Arginase Deficiency

Clinical characteristics: Arginase deficiency in untreated individuals is characterized by episodic hyperammonemia of variable degree that is infrequently severe enough to be life threatening or to cause death. Most commonly, birth and early childhood are normal. Untreated individuals have slowing of linear growth at age one to three years, followed by development of spasticity, plateauing of cognitive development, and subsequent loss of developmental milestones. If untreated, arginase deficiency usually progresses to severe spasticity, loss of ambulation, complete loss of bowel and bladder control, and severe intellectual disability. Seizures are common and are usually controlled easily. Individuals treated from birth, either as a result of newborn screening or having an affected older sib, appear to have minimal symptoms.

Diagnosis/testing: The diagnosis of arginase deficiency is established in a proband with suggestive clinical and/or biochemical findings and confirmed by identification of biallelic pathogenic variants in ARG1 or, in limited instances, by failure to detect arginase enzyme activity (usually <1% of normal) in red blood cell extracts.

Management: Treatment of manifestations: Management should closely mirror that for urea cycle disorders, except that individuals with arginase deficiency are not as likely to have episodes of hyperammonemia; if present, such episodes respond to conservative management (e.g., intravenous fluid administration). Treatment should involve a team coordinated by a metabolic specialist. Routine outpatient management includes restriction of dietary protein and consideration of oral nitrogen-scavenging drugs (in those who have chronic or recurrent hyperammonemia). Treatment of an acutely ill (comatose and encephalopathic) individual requires: rapid reduction of plasma ammonia concentration; use of pharmacologic agents (sodium benzoate and/or sodium phenylbutyrate/phenylacetate) to promote excretion of excess nitrogen through alternative pathways; and introduction of calories supplied by carbohydrates and fat to reduce catabolism and the amount of excess nitrogen in the diet while avoiding overhydration and resulting cerebral edema. Standard treatment for seizures, spasticity, developmental delay / intellectual disability, and joint contractures. In those with persistent hepatic synthetic function abnormalities, fresh-frozen plasma should be considered prior to surgical procedures. In the rare instance of progression to hepatic fibrosis and cirrhosis, liver transplantation can be considered.

Prevention of primary manifestations: Maintenance of plasma arginine concentration as near normal as possible through restriction of dietary protein and use of oral nitrogen-scavenging drugs as necessary to treat hyperammonemia. Liver transplantation eliminates hyperargininemia and presumably the risk for hyperammonemia but is rarely necessary in arginase deficiency.

Surveillance: Regular follow up at intervals determined by age and degree of metabolic stability. Assessment of metabolic control (plasma ammonia, amino acid profile, and nutritional labs) at least monthly for the first year of life and as determined by a metabolic specialist after the first year of life; guanidinoacetate and liver function tests every six to 12 months; monitoring of growth and developmental progress at each visit.

Agents/circumstances to avoid: Valproic acid (exacerbates hyperammonemia).

Evaluation of relatives at risk: Plasma quantitative amino acid analysis, molecular genetic testing (if the family-specific pathogenic variants are known), or enzymatic testing in all sibs (especially younger ones) of a proband to allow early diagnosis and treatment of those found to be affected.

Pregnancy management: In general, affected pregnant women should continue dietary protein restriction and ammonia-scavenging medications (after an appropriate benefit/risk calculation) based on their clinical course before pregnancy.

Other: Immunizations on the usual schedule; appropriate use of antipyretics as indicated (ibuprofen preferred over acetaminophen).

Genetic counseling: Arginase deficiency 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. Heterozygotes (carriers) are asymptomatic. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the ARG1 pathogenic variants in the family are known.