1. Ornithine Transcarbamylase Deficiency Department of Neurosciences Canberra Hospital May 1999

2. Ornithine Transcarbamylase Deficiency 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.

3. Pathophysiology (see urea cycle).Hyperammonemia: Cerebral edema with subsequent raised intracranial pressure is primary response to hyperammonemia. Neurologic symptoms occur in absence of neuronal pathology..Hyperglutaminemia: Strong relationship between hyperammonemia, neurologic dysfunction & CSF glutamine concentration in hepatic encephalopathy.

4. 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.

5. Nonclassical Presentations Genotypic & phenotypic variability Lyonisation in females. Environmental precipitants: Sepsis Postpartum Protein loading Post surgery Drug induced in particular valproate.

6. Late Presentation Both male & females. Clinical features: Vomiting Lethargy, somnolescence, confusion. Ataxia. Amblyopia. Aversion to protein (protein provoked headache). Seizures.

7. Diagnosis Normal LFT. Initially normal CT. EEG which may show diffuse encephalopathy. UCE: low urea. Mild respiratory alkalosis. NH3 Orotic acid in urine. (arginine, citrulline, glutamine) (liver biopsy with measurement of OTC activity)

8. Acute Treatment 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.

9. Long Term Treatment To provide a diet sufficient in protein & energy to promote growth & development while avoiding metabolic disturbances ie protein restriction. Sodium phenylbutyrate. 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.

10. Valproate & OTC Deficiency 5 case reports in literature First report in Lancet 1986. 3/5 died even with correction of hyperammonemia. Probably underrecognised. 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.

11. Screening 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.

12. Summary 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.