Ornithine Transcarbamylase Deficiency
05 November 2004
Ornithine transcarbamylase deficiency is an X-linked metabolic disorder involving the urea cycle. Consequences include hyperammonemia, hyperglutaminemia, hypoarginemia, hypocitrullinemia & episodic encephalopathy , that, if uncontrolled results in brain injury & death.
Cerebral edema with subsequent raised intracranial pressure is primary
response to hyperammonemia.
Neurologic symptoms occur in absence of neuronal pathology.
Strong relationship between hyperammonemia, neurologic dysfunction &
CSF glutamine concentration in hepatic encephalopathy.
Classical (Early onset) Presentation
Baby boy product of normal full term pregnancy with normal labor & no perinatal risk factors is normal for the first 24 hrs.
Over the ensuing days, worsening lethargy, requires stimulation for feeding; then develops problems with vomiting, hypothermia & hyperventilation.
A search for sepsis is unrevealing.
CT shows cerebral edema.
Death is inevitable unless early diagnosis & treatment commenced early.
Maybe a history of consanguinity, neonatal sib deaths, or neonatal male deaths on pedigree analysis.
Genotypic & phenotypic variability
Lyonisation in females.
Drug induced in particular valproate.
Both male & females.
Lethargy, somnolescence, confusion.
Aversion to protein (protein provoked headache).
Initially normal CT.
EEG which may show diffuse encephalopathy.
UCE: low urea.
Mild respiratory alkalosis.
Orotic acid in urine.
(arginine, citrulline, glutamine)
(liver biopsy with measurement of OTC activity)
Early diagnosis & management (delays are fatal)
Discontinue all iv & dietary nitrogen intake.
High parenteral caloric intake to prevent catabolism.
Monitor UCE, pH, Pco2, NH3.
Reduce raised intracranial pressure with osmotherapy (mannitol) not steroids.
Infusions of sodium benzoate, sodium phenylacetate & arginine.
Hemodialysis as emergency procedure if NH3 does not significantly decrease.
Long Term Treatment
To provide a diet sufficient in protein & energy to promote growth & development while avoiding metabolic disturbances ie protein restriction.
Avoidance of high risk situations or initiation of acute treatment of known OTC deficient patients who deteriorate in these situations (sepsis, peripartum, initiation of drugs)
Dialysis as possible long term measure.
Valproate & OTC Deficiency
5 case reports in literature
First report in Lancet 1986.
3/5 died even with correction of hyperammonemia.
Delay in correction of hyperammonemia in known OTC deficiency can also significantly increase mortality.
Many hypotheses concerning Valproate & OTC Deficiency (see chart).
Valproate can cause hyperammonemia in patients with no urea cycle defect.
Who should be screened:
Patients about to commence valproate with unexplained episodes of confusion especially in setting of known stress factors ie sepsis, postpartum.
Known family history of OTC deficiency.
Patients who have become confused on commencing valproate.
Family history of unexplained death in childhood (especially males)
Aversion to protein.
How should we screen?
UCE, LFT, NH3 level.
Provocative test such as allopurinol loading; not protein loading.
Beware of valproate induced hyperammonemic encephalopathy.
Measure UCE, LFT, NH3 urgently.
Cease valproate immediately.
Institute measures to reduce NH3 as delay increases mortality.
Report cases of valproate induced hyperammonemic encephalopathy.
Screen for urea cycle defect of which OTC deficiency is the commonest