The OTC gene is associated with X-linked ornithine transcarbamylase (OTC) deficiency (MedGen UID: 75692).
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OTC: Analysis includes the intronic variant NM_000531.5:c.540+265G>A.
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Pathogenic variants in the OTC gene are the only known cause of ornithine transcarbamylase (OTC) deficiency, which accounts for an estimated 59% of all urea cycle disorder diagnoses.
The OTC gene encodes the ornithine transcarbamylase enzyme which catalyzes the third step of the urea cycle. More specifically this mitochondrial enzyme converts carbamoyl phsophate and ornithine to citrulline and phosphate. The urea cycle is an important mechanism for the conversion of neurotoxic ammonia, a byproduct of protein degradation, to non-toxic urea, which can be safely removed from the body.
Ornithine transcarbamylase (OTC) deficiency
Deleterious mutations in OTC are associated with the urea cycle defect: ornithine transcarbamylase (OTC) deficiency (OMIM 311250). The urea cycle is essential for the conversion of neurotoxic ammonia, the waste product of protein metabolism, to non-toxic urea, which can then be safely excreted from the body (Online Mendelian Inheritance in Man: https://www.omim.org/entry/311250. accessed September 2017).
OTC deficiency often becomes evident in the first few days of life for patients with the severe, early-onset form, as ammonia begins to accumulate in the infant’s blood. Initial symptoms can include lethargy, poor feeding, and poorly controlled breathing rate or body temperature. If left untreated, hyperammonemia can result in seizures, coma, and death (National Library of Medicine. Genetics Home Reference: Ornithine transcarbamylase deficiency. https://ghr.nlm.nih.gov/condition/ornithine-transcarbamylase-deficiency. Accessed September 2017).
Since OTC deficiency is an X-linked condition, the most severe, infantile presentation is most commonly seen in males; however, later-onset forms of the condition can be seen in both males and females (PMID: 9831349). Symptoms of late-onset OTC deficiency can include altered mental status, headaches, vomiting, aversion to high-protein foods, seizures, coma, and death (National Library of Medicine. Genetics Home Reference: Ornithine transcarbamylase deficiency. https://ghr.nlm.nih.gov/condition/ornithine-transcarbamylase-deficiency. Accessed September 2017).
Even after diagnosis and appropriate treatment, individuals with OTC deficiency can develop hyperammonemia due to stressors, such as intercurrent illness, physical injury, prolonged fasting, or extended periods of strenuous activity. For females, pregnancy and delivery are additional stressors that can also result in hyperammonemia. Episodes of hyperammonemia are life threatening. If the individual survives, developmental delay, learning disabilities, and executive function deficits often persist (PMID 24006547).
Based on the Urea Cycle Disorder (UCD) Consortium’s longitudinal study results of 614 patients with UCDs, OTC deficiency was the most common urea cycle disorder and accounted for more than half of the participants (PMID 25135652). Prevalence estimates range from 1 in 14,000 to 1 in 77,000 (National Library of Medicine. Genetics Home Reference: Ornithine transcarbamylase deficiency. https://ghr.nlm.nih.gov/condition/ornithine-transcarbamylase-deficiency. Accessed September 2017).
OTC deficiency is not universally screened for in all U.S. states or countries as part of newborn screening, primarily due to the instability of glutamine and the low specificity and sensitivity for detection of decreases in the citrulline level (PMID 19359120). Therefore, it is important to be familiar with the newborn screening program in your area or the area from which your patient presented. As always, regardless of the status of the newborn’s screen, if a child is symptomatic or hyperammonemic, treatment and genetic testing should be initiated immediately.
Genetically-related (allelic) disorders
There are many other genes on the X chromosome located close to the OTC gene (Xp11.4). Therefore, if patients have a contiguous gene deletion in this area, they may be affected with other conditions along with OTC deficiency. These conditions include: X-linked chronic granulomatous disease, retinitis pigmentosa 3, McLeod neuroacanthocytosis syndrome, Duchenne muscular dystrophy, and oculo-facio-cardio-dental syndrome (OMIM 300166; National Library of Medicine. Genetics Home Reference: Ornithine transcarbamylase deficiency. https://ghr.nlm.nih.gov/condition/ornithine-transcarbamylase-deficiency. Accessed September 2017).
The symptoms associated with OTC deficiency can also occur as the result of other urea cycle disorders, such as N-acetylglutamate synthase (NAGS) deficiency, carbamyl phosphate synthetase I deficiency (CPSI), argininosuccinate synthetase (ASS) deficiency (aka citrullinemia type I), and argininosuccinate lyase (ASL) deficiency. Elevated orotic acid in urine can help differentiate between the various urea cycle defects. Molecular sequencing of the OTC gene is the gold standard for reaching a diagnosis (PMID 24006547).
The OTC (OMIM 300461) gene encodes the enzyme OTC, which catalyzes the third step of the urea cycle (PMID3891325). It is a nuclear-encoded gene that functions in the mitochondria to convert carbamoyl phosphate and ornithine to citrulline and phosphate (Online Mendelian Inheritance in Man: Ornithine Transcarbamylase Deficiency, Hyperammonemia due to. https://www.omim.org/entry/311250. Accessed September 2017).
OTC deficiency is inherited as an X-linked recessive condition. Females can be manifesting carriers and should be under the care of a comprehensive metabolic center. Genetic counseling is essential to ensure families understand the risks to additional family members (male and female), so that appropriate care and surveillance can be instituted.
Patients with OTC deficiency should be cared for at a comprehensive metabolic center by an experienced geneticist with a team that includes a dietician and a genetic counselor (PMID 24006547). Hyperammonemia is a life-threatening emergency and should be treated at a tertiary care center capable of providing hemodialysis if indicated (National Library of Medicine. Genetics Home Reference: Ornithine transcarbamylase deficiency. https://ghr.nlm.nih.gov/condition/ornithine-transcarbamylase-deficiency. Accessed September 2017).
Long-term management of OTC deficiency includes restriction of protein intake (typically with the addition of a medical formula), use of nitrogen-scavenger medications (PMID:11148549), and in some cases, liver transplantation. Citrulline should be supplemented at 170 mg/kg/day (PMC 3488504). Valproate, haloperidol, and systemic corticosteroids are contraindicated for patients with OTC deficiency. Heterozygous females should be monitored carefully throughout pregnancy, delivery, and the postpartum period due to the risk for acute hyperammonemia (PMID: 24006547). Genetic counseling is indicated to evaluate for additional family members who are at risk, so that appropriate genetic testing and clinical surveillance can be initiated.
Please see Gene Reviews (Gene Reviews: Ornithine transcarbamylase deficiency. https://www.ncbi.nlm.nih.gov/books/NBK154378. Accessed September 2017) and/or the American College of Medical Genetics ACT Sheet (Transition to adult health care ACT sheet. https://www.acmg.net/StaticContent/ACT/OTC_Deficiency_Transition.pdf. Accessed September 2017) for more specific treatment and management guidelines.
Review date: September 2017
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*OTC: Analysis includes the intronic variant NM_000531.5:c.540+265G>A.