Clinical characteristics.

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. Distinction between the forms is based primarily on clinical findings, although emerging evidence suggests that measurement of residual argininosuccinate synthase enzyme activity may help to predict those who are likely to have a severe phenotype and those who are likely to have an attenuated phenotype.

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. Even with chronic protein restriction and scavenger therapy, long-term complications such as liver failure and other (rarely reported) organ system manifestations are possible.

The late-onset form may be milder than that seen in the acute neonatal form, but commences later in life for reasons that are not completely understood. 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. Women with onset of severe symptoms including acute hepatic decompensation during pregnancy or in the postpartum period have been reported. Furthermore, previously asymptomatic and non-pregnant individuals have been described who remained asymptomatic up to at least age ten years, with the possibility that they could remain asymptomatic lifelong.

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), elevated plasma citrulline concentration (usually >500 µmol/L), and absent argininosuccinate and/or by identification of biallelic pathogenic variants in ASS1 on molecular genetic testing.

Management.

Treatment of manifestations: Liver transplantation is the only known curative therapy and eliminates the need for dietary restriction. Transplantation is ideally 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.

• Daily routine treatment in those who have not undergone a liver transplantation includes lifelong protein restriction in conjunction with a metabolic nutritionist; nitrogen scavenger medications; arginine supplementation; consideration of carnitine supplementation in those with secondary carnitine deficiency; addressing increased energy/caloric demands through tube feedings (as needed); and routine treatment of developmental delay / intellectual disability.
• Acute inpatient treatment of a metabolic crisis includes addressing hyperammonemia through withholding of all protein intake for a maximum of 24 to 28 hours; pharmacologic nitrogen scavenger therapy; and consideration of dialysis (the most effective means of reducing plasma ammonia concentration rapidly). To address increased catabolism, administration of high-energy fluids (and insulin, as needed) and intravenous intralipids is typically required. However, care must be taken to avoid electrolyte imbalance and fluid overload, which can contribute to the development of increased intracranial pressure. The patient 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).

Prevention of secondary complications: Education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors; written protocols for maintenance and emergency treatment should be provided to parents and primary care providers / pediatricians, and to teachers and school staff. For those affected individuals requiring any sedated procedure where a person cannot eat for an extended period of time, drug treatment should be switched to IV and nutrition with 10% glucose with age-appropriate electrolytes should be administered via IV to promote anabolism starting as soon as the patient is NPO.

Surveillance: Follow up in a metabolic clinic with a qualified metabolic nutritionist and clinical biochemical geneticist is required. Measurement of growth parameters; evaluation of nutrition status and safety of oral intake; assessment for early warning signs of impending hyperammonemic episodes (mood changes, headache, lethargy, nausea, refusal to eat); review of dietary assessment; monitoring of developmental progress/educational needs; assessment of mobility and self-help skills; and measurement of carnitine levels (for those on sodium benzoate) at each visit. Plasma amino acid analysis at least every three months during the first year of life and every six to 12 months in the teenage/adult years (depending on clinical stability).

Agents/circumstances to avoid: Excessive protein intake, prolonged fasting, and obvious exposure to communicable diseases.

Evaluation of relatives at risk: It is important that at-risk sibs be identified as soon as possible, either through molecular genetic testing (if the pathogenic variants in the family are known) or measurement of plasma concentrations of ammonia and citrulline on the first day of life. Elevation of either above acceptable levels (ammonia >100 µmol/L or plasma citrulline >~100 µmol/L) is sufficient evidence to initiate treatment in a newborn.

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.

Genetic counseling.

CTLN1 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 testing for a pregnancy at increased risk are possible if the pathogenic variants in the family are known.

Suggestive 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), elevated plasma citrulline concentration (usually >500 µmol/L), and absent argininosuccinate and/or by the identification of biallelic pathogenic (or likely pathogenic) variants in ASS1 on molecular genetic testing (see Table 1).

Note: (1) Measurement of argininosuccinate synthase (ASS) enzyme activity is not currently widely used because the clinical presentation and relatively specific pattern of metabolites found in affected individuals are sufficient to establish the diagnosis. (2) Historically, determining the prognosis prospectively was difficult in some individuals who fit the biochemical phenotype but may or may not have had serious clinical illness. Newer data suggest that individuals with ≥8% residual ASS enzymatic activity have less frequent and less severe hyperammonemic events, and better cognition. A cutoff value of 8% residual enzymatic activity has been proposed as a threshold for discrimination between severe (≤8% activity) and mild-to-moderate (>8% activity) disease [Zielonka et al 2019] (see ASS Enzyme Activity). (3) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

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.

It has been proposed that measurement of residual enzyme activity can be used to classify individuals as "predicted severe" (≤8% activity) and "predicted attenuated" (>8% activity) [Zielonka et al 2019]. Using this model, individuals with cytosolic urea cycle disorders (inclusive of CTLN1 and argininosuccinic aciduria [ASA]) were overrepresented in a group diagnosed via newborn screening (NBS), while those with a predicted severe phenotype were initially diagnosed after onset of symptoms.

• Severity-adjusted analysis determined that individuals identified by NBS had a lower peak ammonia level than those diagnosed by symptoms. This effect was greater in individuals with residual enzyme activity >8% (initial mean ammonia within normal range) versus those with residual enzyme activity ≤8% (initial mean ammonia 318 µmol/L).
• Early diagnosis by NBS (vs diagnosis after symptom onset) for individuals with CTLN1 and ASA was associated with improved cognitive outcomes [Posset et al 2019].
• However, early diagnosis via NBS was not associated with lower frequency of hyperammonemic events, despite appropriate early treatment [Posset et al 2020].

Genotype-Phenotype Correlations

While certain ASS1 pathogenic variants are identified with particular phenotypes, the phenotype cannot be predicted in all instances [Engel et al 2009].

• Severe, classic (neonatal-onset) CTLN1 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. Other variants in this category include p.Gly14Ser, p.Arg157His, p.Glu191Lys, p.Gly324Ser, and p.Arg363Trp [Engel et al 2009, Laróvere et al 2009, Diez-Fernandez et al 2017].
• Mild (i.e., late-onset) CTLN1 is associated with 12 pathogenic variants, including p.Trp179Arg, p.Tyr190Asp, p.Ala202Glu, p.Val263Met, and p.Val269Met [Engel et al 2009, Diez-Fernandez et al 2017].

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

CTLN1 is the second-most frequent urea cycle disorder, and has been estimated to occur in 1:220,000 births [Posset et al 2020].

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 one in 118,543 [Niu et al 2010]
• In Austria: one in 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 argininosuccinate lyase deficiency: one in 117,000 [Summar et al 2013]

Neonatal ("Classic") Presentation

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

Hyperammonemia. 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). 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.

Classic citrullinemia type I (a defect in step 3 of the urea cycle) shares the phenotype of the typical acute neonatal hyperammonemia displayed by other defects in the first four steps in the urea cycle pathway: carbamoylphosphate synthetase I deficiency (step 1), ornithine transcarbamylase deficiency (step 2), and argininosuccinate lyase deficiency (step 4).

Milder Late-Onset Presentation

The milder late-onset citrullinemia type I phenotype shares a later onset with other disorders such as late-onset ornithine transcarbamylase 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.

Citrullinemia type II (CTLN2; citrin deficiency). The clinical course in adults with CTLN2 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.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CTLN1, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

See also ACMG ACT Sheet (pdf), ACMG Algorithm (pdf).

Transitional care from pediatric to adult-centered multidisciplinary care settings. As CTLN1 is a lifelong disorder with varying implications according to age, smooth transition of care from the pediatric setting is essential for long-term management and should be organized as a well-planned, continuous, multidisciplinary process integrating resources of all relevant subspecialties. Standardized procedures for transitional care do not exist for CTLN1 due to the absence of multidisciplinary outpatient departments.

• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with CTLN1 together with pediatric metabolic experts, dietitians, psychologists, and social workers.
• As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential.

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

One of the most important components of management (as it relates to prevention of secondary complications) is education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors (see Table 8; see also Tables 6 and 7).

Surveillance

Follow up in a metabolic clinic with a qualified metabolic nutritionist and clinical biochemical geneticist is required (see Table 9).

Agents/Circumstances to Avoid

Avoid the following:

• Excess protein intake
• Prolonged fasting
• Obvious exposure to communicable diseases

Evaluation of Relatives at Risk

For early diagnosis and treatment. Because the long-term prognosis for individuals with CTLN1 depends on initial and peak plasma ammonia concentration, it is important that at-risk sibs be identified as soon as possible. Evaluations can include the following:

• 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.
• Newborn full sibs of individuals who had early-onset presentation and in whom prenatal genetic testing has not been performed should be started on a protein-restricted diet with consideration of immediately starting an IV with provision of (1) age-appropriate glucose infusion rates and appropriate electrolytes and (2) protein-free infant formula, pending completion of the diagnostic evaluation.

For liver donation. Relatives who are potential liver donors should undergo molecular genetic testing to clarify their genetic status so that only those who do not have biallelic ASS1 pathogenic variants are evaluated further. In living related-donor transplants for individuals with urea cycle disorders, heterozygosity does not appear to be problematic if the donor is asymptomatic; symptomatic heterozygous donor candidates should not be considered [Häberle et al 2019].

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.

See MotherToBaby for further information on medication use during pregnancy.

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 a temporizing measure for individuals with CTLN1 awaiting transplantation have completed.

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 (CTLN1) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an ASS1 pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an ASS1 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same 2 pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) have no symptoms of the urea cycle defect phenotype.

Sibs of a proband

• If both parents are known to be heterozygous for an ASS1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Sibs should be evaluated immediately after birth and placed on a protein-restricted diet until the diagnostic evaluation is complete (see Management, Evaluation of Relatives at Risk).
• Heterozygotes (carriers) have no symptoms of the urea cycle defect phenotype.

Offspring of a proband. The offspring of an individual with CTLN1 are obligate heterozygotes (carriers) for a pathogenic variant in ASS1.

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

Carrier 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 and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the ASS1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Argininosuccinate synthase enzyme activity can be measured in uncultured fetal tissue obtained by chorionic villus sampling or cultured amniocytes obtained by amniocentesis if the familial pathogenic ASS1 variants have not been identified. However, variability has been observed in citrulline incorporation assay results on normal specimens, which may be explained in part by biologic variation, limiting utility in prenatal diagnosis.

Note: Improvement in diagnostic accuracy using the ratio of citrulline-to-ornithine concentrations in amniotic fluid has been reported, with proposed approach of combining ASS1 sequencing and amniotic fluid citrulline-to-ornithine leading to the highest diagnostic yield [Miller et al 2014].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The translational product argininosuccinate synthase is a homotetramer of 186 kilodaltons. Each monomer consists of a nucleotide-binding domain, a synthetase domain, and a C-terminal helix. 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.

Failure of the urea cycle at this step leads to accumulation of citrulline, glutamine, and ammonia in plasma, and increased orotic acid production and excretion in the urine. Subsequently there are low plasma levels of argininosuccinate and arginine. High citrulline levels differentiate cytosolic from mitochondrial urea cycle disorders. Citrulline includes in its molecular structure one molecule of ornithine and one atom of waste nitrogen, as opposed to argininosuccinate, which carries two atoms of waste nitrogen, making citrulline a poorer waste nitrogen carrier. Urinary excretion of citrulline helps to remove waste nitrogen, though at the expense of two molecules of ornithine per urea equivalent. Hyperammonemic episodes are more frequent in individuals with citrullinemia type I compared to argininosuccinate lyase deficiency, as secondary impairment of ornithine transcarbamylas occurs in part due to poor bioavailability of ornithine [Häberle & Rubio 2016].

Mechanism of disease causation. Loss of function

ASS1-specific laboratory technical considerations. 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.

Author Notes

Kristen N Lee, MD
Division of Pediatric Genetics, Metabolism, and Genomic Medicine
Division of Genetic Medicine
Michigan Medicine
D5240 Medical Professional Building
1500 E Medical Center Drive
Ann Arbor, MI 48109

Dr Lee is a clinical and medical biochemical geneticist in the Pediatric, Adult Medical, and Cancer Genetics Clinics at Michigan Medicine. Her research interests include newborn screening, treatment of genetic disease including clinical trials for metabolic disorders, outcomes in adults with metabolic disorders, medical education for genetics trainees, and delineation of newly recognized genetic syndromes.

Shane C Quinonez, MD
Division of Pediatric Genetics, Metabolism, and Genomic Medicine
Division of Genetic Medicine
Michigan Medicine
D5240 Medical Professional Building
1500 E Medical Center Drive
Ann Arbor, MI 48109

Dr Quinonez is a clinical and clinical biochemical geneticist in the Pediatric, Adult Medical, and Cancer Genetics Clinics at Michigan Medicine. His research interests include the expansion of genetic services in low- and middle-income countries, treatment of genetic disease including clinical trials for metabolic disorders, increasing diversity, equity, and inclusion in the field of genetics, and medical education for genetics trainees.

Author History

Kristen N Lee, MD (2022-present)
Shane C Quinonez, MD (2014-present)
Jess G Thoene, MD; University of Michigan (2004-2022)

Revision History

• 18 August 2022 (ma) Comprehensive update posted live
• 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

Published Guidelines / Consensus Statements

• Häberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, Karall D, Martinelli D, Crespo PS, Santer R, Servais A, Valayannopoulos V, Lindner M, Rubio V, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;7:32. [PubMed]
• Häberle J, Burlina A, Chakrapani A, Dixon M, Karall D, Lindner M, Mandel H, Martinelli D, Pintos-Morell G, Santer R, Skouma A, Servais A, Tal G, Rubio V, Huemer M, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders: first revision. J Inherit Metab Dis. 2019;42:1192-230. [PubMed]
• The Urea Cycle Disorders Conference Group. Consensus statement from a conference for the management of patients with urea cycle disorders. Available online. 2001. Accessed 8-4-22.

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