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.

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 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.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations 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.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis for at-risk pregnancies requires either prior confirmation of enzyme deficiency in an affected family member or prior identification of the disease-causing mutations in the family. 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) for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.

Genetically Related (Allelic) Disorders

No other phenotypes are associated with mutations in ASS1.

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 lethargic, feeds poorly, may vomit, and may develop signs of increased intracranial pressure [Brusilow & Horwich 2006]. 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 2006]. 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 25-year old woman 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 15-month old female 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].

Pregnancy. Although a healthy woman with untreated CTLN1 underwent two successful pregnancies [Potter et al 2004], 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].

Genotype-Phenotype Correlations

Although certain mutations 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 mutations [Engel et al 2009]. The mutation 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 mutations [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 of 545 (13.6%) individuals with urea cycle disorders referred to the Johns Hopkins Hospital from 1974 to 1994 [Brusilow & Horwich 2006].

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].

Evaluations Following Initial Diagnosis

To establish the extent of disease 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
• Genetics consultation

Treatment of Manifestations

Acute management of individuals with citrullinemia type I depends on early diagnosis, control of hyperammonemia, and control of intracranial pressure. Regular attendance at a metabolic clinic with access to a trained metabolic nutritionist is essential to proper management. See the American College of Medical Genetics and [www.acmg.net].

Ucyclyd protocol. The protocol designed by Brusilow and colleagues (Ucyclyd Pharma^®) should be followed. This protocol uses alternative means of waste nitrogen disposition (sodium benzoate and phenylacetate). Buphenyl^® (Ammonaps^®) (oral form of sodium phenylbutyrate) is approved by the FDA. Sodium phenylacetate/sodium benzoate, 10% intravenous solution, received FDA approval as Ammonul^® in February 2005.

Hemodialysis. Failure to control hyperammonia with the Ucyclyd protocol after two doses of medications described above requires emergency use of hemodialysis to reduce the plasma ammonia concentration to an acceptable level, following which institution of the sustaining infusion may be attempted, supplemented with additional doses over one hour as in the initial bolus infusion as needed to control plasma ammonia concentration [Lo et al 2003].

Diet. Concomitant with the Ucyclyd protocol, appropriate protein and calorie nutrition must be provided so that the affected individual does not become catabolic. In small infants, the 40 cal/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 cal/kg/day, advancing (as plasma ammonia concentration allows) to 1.0-1.5 g/kg/day of protein and 100-120 cal/kg/day. Standard TPN solutions of dextrose, aminosol, and intralipid are used.

Prevention of increased intracranial pressure. It is critical to monitor fluid balance, intake, and output and body weight, and to maintain the individual on the dry side of fluid balance: approximately 85 mL/kg of body weight per day in infants; 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.

Prevention of Primary Manifestations

Medication. 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. 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.

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 [2006].

Treatment with L-carnitine has been advocated as auxiliary treatment to prevent systemic hypocarnitinemia, which may result from therapy with acylating agents.

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

Liver transplantation. 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 the 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].

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

Prevention of Secondary Complications

Intercurrent infections (particularly some viral exanthems) may induce a catabolic state. Patients 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 2006].

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.

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.

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.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on testing 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.

Literature Cited

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Revision History

• 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