Question

1. A patient with OTC deficiency has recurrent hyperammonemic events over a 3-month period despite reduced protein intake and increased doses of sodium benzoate and sodium phenylacetate. What are the factors that need to be considered as a cause of the hyperammonemia in this individual? (Consider the dynamic of nitrogen balance over this period.) What is the likely treatment?

Answer 1

Ornithine transcarbamylase (OTC) deficiency can occur as a severe neonatal-onset disease in males (but rarely in females) and as a post-neonatal-onset (partial deficiency) disease in males and females. Males with severe neonatal-onset OTC deficiency are typically normal at birth but become symptomatic from hyperammonemia on day two to three of life and are usually catastrophically ill by the time they come to medical attention. After successful treatment of neonatal hyperammonemic coma, these infants can easily become hyperammonemic again despite appropriate treatment; they typically require liver transplant by age six months to improve quality of life. Males and heterozygous females with post-neonatal-onset (partial) OTC deficiency can present from infancy to later childhood, adolescence, or adulthood. No matter how mild the disease, a hyperammonemic crisis can be precipitated by stressors and become a life-threatening event at any age and in any situation in life. For all individuals with OTC deficiency, typical neuropsychological complications include developmental delay, learning disabilities, intellectual disability, attention deficit hyperactivity disorder (ADHD), and executive function deficits.

Treatment of manifestations:

Treatment is best provided by a clinical geneticist and a nutritionist experienced in the treatment of metabolic disease; treatment of hyperammonemic coma should be provided by a team coordinated by a metabolic specialist in a tertiary care center experienced in the management of OTC deficiency. The mainstays of treatment of the acute phase are the rapid lowering of the plasma ammonia level to ≤200 μmol/L (if necessary, with renal replacement therapy); use of ammonia scavenger treatment to allow excretion of excess nitrogen via alternative pathways; reversal of catabolism, and reducing the risk of neurologic damage. The goals of long-term treatment are to promote growth and development and to prevent hyperammonemic episodes. In severe, neonatal-onset urea cycle disorders, liver transplantation is typically performed by age six months to prevent further hyperammonemic crises and neurodevelopmental deterioration. In females and males with partial OTC deficiency, the liver transplant is typically considered in those who have frequent hyperammonemic episodes. Complications of OTC deficiency, including ADHD and learning disability/intellectual disability, are treated according to the standard of care for these conditions while monitoring for signs of liver disease.

Prevention of primary manifestations:

If neonatal-onset OTC deficiency is diagnosed prenatally, intravenous (IV) treatment with ammonia scavengers within a few hours of birth (before the ammonia level rises) can prevent a hyperammonemic crisis and coma. For preventive measures after the neonatal period see Treatment of manifestations.

Prevention of secondary complications:

Avoid over restriction of protein/amino acids; use gastrostomy tube feedings as needed to help avoid malnutrition; practice careful hand hygiene among all who have contact with the affected individual to minimize risk of infection; give immunizations on the usual schedule, including annual flu vaccine; provide multivitamin and vitamin D supplementation; and use antipyretics appropriately (e.g., ibuprofen is preferred over acetaminophen because of the potential for liver toxicity).

Surveillance:

At the start of therapy, routine measurement of plasma ammonia and plasma amino acids. Assess liver function (depending on symptoms) every three to six months or more often when previously abnormal. Perform neuropsychological testing at the time of expected significant developmental milestones.

Agents/circumstances to avoid:

Valproate, haloperidol, systemic corticosteroids, fasting, and physical and psychological stress.

Evaluation of relatives at risk:

If the pathogenic variant in the family is known and if prenatal testing has not been performed, it is appropriate to perform biochemical and molecular genetic testing on at-risk newborns (males and females) as soon after birth as possible so that the appropriate treatment or surveillance (for those with the family-specific pathogenic variant) can be promptly established. If the pathogenic variant in the family is NOT known, biochemical analysis (plasma amino acid analysis, ammonia level), an allopurinol challenge test (in older individuals), and/or OTC enzyme activity measurement in liver (males only) can be performed. Preventive measures at birth should be instituted until such a time as the diagnosis can be ruled out.

Pregnancy management:

Heterozygous females are at risk of becoming catabolic during pregnancy and especially in the postpartum period. Those who are symptomatic need to be treated throughout pregnancy as necessary; those who are asymptomatic need to avoid catabolism in the peripartum and postpartum periods and should be treated as needed.

Genetic counseling.

OTC deficiency is inherited in an X-linked manner. If an affected male reproduces, none of his sons will be affected and all of his daughters will inherit the pathogenic variant and may or may not develop clinical symptoms related to the disorder. Heterozygous females have a 50% chance of transmitting the pathogenic variant with each pregnancy: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant may or may not develop clinical findings related to the disorder. Carrier testing for females at risk of being heterozygous and prenatal testing for pregnancies at increased risk is possible if the OTC pathogenic variant has been identified in an affected family member.