Citrullinemia

Actionability Pediatric Summary Report

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: ASS1 (HGNC:758)
• Literature Search: 10/26/2020
• Curation Status: Released (1.0.4)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
ASS1	citrullinemia type I (0008988)	215700	Strong Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion computed according to the rubric.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity and mortality due to hyperammonemic crises / Referral to specialist to guide dietary management, arginine, and nitrogen scavengers and emergency management to mitigate hyperammonemic crises	2	3C	3B	2	10CB

Severity of Outcome

Prevalence of the Genetic Condition

Citrullinemia type 1 (CTLN1) has been estimated to occur in 1/57,000 to 1/100,000 births. Estimates from newborn screening programs are: 2/44,300 newborns in Korea, 1/200,000 newborns in New England, 1/118,543 newborn in Taiwan, 1/77,811 newborns in Austria, and 1/250,000 newborns in a study that included Texas, New York, Michigan, California, Massachusetts, North Carolina and Wisconsin. In a study of 614 patients in a urea cycle disorder registry that included 87 with CTLN1, 57 (66%) had the neonatal form and 30 (34%) had the late onset form.

Clinical Features (Signs / symptoms)

CTLN1 results from deficiency of argininosuccinate synthase in the urea cycle. It presents as a clinical spectrum that includes several forms. The distinction between forms is based on clinical findings and is not clear-cut. A hallmark feature is hyperammonemia that can be triggered by protein overload, catabolic events, or certain drugs and can lead to neurological deficits. Liver failure is now recognized as a primary presentation of CTLN1. Hepatic dysfunction, when present, is often noted at the time of initial hyperammonemic episode but has also developed in individuals not experiencing significant hyperammonemia. Clinical forms include:

• An acute neonatal form (“classic” form): Infants appear normal at birth, but within a week on a full protein diet may develop progressive lethargy, somnolence, poor feeding, rapid breathing, vomiting, and seizures. Increased intracranial pressure (ICP), secondary to hyperammonemia, may develop and result in increased neuromuscular tone, spasticity, and ankle clonus.

• A late-onset form (“non-classic” form): Signs and symptoms may occur at any age and may be milder than the acute neonatal form for unknown reasons. Episodes of hyperammonemia are similar to the acute neonatal form, but initial neurologic findings may be more subtle due to the older age of individuals. Findings include recurrent lethargy, somnolence, intense headache, scotomas, migraine-like episodes, ataxia, slurred speech, intellectual disability, respiratory alkalosis, and rapid breathing.

• A form without symptoms or hyperammonemia.

• A form in women with onset of severe symptoms during pregnancy or post-partum, which lead to psychosis, coma, and death.

Natural History (Important subgroups & survival / recovery)

For the classic form, without prompt intervention, hyperammonemia and accumulation of other toxic metabolites result in increased ICP, seizures, loss of consciousness, and death. Children diagnosed and treated promptly may survive for an indeterminate period of time, but usually with significant neurologic deficits and recurrent hyperammonemic crises. The longest survival of an untreated infant with classic CTLN1 is 17 days. For the non-classic form, without prompt intervention, increased ICP occurs with seizures, loss of consciousness, and death. Determining the prognosis prospectively can be difficult in some individuals who fit the biochemical phenotype but may or may not have serious clinical illness. CTLN1 in adulthood can be unmasked by serious stressors including pregnancy and childbirth, which typically presents as hyperammonemia. Rare cases with adult-onset CTLN1 have presented with acute liver failure. Current mortality among neonatal plus late onset has been estimated as 7%, likely due to increased neonatal screening and improved treatment.

Likelihood of Outcome

Prevalence of Genetic Variants

The prevalence of pathogenic variants in ASS1 associated with CTLN1 is unknown. However, a pathogenic variant in ASS1 has been detected in 96% of patients with CTLN1.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

For “classic” CTLN1, 56% of infants are symptomatic by age 4 days and 67% by age one week.

Tier 3

A study investigating the correlation between CTLN1 disease severity and residual argininosuccinate synthase activity reported a mean number of 1.23 (SD=1.33; range=0.34-5.5) hyperammonemic events per year in patients with ≤8.1% enzyme activity (n=17), while patients with higher enzyme activity (n=26) had a mean number of 0.08 (SD=0.25; range=0-1.0) hyperammonemic events per year.

Tier 5

In a case series of 38 individuals with biochemically diagnosed CTLN1, 7 individuals (18%) were either diagnosed or had their first presenting symptom at 18 years and older (range 18 to 39 years). Of the 15 individuals that became pregnant, 4 (27%) developed severe symptoms such as psychosis during pregnancy of postpartum.

Tier 5

Expressivity

CTLN1 is associated with a spectrum of clinical presentations. Though certain pathogenic variants are associated with some phenotypes, the phenotype cannot be predicted in all instances.

Tier 3

Intervention Effectiveness

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making following newborn screening: https://www.acmg.net/PDFLibrary/Citrullinemia.pdf

To establish the extent of disease and needs in an individual diagnosed with CTLN1, the

following evaluations are recommended:

• Measurement 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.

Tier 4

The mainstay of long-term management is dietary treatment based on minimizing the nitrogen load on the urea cycle under the expertise of a specialist metabolic dietician. The amount of natural protein tolerated by each patient must be individually determined, including avoidance of over-restriction which may compromise growth and cause metabolic instability. If protein tolerance is very low and patient is not metabolically stable, then essential amino acid supplementation may be needed. Dietary management plans can change with stages of development or situations such as pregnancy and lactation. However, asymptomatic patients and patients with the mild phenotype may not require dietary therapy. No effectiveness evidence was available for dietary treatment alone; however, it has been assessed in trials in conjunction with other treatments (see below).

Tier 2

Long-term treatment may also include nitrogen scavengers, including sodium benzoate or sodium phenylbutyrate (PBA).

Tier 2

L-arginine is an essential amino acid because of its impaired synthesis and must be supplemented as such or as its precursor L-citrulline. Citrulline serves as a vehicle for nitrogen removal via their excretion in the urine and thus arginine administration reduces the frequency of hyperammonemic episodes. A study of 88 patients with urea cycle disorders (14 had CTLN1) reported that long-term management with protein restriction combined with more extensive management (arginine/citrulline, essential amino acid supplements, and sodium benzoate) led to increased survival compared to protein restriction alone (63.6% vs. 38.6%, respectively; p=0.045), though this difference was limited to cases that presented neonatally.

Tier 2

A study described outcomes in 3 patients with CTLN1 identified prenatally and treated prospectively at birth with dietary modifications and sodium benzoate, sodium phenylacetate, and arginine. All patients survived (follow-up ranged from 42 to 83 months) and, though all had some developmental delay, outcomes were more favorable compared to patients rescued from hyperammonemic coma.

Tier 5

In the event of an intercurrent illness or other event that can precipitate a hyperammonemic episode (e.g., menarche, menses, pregnancy, menopause, childbirth), an emergency or “sick-day” regimen should be developed. This should include decrease of protein intake, increase of non-protein calories (e.g., glucose), maximize nitrogen scavenger prescription, fluid intake, and aggressive treatment of the underlying illness. Patients should carry an emergency card or bracelet and instructions for emergency treatment. The report of fatal hyperammonemia under severe catabolic circumstances in asymptomatic patients highlights the need for adopting an emergency protocol for hyperammonemia even in asymptomatic patients.

Tier 2

Early clinical suspicion and prompt diagnosis of hyperammonemia episodes are crucial for favorable outcomes. The start of ammonia detoxification and measures to reverse catabolism must not be delayed. Treatment of patients in hyperammonemic crisis depends in the severity of the hyperammonemia and clinical status and includes stopping protein intake, intravenous 10% glucose to prevent catabolism, L-arginine, maintaining hydration, ammonia scavengers (sodium benzoate or sodium PBA), hemo(dia)filtration, and regular monitoring of blood ammonia levels. Patients should then be transferred without delay to a specialist care center.

Tier 2

A 25-year open-label, uncontrolled clinical trial of intravenous sodium phenylacetate and sodium benzoate as an emergency treatment of acute hyperammonemia reported that 299 patients with urea cycle disorders (80 with CTLN1) experienced a total of 1181 episodes of hyperammonemia and survived 96% (1132/1181) of them, with an overall survival of 84% (250/299).

Tier 5

Elective surgery should be performed in centers with a metabolic department including emergency treatment options for hyperammonemia. To minimize decompensation risks, elective surgery should be undertaken when the patient is completely well, including no minor intercurrent illness and normal ammonia/amino acid levels. The day before surgery, drug treatment should be switched to IV and glucose (10%) infused to ensure anabolism. The patient should be first on the day’s surgical schedule. Post-surgery, close monitoring of the clinical status and ammonia levels is required, shifting to oral medications and diet and stopping the IV glucose only if the patient is well and metabolically stable.

Tier 2

The only available curative treatment is liver transplantation, allowing return to a normal diet and stopping drug administration which leads to a better quality of life. It may be considered in all patients with severe neonatal onset, progressive liver disease, or recurrent metabolic decompensation and hospitalizations despite medical therapy. It does not reverse established neurological sequelae. Ideally it should be performed in a patient without severe neurological damage while in a stable metabolic condition. The 5-year post-transplantation survival rate for patients with urea cycle disorders is now approximately 80%.

Tier 2

A retrospective review described outcomes in 7 patients with CTLN1 who underwent liver transplantation (median age at transplant was 2.4 years [range: 1.3-6.5 years]; median follow-up was 3.1 years [range: 0.1-4.1 years]). All received standard medical and dietary care prior to transplant and underwent transplant due to frequent metabolic decompensation (n=4), elective (n=2), and acute liver failure (n=1). One child required retransplantation due to hepatic artery thrombosis. Graft and patient survival were 86% and 100%, respectively.

Tier 5

Surveillance

Patients, including asymptomatic patients, should be regularly monitored with:

• Biochemical tests: plasma ammonia, plasma amino acid profiles

• Clinical data: growth, signs of protein/vitamin deficiency, neurological exam, neurocognitive development, and liver size and structure

• Drug review

• Diet: protein intake, adjusted as needed for age and growth

• History of intercurrent illness

• Use of emergency regimen

• Echocardiogram for pulmonary hypertension.

Tier 2

Circumstances to Avoid

Every effort should be made to avoid triggering events.

Tier 2

Patients should avoid dehydration, an especially common occurrence among adults in connection with alcohol intake, excessive exercise, hiking, and airline flights.

Tier 2

Intravenous steroids for asthma and administration of valproic acid are contraindicated.

Tier 2

Nature of Intervention

Nature of Intervention

Interventions and treatments in this report include dietary therapy, amino acid supplementation, nitrogen scavengers, and liver transplant. A protein-restrictive diet may be burdensome. Nitrogen scavengers may be administered via granules, tablets, or liquid preparations or intravenously during acute episodes. At recommended doses, nitrogen scavengers are safe, but metabolic acidosis has been observed with high doses. Repeated boluses of scavengers and long-term treatment can lead to hypokalemia. Sodium PBA causes menstrual dysfunction/amenorrhea in ~25% of post-pubertal females and can decrease appetite, disturb taste, and cause disagreeable body odor. It may deplete branched-chain amino acids and increase the risk of endogenous protein catabolism. Since scavengers are esterified with coenzyme A, they could cause acetyl-CoA depletion, resulting in mitochondrial dysfunction and decreased N-acetylglutamate synthesis. Low albumin levels have been reported in some sodium PBA-treated patients, possibly because of decreased leucine and glutamine availability. Liver transplant requires immunological therapy and long-term follow-up. The inability to synthesize arginine extrahepatically persists, but this metabolic aberration has no recognized clinical impact.

Context: Adult Pediatric

Chance to Escape Clinical Detection

All states in the US include CTLN1 in their newborn screening programs by screening for elevated citrulline.

Context: Adult Pediatric

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			ASS1			215700	0008988

References List

Acute neonatal citrullinemia type I. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=247546

Adult-onset citrullinemia type I. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=247573

British Inherited Metabolic Disease Group. Hyperammonaeimia: Urea Cycle Disorders – Citrullinaemia and Argininosuccinic aciduria. (2005) URL: http://www.bimdg.org.uk/store/guidelines/ER-UCD2-v4_399113_09092016.pdf

CITRULLINEMIA, CLASSIC. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 215700, (2016) World Wide Web URL: http://omim.org/

Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A. (2007) Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. The New England journal of medicine. 356(1533-4406):2282-92.

Gao HZ, Kobayashi K, Tabata A, Tsuge H, Iijima M, Yasuda T, Kalkanoglu HS, Dursun A, Tokatli A, Coskun T, Trefz FK, Skladal D, Mandel H, Seidel J, Kodama S, Shirane S, Ichida T, Makino S, Yoshino M, Kang JH, Mizuguchi M, Barshop BA, Fuchinoue S, Seneca S, Zeesman S, Knerr I, Rodés M, Wasant P, Yoshida I, De Meirleir L, Abdul Jalil M, Begum L, Horiuchi M, Katunuma N, Nakagawa S, Saheki T. (2003) Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients. Human mutation. 22(1098-1004):24-34.

Haberle 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. (2012) Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet journal of rare diseases. 7(1750-1172):32.

Maestri NE, Hauser ER, Bartholomew D, Brusilow SW. (1991) Prospective treatment of urea cycle disorders. The Journal of pediatrics. 119(0022-3476):923-8.

National Organization for Rare Disorders. Urea Cycle Disorders (UCD). (2013) URL: https://rarediseases.org/physician-guide/urea-cycle-disorders/

Quinonez SC, Thoene JG. (1993) Citrullinemia Type I. GeneReviews^®.

Singh RH, Rhead WJ, Smith W, Lee B, Sniderman King L, Summar M. (2005) Nutritional management of urea cycle disorders. Critical care clinics. 21(0749-0704):S27-35.

Urea Cycle Disorders Conference group.. (2001) Consensus statement from a conference for the management of patients with urea cycle disorders. The Journal of pediatrics. 138(1 Suppl):S1-5.

Vara R, Dhawan A, Deheragoda M, Grünewald S, Pierre G, Heaton ND, Vilca-Melendez H, Hadžić N. (2018) Liver transplantation for neonatal-onset citrullinemia. Pediatric transplantation. 22(1399-3046):e13191.

Wykowski J, Keller C, Kucybala K. (2022) Adult-Onset Type 1 Citrullinemia Presenting as Postpartum Acute Liver Failure. The American journal of medicine. 135(1555-7162):e22-e23.

Zielonka M, Kölker S, Gleich F, Stützenberger N, Nagamani SCS, Gropman AL, Hoffmann GF, Garbade SF, Posset R. (2019) Early prediction of phenotypic severity in Citrullinemia Type 1. Annals of clinical and translational neurology. 6(2328-9503):1858-1871.