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Citrullinemia Type I

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

, MD and , MD.

Author Information

Initial Posting: ; Last Update: September 1, 2016.

Summary

Clinical characteristics.

Citrullinemia type I (CTLN1) presents as a clinical spectrum that includes an acute neonatal form (the "classic" form), a milder late-onset form (the “non-classic” 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 increased 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.

The diagnosis of CTLN1 is established in a proband with elevated plasma ammonia concentration (>150 µmol/L; may range to ≥2000-3000 µmol/L) and plasma citrulline concentration (usually >1000 µmol/L) and/or by the identification of biallelic pathogenic variants in ASS1 on molecular genetic testing.

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; L-carnitine to prevent systemic hypocarnitinemia. Liver transplantation, the only known cure for CTLN1, is best performed between age three months (and/or attainment of 5 kg body weight) and one year to decrease complications and improve survival; liver transplantation does not reverse any neurologic sequelae present at the time of transplant.

Prevention of secondary complications: Medical attention during intercurrent infections to prevent hyperammonemia; routine vaccinations including annual influenza vaccine.

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. Monitoring should be frequent in neonates and infants, based on disease severity, but may be extended to every six months to annually in older individuals, depending on clinical stability.

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

Evaluation of relatives at risk: In utero diagnosis if the pathogenic variants in the family are known permits appropriate oral therapy beginning with the first feeds. Alternatively, sibs should be evaluated on day one of life by measurement of plasma concentrations of ammonia and citrulline; elevation of either above acceptable levels (ammonia >100 µmol/L or plasma citrulline >~100 µmol/L) is sufficient evidence to initiate treatment.

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 pathogenic variants in the family are known.

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).

Suggestive Findings

Citrullinemia type I (CTLN1) should be suspected in individuals with the following newborn screening results, clinical features (by age), and supportive laboratory findings.

Newborn Screening Results

Elevated citrulline is detected in dried blood spots on newborn screen by tandem mass spectroscopy (MS/MS). Note: As of this writing, all states include CTLN1 in their newborn screening programs.

Clinical Features

Neonatal presentation. Sign and symptoms classically occur within the first week of life while on a full protein diet:

  • Increasing lethargy
  • Somnolence
  • Refusal to feed
  • Vomiting
  • Tachypnea
  • Stroke
  • Increased intracranial pressure (secondary to hyperammonemia) resulting in increased neuromuscular tone, spasticity, and ankle clonus

Non-classic presentation. Signs and symptoms may occur at any age and may not present as acutely as in the neonate:

  • Recurrent lethargy and somnolence
  • Intense headache
  • Scotomas
  • Migraine-like episodes
  • Ataxia and slurred speech
  • Intellectual disability

Supportive Laboratory Findings

Plasma ammonia concentration

  • Neonate. Initial plasma ammonia concentration in the severe form may be 1000-3000 µmol/L (normal: 40-100 µmol/L).
  • Late-onset. Chronic or recurrent hyperammonemia, often with a lower plasma concentration than in the classic form (adult upper limit of normal: <60 µmol/L).

Plasma quantitative amino acid analysis

  • Citrulline. Usually >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 analysis. Normal, although 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.

Establishing the Diagnosis

The diagnosis of CTLN1 is established in a proband with elevated plasma ammonia concentration (>150 µmol/L; may range to ≥2000-3000 µmol/L) and plasma citrulline concentration (usually >1000 µmol/L) and/or by the identification of biallelic pathogenic variants in ASS1 on molecular genetic testing (see Table 1).

Note: Determining the prognosis prospectively can be difficult in some individuals who fit the biochemical phenotype but may or may not have serious clinical illness.

Molecular genetic testing approaches can include single-gene testing and use of a multi-gene panel.

  • Single-gene testing. Sequence analysis of ASS1 is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
  • A multi-gene panel that includes ASS1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests.

Table 1.

Molecular Genetic Testing Used in Citrullinemia Type I

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
ASS1Sequence analysis 396% 4, 5
Gene-targeted deletion/duplication analysis 6See footnote 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

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%).

5.

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

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

Exon and multiexon deletions were reported by Engel et al [2009].

Argininosuccinate synthase (ASS) enzyme activity. Incorporation of radiolabeled citrulline into argininosuccinic acid is measured in cultured fibroblasts (see also Prenatal Testing and Preimplantation Genetic Diagnosis). 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.
  • 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 Characteristics

Clinical Description

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

Neonatal (“classic”) 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 2001]. Fifty-six percent of infants with classic citrullinemia type I are symptomatic by age four days and 67% by age one week [Bachmann 2003a].

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.

Non-classic form. The clinical course may be similar to or milder than that seen in the acute neonatal form, but commences later in life for reasons that are not completely understood. However, specific ASS1 pathogenic variants may be associated with the non-classic form (see Genotype-Phenotype Correlations and Molecular Genetics). 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 2001]. Without prompt intervention, increased intracranial pressure occurs, with increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death.

Liver failure is now recognized as a primary presentation of CTLN1, contradicting established dogma of CNS symptoms as the primary finding [Salek et al 2010, Faghfoury et al 2011, Lee et al 2013, Rüegger et al 2014]. Hepatic dysfunction, when present, is frequently noted at the time of the initial hyperammonemic episode but has also developed in an affected individual who was not experiencing significant hyperammonemia (>250 µmol/L) at the time [Lee et al 2013].

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 (diagnosed at age 23 years) and bilateral cataracts (diagnosed at age 27 years) [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 appears that they could 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 pathogenic variants 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 has been estimated to occur in 1:57,000 births [Brusilow & Horwich 2001].

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]
  • In Texas, New York, Michigan, California, Massachusetts, North Carolina and Wisconsin, estimated combined prevalence of CTLN1 and ASLD: one in 117,000 [Summar et al 2013]

Differential Diagnosis

Conditions that may result in elevated citrulline on newborn screening are citrullinemia II (citrin deficiency), argininosuccinic aciduria, and pyruvate carboxylase deficiency.

Citrullinemia type II (CTLN2) is caused by citrin deficiency resulting from biallelic pathogenic variants 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 mild hyperammonemia and citrullinemia. Biallelic pathogenic variants in SLC25A13 also lead 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, which may cause inhibition of N-acetylglutamate synthase (see Urea Cycle Disorders Overview Figure 2).

Dihydrolipoamide dehydrogenase (DLD) deficiency has also been reported to display increased citrulline, ammonia and glutamine [Haviv et al 2014]. DLD deficiency is caused by biallelic pathogenic variants in DLD.

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.

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
  • Consultation with a clinical geneticist

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 ACMG-ACT Sheet, ACMG Algorithm.

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 [Häberle et al 2012].

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 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 possible 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 [2001] and Häberle et al [2012].
  • Glycerol phenylbutyrate (Ravicti®) is a more palatable option. The initial dosage for phenylbutyrate-naïve patients 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 than100 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 urea cycle disorders is the only known curative therapy [Morioka et al 2005]. Transplantation eliminates the need for dietary protein restriction but does not reverse any neurologic sequelae that affected individuals may have at the time of transplant.

Liver transplantation should ideally be performed in affected individuals who are younger than age one year (prior to the development of any neurocognitive impairment) but older than age three months and/or above 5 kg body weight, to decrease complications and improve survival rates [Häberle et al 2012].

  • 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].
  • Survival rates in those who underwent liver transplantation prior to age two years was between 90% and 95% five years post transplant [Bourdeaux et al 2007, Perito et al 2014].
    Note: Although liver transplantation cures the ASS enzyme deficiency, arginine is extrahepatically synthesized and remains low post-transplantation, requiring ongoing supplementation.
  • Living related-donor liver transplantation
    • 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 (200-400 µmol/L). The mother, a heterozygote, had 28% residual ASS1 enzyme activity [Ando et al 2003].

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.

Age-appropriate immunizations including the influenza vaccine should be provided.

Surveillance

Follow up in a metabolic clinic with a qualified metabolic nutritionist and clinical biochemical geneticist is required. Monitoring should include:

  • Evaluation of early warning signs of impending hyperammonemic episodes including mood changes, headache, lethargy, nausea, vomiting, refusal to feed, and ankle clonus;
  • Plasma ammonia and amino acid analysis to identify hyperammonemia and deficiency of essential amino acids and impending hyperammonemia, respectively. Plasma glutamine concentration may rise 48 hours in advance of increases in plasma ammonia concentration [Brusilow & Horwich 2001].

Monitoring should occur frequently in neonates and infants, based on disease severity.

As affected individuals become older (teenage years and adulthood), clinical and biochemical monitoring can be extended to every six months to annually depending on clinical stability.

Agents/Circumstances to Avoid

Avoid the following:

  • Excess protein intake
  • Obvious exposure to communicable diseases

Evaluation of Relatives at Risk

Because the long-term prognosis for individuals with citrullinemia type I depends on initial and peak plasma ammonia concentration, it is important that at-risk sibs be identified as soon as possible.

Evaluations can include:

  • Molecular genetic testing if the pathogenic variants in the family are known; in utero diagnosis (which permits appropriate oral therapy beginning with first feeds), if possible, is preferred.
  • 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 has recently finished.

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

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.
  • 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 CTNL1 are obligate heterozygotes (carriers) for a pathogenic variant in ASS1.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier of an ASS1 pathogenic variant.

Carrier (Heterozygote ) Detection

Carrier testing for at-risk relatives requires prior identification of the ASS1 pathogenic variants in the family.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

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

  • Molecular genetic testing. Once the ASS1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible options.
  • Argininosuccinate synthase enzyme activity can be measured in uncultured fetal tissue obtained by chorionic villus sampling (CVS) or cultured amniocytes obtained by amniocentesis if the familial pathogenic ASS1 variants have not been identified.
    Note: 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].

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.

  • My46 Trait Profile
  • 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)
    United Kingdom
    Phone: 0800-652-3181
    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

GeneChromosome LocusProteinLocus SpecificHGMD
ASS19q34​.11Argininosuccinate synthaseASS1 @ LOVDASS1

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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 near the 5' end of exon 3. At least 14 ASS1 pseudogenes are known. For a detailed summary of gene and protein information, see Table A, Gene.

Benign (or mild clinical disease) allelic variants. In the homozygous state p.Gly362Val is associated with mild or no clinical symptoms, as is compound heterozygosity for c.[323G>T];[970+5G>A] [Häberle et al 2002]. Fifty percent of individuals with non-classic presentations were found to be homozygous for one of the the following three missense variants: p.Trp179Arg, p.Val263Met, or p.Gly362Val [Rüegger et al 2014].

Table 2.

ASS1 Variants Associated with Mild or No Clinical Symptoms

Genotype 1, 2DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
Homozygousc.257G>Ap.Arg86HisNM_000050​.4
NP_000041​.2
Homozygousc.535T>Cp.Trp179Arg
Homozygousc.787G>Ap.Val263Met
Homozygousc.794G>Ap.Arg265His
Homozygousc.851C>Tp.Thr284Ile
Homozygousc.1085G>Tp.Gly362Val
Compound heterozygousc.[323G>T];[970+5G>A]--
Homozygousc.773+49C>T--

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.
2.

Pathogenic allelic variants. Engel et al [2009] defined 87 ASS1 pathogenic variants 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 variants 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 Genotype- Phenotype Correlations and Table 3.

Table 3.

ASS1 Pathogenic Variants Discussed in the GeneReview

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
c.257G>Ap.Arg86His 2NM_000050​.4
NP_000041​.2
c.421-2A>G
(IVS6-2A>G)
--
c.794G>Ap.Arg265His 2
c.910C>Tp.Arg304Trp
c.1168G>Ap.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.

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. Mutated 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

  • Urea Cycle Disorders Conference Group. Consensus statement from a conference for the management of patients with urea cycle disorders. Available online. 2001. Accessed 10-6-16.

Literature Cited

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Chapter Notes

Revision History

  • 1 September 2016 (ma) Comprehensive update posted live
  • 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
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