OTC Deficiency Overview

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A urea cycle disorder is a genetic condition caused by mutations that lead to a deficiency of one of six enzymes in the urea cycle, which is responsible for removing ammonia from the bloodstream.
This cycle converts ammonia into urea, which is then excreted through urine. In these disorders, ammonia accumulates in the blood, becoming toxic and potentially causing brain damage, coma, or death.
OTC (ornithine transcarbamylase) helps convert carbamyl-phosphate and ornithine into citrulline.
It is the most common urea cycle disorder and is inherited in an X-linked manner.
Diagnosis is confirmed through genetic testing or liver enzyme analysis.
The severity and timing of urea cycle disorders can vary greatly, depending on the specific mutation and the extent of enzyme function. Severe mutations lead to little or no enzyme activity, causing more serious disorders. In contrast, milder mutations allow for some enzyme function, leading to less severe cases of the disorder.

Stages, Onset, & Severity

The severity of the disorder varies depending on the mutation and enzyme function, with more severe mutations resulting in less ability to detoxify ammonia, while milder mutations allow for partial detoxification.
The OTC gene is on the X-chromosome, so males, with only one X, are more likely to have severe symptoms.
Complete OTC deficiency, the most severe form, causes dangerously high ammonia levels in the blood shortly after birth, leading to symptoms within the first week. Even if infants survive the initial crisis, they remain at risk for future episodes.
Females with one normal and one abnormal gene might show no symptoms, though could experience mild signs.
Females experience a range of symptoms from mild to severe, depending on how the X-chromosome inactivation occurs in different tissues, particularly in the liver.
Partial OTC deficiency, a milder form, can develop at any age, often triggered by stress or illness, with females generally having less severe ammonia buildup than males.

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Poor feeding/protein intolerance/vomiting
Headaches/Migraines
Progressive Lethargy/delerium/fatigue
Confusion/trouble concentrating
Seizures/Coma
Diminished muscle tone
Respiratory abnormalities
Accumulation of fluid in the brain
irritability/mood changes/abnormal behavior
In infants with OTC deficiency, hyperammonemic crises are often misdiagnosed as sepsis.

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There is no real cure for the disease at the moment. Some countries have started experimenting with gene therapy that would essentially eradicate the defect gene from the patients genome.
Treatment
- Liver transplant
- Medications
- CRRT (Dialysis)
- Intravenous medication dosing (Ammonul)

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The complete answer is not yet known.
Previous studies showed that life expectancy for severely affected patients has been shortened & about half of children with newborn-onset disease did not survive past age 5.
Neonatal-onset OTC & CPS1 deficiencies tend to have a worse prognosis compared to other urea cycle disorders.
Late-onset cases generally have a good survival rate, but there remains a significant risk of life-threatening or debilitating hyperammonemic episodes.
A new study is currently underway to address this topic.