Valproate as a Cause of Hyperammonemia in Heterozygotes With ornithine-transcarbamylase Deficiency

Ornithine-transcarbamylase (OTC) deficiency is the most common inherited cause of hyperammonemia. In males, OTC deficiency often leads to death in the neonatal period, but occasionally the symptoms begin in the juvenile or adult stage. Elderly affected men and heterozygote females ^[1] may show several nonspecific or episodic symptoms such as delayed growth, mental retardation, bizarre behavior, irritability, lethargy, migraine, headaches, vomiting, ataxia, tremors, seizures, and coma. Variation of time of onset and severity of the symptoms may be due to different OTC mutations, lyonization with nonrandom X chromosome inactivation, or epistatic or extragenetic factors. Puerperium, infection, surgery, or a nitrogen load may precipitate attacks. We report a previously undiagnosed heterozygote OTC-deficient patient who developed symptomatic hyperammonemia after the introduction of valproic acid.

Case report. A 7-year-old girl was referred for management of generalized tonic-clonic seizures that started 6 months before referral. Apart from frequent vomiting when she had fever or upper respiratory infections, her history was uneventful. Pregnancy and delivery were normal. Developmental milestones were normal and her motor and language skills were adequate for her age. She was attending regular school, where she was performing well. She was the single child of healthy, unrelated parents. Two male cousins born of a maternal aunt died of unknown causes within the first month of life.

She had generalized tonic-clonic seizures occurring once a month since the age of six. EEG showed bilateral spike activities in the frontal and temporal areas.

When we first saw her, her neurologic examination was normal. Valproate (VPA) was introduced to control seizures, using a dosage of 20 mg/kg/d. One day later, she became irritable, with headaches and frequent vomiting. On the third day, she developed severe psychomotor agitation with visual and auditory hallucinations. Neurologic examination showed a girl with alternating periods of drowsiness and agitation who did not follow verbal commands. She could not walk or sit and could not fix or follow objects. Neurologic examination did not show focal signs. CT was normal. Laboratory tests showed VPA 60 micrograms/ml (therapeutic range, 50 to 100), ammonium 170 micromolars (normal, <50), glutamine 1,250 micromolars/l (normal, 243 to 822), alanine 800 micromolars/l (normal, 100 to 400), citrulline 7 micromolars/l (normal, 15 to 30), and lysine 92 micromolars/l (normal, 40 to 162). Orotic acid was 3.5 mM/M creatinine (normal, <1.3). These results were consistent with the diagnosis of OTC deficiency. A liver biopsy was planned to confirm this diagnosis, but the child's parents refused. We were not able to perform a direct DNA analysis. Her karyotype was 46,XX (high-resolution banding; 50 cells).

We decided to interrupt VPA therapy. There was a progressive improvement of the clinical situation, and 4 days after stopping VPA the girl showed only some periods of somnolence. One week later, the neurologic examination was normal but the biochemical anomalies had persisted, with abnormal levels of ammonium, glutamine, citrulline, alanine, and orotic acid. After discharge she was evaluated monthly, and 6 months after stopping VPA there were no further episodes of symptomatic hyperammonemia.

Discussion. To our knowledge, there are only two previous and conclusive reports of symptomatic hyperammonemia precipitated by VPA therapy in heterozygotes with OTC deficiency. The first report ^[2] is of a 32-year-old woman with headaches and occasional seizures since childhood. She was mentally normal and there was no relevant family history. She died in spite of intensive medical care. The second report ^[3] is of a 22-year-old woman with mental retardation, episodic violent and bizarre behavior, and a history of meat avoidance and frequent vomiting. Her brother and two maternal uncles died of unknown causes in the neonatal period. This patient showed several behavioral anomalies even after stopping VPA.

We describe another heterozygote OTC patient with hyperammonemia during VPA therapy. Apart from seizures, this patient was mentally normal and her medical history was uneventful. However, her family history revealed that two male cousins born of a maternal aunt died in the first month of life. This fact is consistent with X-linked inheritance.

Because VPA may induce symptomatic hyperammonemia in previously normal OTC heterozygotes, we advise that this product must be used with caution not only in males but also in females in whom a urea cycle disorder is suspected. This suspicion must be raised if the pedigree analysis shows a family history of unexplained death in childhood, aversion to protein, or episodes of acute cortical dysfunction such as seizures, episodic vomiting, nausea, lethargy, drowsiness, stupor, or coma, particularly if precipitated by stressful factors. In these cases the diagnosis of OTC deficiency should be ruled out before the introduction of VPA. This can be accomplished by using the nitrogen loading test or preferably a single oral dose of allopurinol. Both tests significantly increase the urinary excretion of orotic acid in OTC-deficient patients ^[4]. Because these tests are not 100% accurate, some asymptomatic carriers can only be identified by DNA analysis ^[5] or histochemical identification of OTC-deficient hepatocytes ^[6] or enterocytes in biopsy specimens ^[7].

On the other hand, the patients who develop severe side effects after the introduction of VPA (including those without a suspect family history) should be screened for an OTC deficiency. The measurement of plasma ammonium and amino acids showing hyperammonemia associated with high levels of glutamine and low levels of citrulline in combination with an increased excretion of urinary orotic acid will be useful in the identification of these patients.