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Pediatric Summary Report Secondary Findings in Pediatric Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening Permalink P Current Version Rule-Out Dashboard Release History Status (Pediatric): Passed (Consensus scoring is Complete) Curation Status (Pediatric): Released 1.0.0 Status (Adult): Passed (Consensus scoring is Incomplete) A

GENE/GENE PANEL: ASS1

Condition: Citrullinemia

Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

Gene Condition Pairs(s)

Final Assertion

ASS1⇔0008988 (citrullinemia, classic)

Strong Actionability

Final Consensus Scoresa

Outcome / Intervention Pair

Severity

Likelihood

Effectiveness

Nature of the
Intervention

Total
Score

Gene Condition Pairs: ASS1 ⇔ 0008988 (OMIM:215700)

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

10CB

a. To see the scoring key, please go to : https://www.clinicalgenome.org/site/assets/files/2180/actionability_sq_metric.png

Topic

Narrative Description of Evidence

Ref

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

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.

1 2

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.

1 2 3 4 5 6 7

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. Current mortality among neonatal plus late onset has been estimated as 7%, likely due to increased neonatal screening and improved treatment.

1 2 3

2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.

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)

3 5 8 9

Long-term treatment may also include nitrogen scavengers, including sodium benzoate or sodium phenylbutyrate (PBA). (Tier 2)

3 5 8 9

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)

3 9

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)

3 5 8 9

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)

3 5 8 9

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)

3 9

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)

3 5 8 9

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)

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Recessive

1 3 5 6 7

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
(Include 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)

Relative Risk
(Include any high risk racial or ethnic subgroups)

Information on relative risk was not available for the Pediatric context.

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)

4. What is the Nature of the 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.

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

All states in the US include CTLN1 in their newborn screening programs by screening for elevated citrulline. (Tier 4)

However, patients manifesting severe neonatal hyperammonemia benefit little from newborn screening or even from early diagnosis because of their poor prognosis. Otherwise, the duration and severity of hyperammonemia strongly correlates with brain damage; thus, prompt diagnosis and treatment are essential to optimize outcomes. (Tier 3)

Description of sources of evidence:

Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.

Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.

Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.

Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.

Tier 5: Evidence from a non-systematically identified source.

Date of Search: 10.26.2020

Gene Condition Associations

Gene

Condition Associations

OMIM Identifier

Primary MONDO Identifier

Additional MONDO Identifiers

ASS1

215700

0008988

Reference List

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

2. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. CITRULLINEMIA, CLASSIC. MIM: 215700: 2016 Jul 07. World Wide Web URL: http://omim.org.

3. 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. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. (2012) 7:32.

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

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

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

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

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

9. Consensus statement from a conference for the management of patients with urea cycle disorders. J Pediatr. The Journal of pediatrics. (2001) 138(1 Suppl):S1-5.

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

11. Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med. (2007) 356(1533-4406):2282-92.

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

13. Zielonka M, Kölker S, Gleich F, Stützenberger N, Nagamani SCS, Gropman AL, Hoffmann GF, Garbade SF, Posset R. Early prediction of phenotypic severity in Citrullinemia Type 1. Ann Clin Transl Neurol. (2019) 6(2328-9503):1858-1871.