Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released 1.0.1
• Status (Adult): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: ASL
• Condition: Argininosuccinate Lyase Deficiency
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• ASL ⇔ 0008815 (argininosuccinic aciduria): Moderate Actionability

Actionability Rationale

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

Final Consensus Scores

Gene Condition Pairs: ASL ⇔ 0008815 (OMIM:207900)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity and mortality due to hyperammonemic crises / Referral to specialty team to guide dietary management and arginine and emergency management to mitigate hyperammonemic crises	2	3N	2C	2	9NC

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

Prevalence of the Genetic Condition

Argininosuccinate lyase deficiency (ASLD) has an estimated prevalence of 1:70,000 to 1:218,000 live births worldwide. However, ASLD is very likely underdiagnosed, making it difficult to assess the true frequency in the general population. [1, 2, 3]

Clinical Features

ASLD is due to a deficiency of the urea cycle enzyme argininosuccinate lyase (ASL). Clinical presentation of ASLD is variable and the two most common forms are:
• The severe neonatal-onset form, which is indistinguishable from other urea cycle disorders. It is characterized by hyperammonemia within the first few days after birth that can manifest as increasing lethargy, somnolence, refusal to feed, vomiting, tachypnea, and respiratory alkalosis. Absence of treatment leads to worsening lethargy, seizures, coma, and even death.
• The late-onset form manifestations range from episodic hyperammonemia triggered by acute infection, stress, or non-compliance with dietary and/or medication recommendations to cognitive impairment, behavioral abnormalities, and/or learning disabilities in the absence of any documented episodes of hyperammonemia.
Manifestations of ASLD that appear to be unrelated to the severity or duration of hyperammonemic episodes include neurocognitive deficiencies (attention deficit/hyperactivity disorder, developmental delay, seizures, and learning disability), liver disease (hepatomegaly, hepatitis, cirrhosis), trichorrhexis nodosa (coarse brittle hair that breaks easily), hypokalemia, and systemic hypertension. [1, 2, 3, 4, 5, 6]

Natural History

The late onset form can manifest at any age outside the newborn period. Some patients can be clinically asymptomatic despite showing clear biochemical signs of the disease. With early diagnosis and treatment, hyperammonemic episodes can be avoided but long-term complications (neurocognitive impairment, hepatic disease, and arterial hypertension) are frequent and have a negative effect on life-expectancy and quality of life. [1, 2]

2. How effective are interventions for preventing harm?

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.

Recommendations following the initial diagnosis of ASLD include:
• Consultation with a metabolic physician/biochemical geneticist and specialist metabolic dietician
• Neurocognitive assessment
• Baseline evaluation for hepatic involvement including hepatomegaly, hepatitis, and signs of liver failure
• Plotting of systolic and diastolic blood pressure on centile charts based on age and stature. (Tier 4) [1]

Long-term management aims to achieve normal development, prevent hyperammonemia, and includes: low protein diet to minimize nitrogen load on the urea cycle; essential amino acid, vitamin, and mineral supplementation when natural protein tolerance is too low to achieve normal growth and metabolic status; and medications to increase waste nitrogen excretion (can include arginine, sodium benzoate, and sodium phenylbutyrate for ASLD). (Tier 2) [4, 5]

Increasing reliance on newborn screening (NBS) programs for early diagnosis of ASLD allows evaluation of early treatment on disease progression, especially in the late-onset form. One study reported long-term outcomes of 13 infants diagnosed between age 4 and 6 weeks by NBS. All had low ASL enzyme activity. Despite optimal therapy with protein restriction and arginine supplementation, 4 (31%) had learning disability, 3 (23%) had mild developmental delay, 3 (23%) had seizures, and 6 (46%) had an abnormal EEG including abnormal sharp irregular background activity, frequent bilateral paroxysms, and increased slow wave activity. In a second study of 17 individuals with ASLD diagnosed by NBS, IQ was average or above average in 11 (65%), low average in five (29%), and in the mild intellectual disability range in one (6%). Four (24%) had an abnormal EEG without evidence of clinical seizures. Overall favorable outcomes in persons in this cohort may be attributable not only to early dietary and therapeutic interventions but also to the high proportion of persons with very mild disease. (Tier 3) [1]

Early clinical suspicion or prompt diagnosis of hyperammonemia is crucial for favorable outcomes. Patients should have a written treatment protocol with them to outline acute management and define specific medication dosage to hasten accurate treatment. The protocol should include contact information for the metabolic team and should be updated as the child grows. Protein intake should be stopped, and glucose given to prevent catabolism. Intravenous therapy with ammonia scavenging drugs should be started when ammonia elevation causes any central nervous system symptoms. High-dose arginine and sodium phenylbutyrate/sodium phenylacetate are very effective in reducing plasma levels of ammonia in patients with ASLD. However, there is no consensus at what ammonia level intravenous therapy should be started if no symptoms are present. Preparation for dialysis for ammonia clearance (preferably by hemodialysis) may take several hours and should be made as soon as possible, even before arrival of the patient. Any underlying trigger for the episode (e.g., infection) should be treated promptly. (Tier 2) [4, 5, 6]

To avoid hyperammonemic crises during intercurrent illness, a “sick day” regimen should be established. This may involve decreasing protein intake, increasing non-protein calories, and adjusting medication dosage. (Tier 2) [4, 5]

The changing needs of special situations such as pregnancy and lactation necessitate careful dietary management plans. (Tier 2) [4]

Elective surgery should be performed in centers with a metabolic department including emergency treatment options for hyperammonemia. (Tier 4) [4]

Liver transplant is the only available curative treatment. However, though it cures the hyperammonemia, it does not correct the arginine deficiency and arginine supplementation may still be needed. It may be considered in all patients with severe neonatal onset and is also indicated for patients with progressive liver disease, recurrent metabolic decompensations, hospitalizations despite medical therapy, and poor quality of life. Ideally, it should be performed in a patient without severe neurological damage while in a stable metabolic condition. Reported post-transplant survival in patients with and without urea cycle disorders has been the same, attaining ~95% at one year and ~90% at 5 years in large pediatric liver transplantation programs with “good” or “excellent” self-reported quality of life at 6–121 months post-transplant. (Tier 2) [4, 5]

Surveillance

Patient monitoring is lifelong (intervals should be individualized based on age, growth, severity, metabolic stability, and compliance with diet and drug therapy) and includes:
• Clinical monitoring: growth; head circumference; appearance of hair, skin, and nails; neurological examination; neurocognitive development; and neuroimaging
• Dietary assessment, including monitoring of protein intake
• Biochemical tests: plasma ammonia, plasma amino acids, vitamins (including cobalamin), minerals, trace elements, carnitine, ferritin, cholesterol and triglycerides in plasma, essential fatty acids in red blood cells and plasma, hemoglobin, albumin, pre-albumin, and urea ketones
• Dietary and drug review
• History of intercurrent illnesses and use of the emergency regimen. (Tier 2) [4, 5]

Other long-term surveillance should include:
• Measurement of blood pressure using the appropriate-sized cuff & plotting the centile values for age & stature (at each clinic visit)
• Liver function tests (ALT, AST) (every 6-12 months)
• Serum electrolyte analysis (every 1-2 years). (Tier 4) [1]

Circumstances to Avoid

Patients with ASLD should avoid excess protein intake, large boluses of protein or amino acids, less than recommended intake of protein, prolonged fasting or starvation, obvious exposure to communicable diseases, valproic acid, and intravenous steroids. (Tier 4) [1]

Ibuprofen for fever relief is preferred over acetaminophen as high doses of acetaminophen are potentially toxic to the liver. (Tier 2) [5]

Antiemetics should be used with extreme caution as they may mask signs of hyperammonemia. (Tier 2) [5]

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

Mode of Inheritance

Autosomal Recessive [1, 2, 3, 4]

Prevalence of Genetic Variants

Information on the prevalence of pathogenic variants associated with ASLD was not available.
Pathogenic variants in ASL are found in >90% of ASLD cases. (Tier 4) [1]

Penetrance

A study reviewed the clinical presentations and outcomes of patients with urea cycle defects, including 20 patients with ASLD (14 with neonatal-onset, 6 with late-onset). A mortality rate of about 60% was observed in the neonatal-onset group, while all late-onset patients were alive at time of publishing. The long-term neurological outcomes of 6 neonatal ASLD patients were presented: 4 had persistent learning disorders or mild neurological signs, one patient was reported to have severe neurological symptoms, while the final patient had an absence of neurological signs or psychomotor delay at age 0.5yrs. Two of these neonatal onset patients had died (at 8 years and 20 years of age). Of the 6 late-onset patients, 3 were reported to have long-term neurological outcomes of persistent learning disorders or mild neurological signs (age range: 8-20 years), while the remaining 3 had an absence of neurological signs or psychomotor delay (age range: 4-7 years). (Tier 5) [7]

Relative Risk

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

Expressivity

Some patients can be clinically asymptomatic despite showing clear biochemical signs of the disease. (Tier 4) [2]

Though the phenotypic manifestations may vary, in a family with one child with the severe neonatal-onset form subsequent children are likely to have the severe neonatal-onset form. In contrast, the phenotype of late-onset forms associated with partial ASL enzyme activity is variable. (Tier 4) [1]

4. What is the Nature of the Intervention?

Nature of Intervention

The interventions included in this report include dietary management that could be burdensome, nitrogen scavengers that are typically given orally several times a day with meals to avoid mucositis or gastritis, liver transplantation, and emergency protocols for hyperammonemia episodes. Nitrogen scavengers appear to be safe at recommended doses but may result in hypokalemia and metabolic acidosis with repeated boluses and high doses. Liver transplant requires immunological therapy and long-term follow-up. [4]

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

Chance to Escape Clinical Detection

All 50 states in the US include ASLD in their newborn screening programs. (Tier 4) [1]

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) [4]

Date of Search: 05.04.2021

Reference List

1. Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A. Argininosuccinate Lyase Deficiency. GeneReviews®. (1993)

2. Argininosuccinic aciduria. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=23

3. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. ARGININOSUCCINIC ACIDURIA. MIM: 207900: 2018 Sep 05. World Wide Web URL: http://omim.org.

4. 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.

5. 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.

6. British Inherited Metabolic Disease Group. Hyperammonaemia: Urea Cycle Disorders - Citrullinemia and Argininosuccinic Aciduria. (2017) Accessed: 2021-05-04. Website: https://www.bimdg.org.uk/store/guidelines/ER-UCD2-v4_403123_09092016.pdf

7. Nassogne MC, Héron B, Touati G, Rabier D, Saudubray JM. Urea cycle defects: management and outcome. J Inherit Metab Dis. (2005) 28(0141-8955):407-14.