Rare genetic anomaly of the urea cycle characterized by complete or partial lack of the enzyme ornithine transcarbamylase (OTC) resulting in hyperammonemia. Clinically, patients present vomiting, refusal to eat, progressive lethargy, and coma.
Ornithine Transcarbamylase Deficiency.
Approximately 1:80,000 live births. Estimated prevalence for disorders of urea cycle is approximately 1:30,000 overall.
Partially dominant X-linked (Xp21.1) without a specific mutation of the OTC gene identified. The phenotype of heterozygote females cannot be predicted because of random inactivation of the X chromosome. Some female carriers present clinical symptoms in the postpartum period, at the time of uterine involution.
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. Ornithine carbamoyltransferase is one of the 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. Complete enzymatic deficiency in boys is often fatal.
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 (pseudo ☞Reye Syndrome), surgery, increased catabolism, or a protein-rich diet.
Basic Treatment: Low-protein diet must be 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.
Seizures: Sodium valproate should not be used because it may precipitate acute metabolic decompensation. Liver transplantation is curative.