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Ornithine transcarbamylase deficiency
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.
ORPHA:664Classification level: Disorder
Ornithine transcarbamylase deficiency (OTCD) is the most common type of urea cycle disorder. Worldwide prevalence estimates range between 1/56,500 to 1/113,000 live births.
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.
OTCD is due to mutations in the OTC gene (Xp21.1) which encodes OTC, responsible for catalyzing the synthesis of citrulline (in liver and small intestine) from carbamoyl phosphate and ornithine. Mutations that abolish OTC activity completely result in the severe, neonatal-onset form while mutations leading to decreased OTC activity result in the late-onset phenotypes.
Diagnosis is based on clinical manifestations and plasma ammonia levels are typically high (>200 µmol/L) when encephalopathy is present. Plasma amino acid analysis reveals low citrulline and arginine levels and high glutamine. Urine organic acid analysis usually reveals elevated orotic acid levels. Molecular genetic testing confirms diagnosis.
Differential diagnoses include carbamoyl-phosphate synthetase deficiency, argininosuccinic aciduria, hyperammonemia due to N-acetylglutamate synthase deficiency, citrullinemia type 1 and argininemia.
Prenatal diagnosis is possible in families with a known disease causing mutation.
OTCD is inherited in an X-linked manner. Where the female parent is a carrier, male offspring have a 50% risk of inheriting the disease. Where the male is affected, male offspring are unaffected and females are obligate carriers. Female heterozygotes may be symptomatic due to skewed X-chromosome inactivation.
Management and treatment
Patients presenting with a hyperammonemic coma must be treated immediately in a tertiary care center where plasma ammonia levels must be lowered (by hemodialysis or hemofiltration methods), ammonia scavenger therapy implemented, catabolism reversed (through glucose and lipid infusions) and special care taken to reduce the risk of neurological damage (electroencephalogram surveillance and treatment of seizures if necessary). Long-term therapy involves life-long restriction of protein intake and nitrogen scavenger therapy (with sodium benzoate and/or sodium or glycerol phenylbutyrate). A liver transplantation may also be considered in patients with severe, neonatal-onset OTCD (usually performed by 3-6 months of age) or those with frequent hyperammonemic episodes. Valproate, haloperidol, fasting and known stressors should be avoided. Pregnant women with OTCD should be carefully monitored, especially also in the postpartum period.
Prognosis depends on disease severity but is considered bleak in patients with early neonatal disease. Without early diagnosis and treatment of hyperammonemic episodes, the neurological outcome is poor.
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