Lichter-Konecki U, Caldovic L, Morizono H, Simpson K, Ah Mew N, MacLeod E, Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, and Amemiya A
Clinical Characteristics: Ornithine transcarbamylase (OTC) deficiency can occur as a severe neonatal-onset disease in males (but rarely in females) and as a post-neonatal-onset (also known as "late-onset" or partial deficiency) disease in males and females. Males with severe neonatal-onset OTC deficiency are asymptomatic at birth but become symptomatic from hyperammonemia in the first week of life, most often 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 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, and executive function deficits., Diagnosis/testing: The diagnosis of OTC deficiency is established in a male proband with suggestive clinical and laboratory findings and at least ONE of the following: A hemizygous pathogenic variant in OTC by molecular genetic testing. A markedly abnormal increase of orotic acid excretion (≥20 umol/mmol creatinine) in a random urine collection or after an allopurinol challenge test, along with a past medical history of biochemical features consistent with OTC deficiency (e.g., elevated ammonia, elevated glutamine and low-to-normal citrulline), as well as absence of biochemical or DNA evidence suggestive of another inborn error of metabolism. Decreased OTC enzyme activity in liver. The diagnosis of OTC deficiency is usually established in a female proband with the suggestive clinical and laboratory findings and with at least ONE of the following: A heterozygous pathogenic variant in OTC by molecular genetic testing. A markedly abnormal increase of orotic acid excretion (≥20 umol/mmol creatinine) in a random urine collection or after an allopurinol challenge test, along with a past medical history of biochemical features consistent with OTC deficiency (e.g., elevated ammonia, elevated glutamine and low-to-normal citrulline), as well as absence of biochemical or DNA evidence suggestive of another inborn error of metabolism. Measurement of OTC enzyme activity in liver is not a reliable means of diagnosis in females., Management: Treatment of manifestations: Treatment is best provided by a metabolic physician / biochemical geneticist and specialist metabolic dietitian; 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 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, liver transplant is typically considered in those who have frequent hyperammonemic episodes. Complications of OTC deficiency, including developmental delay and intellectual disability, are treated according to the standard of care for these conditions while monitoring for signs of liver disease. Surveillance: At the start of therapy, routine measurement of plasma ammonia and plasma amino acids every two weeks with gradual extension of the intervals between testing. Laboratory analysis for vitamin and mineral deficiencies annually or as indicated by the metabolic dietician. 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, fasting, systemic corticosteroids, 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 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 should be instituted at birth and maintained until the diagnosis has been 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 according to pre-pregnancy protocols adapted for needs during pregnancy; those who are asymptomatic need to avoid catabolism in the peripartum and postpartum periods and should be treated accordingly., Genetic Counseling: OTC deficiency is inherited in an X-linked manner. If the mother of a proband has an OTC pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may or may not develop clinical findings related to the disorder. Males with OTC deficiency transmit the pathogenic variant to all of their daughters and none of their sons. Molecular genetic heterozygote testing for at-risk female relatives and prenatal and preimplantation genetic testing for OTC deficiency are possible if the OTC pathogenic variant has been identified in the family., (Copyright © 1993-2022, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.)