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.

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.

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 multigene 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 multigene 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 are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

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 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].

• Severe, classic citrullinemia type I typically results from 22 defined pathogenic variants [Engel et al 2009]. The pathogenic variant in exon 15, p.Gly390Arg, remains the most prevalent associated with the classic phenotype [Engel et al 2009, Laróvere et al 2009].
• Mild (i.e., late-onset) citrullinemia type I is associated with 12 pathogenic variants [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]

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, UCD Conference Group 2001]. See ACMG-ACT Sheet, ACMG Algorithm.

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 CTLN1 awaiting transplantation has recently finished.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

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 (i.e., carriers of one ASS1 pathogenic variant).
• 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 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.
• 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].

Published Guidelines / Consensus Statements

• The Urea Cycle Disorders Conference Group. Consensus statement from a conference for the management of patients with urea cycle disorders. Available online. 2001. Accessed 5-29-19. [PubMed: 11148543]

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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 live
• 7 July 2004 (me) Review posted live
• 9 February 2004 (jt) Original submission