Ornithine Carbamoyltransferase Deficiency (OTCD)

Rare genetic disorder characterized by complete or partial lack of the enzyme ornithine transcarbamylase (OTC). Lack of the enzyme results in excessive hyperammonemia, which is known as a neurotoxin. Clinically, patients present vomiting, refusal to eat, progressive lethargy, and coma.

Ornithine Transcarbamylase Deficiency.

The urea cycle disorders are a group of rare disorders that affect the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. Failure to break down nitrogen results in the abnormal accumulation of nitrogen, in the form of ammonia, in the blood.

Approximately 1:80,000 live births. Estimated prevalence for disorders of urea cycle is approximately 1:30,000 population.

Partially dominant X-linked (Xp21.1). The phenotype of heterozygote females cannot be predicted because of random inactivation of the X chromosome. Some female carriers present clinical symptoms a few weeks after delivery, at the time of uterine involution.

Ornithine carbamoyltransferase is one of six enzymes that play a role in the breakdown and removal of nitrogen in the body, a process known as the urea cycle. The entire urea cycle resides exclusively in periportal hepatocytes. It is an essential pathway for waste nitrogen excretion. It is involved in a cascade of six enzymatic transformations converting toxic ammonia to nontoxic water-soluble urea.

Elevated blood NH4 level in a lethargic or comatose patient; liver biopsy; increased urinary orotic acid levels.

Neonatal Presentation: Starts within the first 4 days of life: refusal to feed, irritability, persistent vomiting, mild respiratory alkalosis, followed rapidly by neurologic signs with coma, convulsions, hypotonia.

Late-Onset Presentation: Long history of chronic hepatogastric symptoms such as recurrent episodes of vomiting, failure to thrive, and hepatomegaly. Others present a neurologic picture of chronic encephalopathy; behavioral disorders such as agitation, delirium, and irritability; or Reye-like syndrome following sodium valproate therapy for seizures. Some patients spontaneously avoid protein-rich food and remain relatively asymptomatic. Death may occur during a metabolic crisis precipitated by infection, surgery, increased catabolism, or a protein-rich diet.

In case of seizures, sodium valproate should not be used because it may precipitate acute metabolic decompensation. Liver transplantation is curative.

Basic treatment is a low-protein diet carefully adapted to the child's needs and metabolic tolerance and administration of ammonia-scavenging drugs (Na-benzoate, Na-phenylbutyrate, l-arginine) three to four times per day. Their administration should be linked to meals to maximize their effect.

In case of hyperammonemia:

• Stop protein intake and restrict fluid volume if there is any concern about cerebral edema. Provide a high-energy intake orally or IV (glucose 10-20%).
• Use alternative pathways for nitrogen elimination: give Na-benzoate up to 500 mg/kg/day, Na-phenylbutyrate up to 600 mg/kg/day, and l-arginine 300 mg/kg/day orally or IV. Because these drugs lead to K wasting, K blood levels should be monitored.
• Treat sepsis and convulsions.

Check blood glucose and NH4 levels. Ensure Na-benzoate, Na-phenylbutyrate, and l-arginine are available for emergency treatment of hyperammonemia. Seizure medication must be maintained. Check fluid and electrolyte status, especially in presence of renal dysfunction.

Prolonged fasting should be avoided. Intravenous glucose (5 or 10% solution) should be used to avoid protein catabolism. Monitoring of blood glucose, ammonium, and lactate levels must be done regularly. Prevention of hypovolemia at all times, especially if altered renal function. If there is a risk of nasal, pharyngeal, or gastric bleeding, a gastric tube should be inserted to remove swallowed blood, which provides a protein load that may trigger acute metabolic decompensation. Prolonged postoperative metabolic monitoring must be provided for early diagnosis of acute decompensation.

Pathology of the urea cycle should be borne in mind when dealing with a supposed “normal” child who does not wake up after uneventful anesthesia. In case of fever, ibuprofen is preferred over acetaminophen; sodium valproate and haloperidol can unmask a previously undiagnosed urea cycle defect.

Urea Cycle Disorders: Group of rare disorders characterized by accumulation of hyperammonemia and clinically presenting with a lack of appetite, vomiting, drowsiness, seizures, and/or coma. Other features include hepatomegaly and cerebral dysfunction caused by the urea level. Life-threatening complications may result. In addition to OTCD, carbamyl phosphate synthetase (CPS) deficiency, citrullinemia (argininosuccinate synthetase deficiency), argininosuccinate lyase deficiency, argininemia, and N-acetylglutamate synthetase (NAGS) deficiency must be considered in individuals affected with these symptoms.

Reye Syndrome: Rare childhood disease characterized by liver failure, encephalopathy, hypoglycemia, and hyperammonemia. It can be triggered by use of aspirin in children recovering from chickenpox or influenza (viral infection). Deficiencies of the urea cycle enzymes have been suggested as a possible mechanism in the development of Reye syndrome. Clinical features include vomiting, diarrhea, rapid breathing, irritability, fatigue, and behavioral changes. Neurologic symptoms may be life-threatening and include generalized seizures, stupor, and coma.

Organic Acidemias: Group of rare inherited metabolic disorders characterized by the presence of hyperammonemia, hyperacidemia, thrombocytopenia, and muscle weakness.

Argininemia: Urea cycle disorder that leads to hyperammonemia and neurologic symptoms that are less severe than in other forms of urea cycle abnormalities.

Citrullinemia: Syndrome arising from argininosuccinate synthetase deficiency leading to hyperammonemia and neurologic consequences.

HHH Syndrome: Genetically transmitted inborn error of metabolism resulting from a defect in the transport of ornithine into the mitochondrial matrix, clinically characterized by early growth retardation, learning disabilities, periodic confusion, and ataxia.

Methylmalonic Acidemia (MMA): Heterogeneous inborn error of metabolism leading to metabolic acidosis and accumulation of methylmalonic acid and its by-products.

N-Acetylglutamate Synthetase Deficiency: Congenital mitochondrial disorder affecting the metabolism of ammonium and results in hyperammonemia.

Propionic Acidemia: Inborn error of metabolism affecting the mitochondrial catabolism of valine and isoleucine. Untreated, this results in ketoacidosis, lethargy, coma, and finally death.