OTC gene
Also known as: OTC deficiency; Ornithine Carbamoytransferase Deficiency; Hyperammonemia due to OTC deficiency
OMIM#311250 https://omim.org/entry/311250
1. The disease
A rare, genetic disorder of urea cycle metabolism and ammonia detoxification characterized by either a severe, neonatal-onset disease found mainly in males, or later-onset (partial) forms of the disease. Both present with episodes of hyperammonemia that can be fatal and which can lead to neurological sequelae. Ornithine transcarbamylase deficiency (OTCD) is the most common type of urea cycle disorder. Lack of early signs or symptoms does not exclude the diagnosis.
2. The Symptoms
- Males with the severe, neonatal-onset type are normal at birth but develop poor sucking, hypotonia and lethargy after a few days, rapidly progressing into somnolence and coma. Seizures and hyperventilation may also be present. If untreated, severe encephalopathy will develop with a high risk for death.
- Patients with a milder form can present at any age. In infants, symptoms can be induced when switching from breast milk to whole milk.
- In children and adults, environmental stressors (i.e. fasting, high protein diet, pregnancy and the postpartum period, intercurrent illness, surgery) can trigger episodes of hyperammonemic encephalopathy along with nausea, vomiting, headaches, erratic behavior, delirium and combativeness. These episodes can also result in hyperammonemic coma. Neurological complications of hyperammonemic coma include developmental delay and, sometimes, severe cognitive impairment.
- Many female carriers are asymptomatic; however, they can be affected to the same extent as males if the degree of X-inactivation of the disease allele is unfavorable.
- Coagulopathy is a frequent finding during metabolic decompensation and sometimes evolves into acute liver failure.
3. Actions to take in case of early diagnosis
- Babies with a positive genetic test (having 1 pathogenic variant in hemizygous state in the gene OTC (being a male in the only X chromosome or a female with abnormality in the X chromosome or with skewed X inactivation even in heterozygous state should continue breastfeeding and avoid baby formulas.
- Early treatment is essential in preventing chronic symptoms.
- Biochemical correlation is essential for confirming diagnosis with plasma quantitative amino acids (very low citrulline with high glutamine), ammonia levels (very high) and urinary organic acids (high orotic acid). Biochemical NBS with tandem mass spectrometry can also help in detecting the low citruline.
- OTC is a lifelong disease that requires lifetime management and regular follow-up with a metabolic physician and dietician, a part from a multidisciplinary approach to care.
- A life-long diet low in natural protein, supplements of essential amino acids, citrulline and arginine as needed.
- Nitrogen scavenging therapy (with sodium benzoate and/or sodium phenylacetate/phenylbutyrate and arginine) or hemodialysis in the emergency should decrease ammonia levels.
- Early liver transplantation for those with neonatal-onset OTCD can correct metabolic abnormalities but does not reverse any neurological complications. Valproic acid should be avoided.
- Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.