda T, Kalkanoglu HS, Dursun A, Tokatli A, Coskun T, Trefz FK, Skladal D, Mandel H, Seidel J, Kodama S, Shirane S, Ichida T, Makino S, Yoshino M, Kang JH, Mizuguchi M, Barshop BA, Fuchinoue S, Seneca S, Zeesman S, Knerr I, Rodés M, Wasant P, Yoshida I, De Meirleir L, Abdul Jalil M, Begum L, Horiuchi M, Katunuma N, Nakagawa S, Saheki T. Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients. Hum Mutat. 2003;22:24–34. [PubMed: 12815590]
  14. Güçer S, Aşan E, Atilla P, Tokatli A, Cağlar M. Early cirrhosis in a patient with type I citrullinaemia (CTLN1). J Inherit Metab Dis. 2004;27:541–2. [PubMed: 15334737]
  15. Häberle J, Meli C, Parini R, Rigoldi M, Vilaseca M. Severe first manifestation of citrullinemia type I in the postpartum period. Mol Genet Metab. 2009;98:1–2.
  16. Häberle J, Pauli S, Linnebank M, Kleijer WJ, Bakker HD, Wanders RJ, Harms E, Koch HG. Structure of the human argininosuccinate synthetase gene and an improved system for molecular diagnostics in patients with classical and mild citrullinemia. Hum Genet. 2002;110:327–33. [PubMed: 11941481]
  17. Häberle J, Pauli S, Schmidt E, Schulze-Eilfing B, Berning C, Koch HG. Mild citrullinemia in Caucasians is an allelic variant of argininosuccinate synthetase deficiency (citrullinemia type 1). Mol Genet Metab. 2003;80:302–6. [PubMed: 14680976]
  18. Häberle J, Vilaseca MA, Meli C, Rigoldi M, Jara F, Vecchio I, Capra C, Parini R. First manifestation of citrullinemia type I as differential diagnosis to postpartum psychosis in the puerperal period. Eur J Obstet Gynecol Reprod Biol. 2010;149:228–9. [PubMed: 20005624]
  19. Haviv R, Zeharia A, Belaiche C, Haimi Cohen Y, Saada A. Elevated plasma citrulline: look for dihydrolipoamide dehydrogenase deficiency. Eur J Pediatr. 2013 [PubMed: 23995961]
  20. Hayakawa M, Kato Y, Takahashi R, Tauchi N. Case of citrullinemia diagnosed by DNA analysis: including prenatal genetic diagnosis from amniocytes of next pregnancy. Pediatr Int. 2003;45:196–8. [PubMed: 12709149]
  21. Hong KM, Paik MK, Yoo OJ, Hahn SH. The first successful prenatal diagnosis on a Korean family with citrullinemia. Mol Cells. 2000;10:692–4. [PubMed: 11211875]
  22. Ito T, Sumi S, Kidouchi K, Ban K, Ueta A, Hashimoto T, Togari H, Wada Y. Allopurinol challenge tests performed before and after living-related donor liver transplantation in citrullinaemia. J Inherit Metab Dis. 2003;26:87–8. [PubMed: 12872848]
  23. Kasper DC, Ratschmann R, Metz TF, Mechtler TP, Möslinger D, Konstantopoulou V, Item CB, Pollak A, Herkner KR. The national Austrian newborn screening program - eight years’ experience with mass spectrometry. past, present, and future goals. Wien Klin Wochenschr. 2010;122:607–13. [PubMed: 20938748]
  24. Kim IK, Niemi AK, Krueger C, Bonham CA, Concepcion W, Cowan TM, Enns GM, Esquivel CO. Liver transplantation for urea cycle disorders in pediatric patients: a single-center experience. Pediatr Transplant. 2013;17:158–67. [PubMed: 23347504]
  25. Laróvere LE, Angaroni CJ, Antonozzi SL, Bezard MB, Shimohama M, de Kremer RD. Citrullinemia type I, classical variant. Identification of ASS-p~G390R (c.1168G>A) mutation in families of a limited geographic area of Argentina: a possible population cluster. Clin Biochem. 2009;42:1166–8. [PubMed: 19358837]
  26. Lee BH, Kim YM, Heo SH, Kim GH, Choi IH, Lee BS, Kim EA, Kim KS, Jhang WK, Park SJ, Yoo HW. High prevalence of neonatal presentation in Korean patients with citrullinemia type 1, and their shared mutations. Mol Genet Metab. 2013;108:18–24. [PubMed: 23246278]
  27. Majoie CBLM, Mourmans JM, Akkerman EM, Duran M, Poll-The BT. Neonatal citrullinemia: comparison of conventional MR, diffusion-weighted, and diffusion tensor findings. AJNR Am J Neuroradiol. 2004;25:32–5. [PubMed: 14729525]
  28. Marsden D. Expanded newborn screening by tandem mass spectrometry: the Massachusetts and New England experience. Southeast Asian J Trop Med Public Health. 2003;34 Suppl 3:111–4. [PubMed: 15906712]
  29. Niu DM, Chien YH, Chiang CC, Ho HC, Hwu WL, Kao SM, Chiang SH, Kao CH, Liu TT, Chiang H, Hsiao KJ. Nationwide survey of extended newborn screening by tandem mass spectrometry in Taiwan. J Inherit Metab Dis. 2010;33 Suppl 2:S295–305. [PubMed: 20567911]
  30. Potter MA, Zeesman S, Brennan B, Kobayashi K, Gao HZ, Tabata A, Saheki T, Whelan DT. Pregnancy in a healthy woman with untreated citrullinemia. Am J Med Genet A. 2004;129A:77–82. [PubMed: 15266621]
  31. Ruitenbeek W, Kobayashi K, Iijima M, Smeitink JA, Engelke UF, De Abreu RA, Kwast HT, Saheki T, Boelen CA, De Jong JG, Wevers RA. Moderate citrullinaemia without hyperammonaemia in a child with mutated and deficient argininosuccinate synthetase. Ann Clin Biochem. 2003;40:102–7. [PubMed: 12542919]
  32. Saheki T, Kobayashi K. Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD). J Hum Genet. 2002;47:333–41. [PubMed: 12111366]
  33. Salek J, Byrne J, Box T, Longo N, Sussman N. Recurrent liver failure in a 25-year-old female. Liver Transpl. 2010;16:1049–53. [PubMed: 20818742]
  34. Summar M. Current strategies for the management of neonatal urea cycle disorders. J Pediatr. 2001;138:S30–S39. [PubMed: 11148547]
  35. Urea Cycle Disorders Conference group. Consensus statement from a conference for the management of patients with urea cycle disorders. J Pediatr. 2001;138(1) Suppl:S1–5. [PubMed: 11148543]
  36. Whitington PF, Alonso EM, Boyle JT, Molleston JP, Rosenthal P, Emond JC, Millis JM. Liver transplantation for the treatment of urea cycle disorders. J Inherit Metab Dis. 1998;21:112–8. [PubMed: 9686349]
  37. Yazaki M, Hashikura Y, Takei Y, Ikegami T, Miyagawa S, Yamamoto K, Tokuda T, Kobayashi K, Saheki T, Ikeda S. Feasibility of auxiliary partial orthotopic liver transplantation from living donors for patients with adult-onset type II citrullinemia. Liver Transpl. 2004;10:550–4. [PubMed: 15048800]
  38. Yoon HR, Lee KR, Kim H, Kang S, Ha Y, Lee DH. Tandem mass spectrometric analysis for disorders in amino, organic and fatty acid metabolism: two year experience in South Korea. Southeast Asian J Trop Med Public Health. 2003;34:115–20. [PubMed: 15906713]

Chapter Notes

Revision History

  • 23 January 2014 (me) Comprehensive update posted live
  • 11 August 2011 (me) Comprehensive update posted live
  • 2 June 2009 (me) Comprehensive update posted live
  • 22 April 2008 (cd) Revision: deletion/duplication analysis available clinically
  • 22 December 2006 (me) Comprehensive update posted to live Web site
  • 7 July 2004 (me) Review posted to live Web site
  • 9 February 2004 (jt) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1458PMID: 20301631
PubReader format: click here to try

Views

Tests in GTR by Gene

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...