1 Department of Neurology 2 Department of Nephrology 3 Unit of Paediatric Nephrology, Meir Hospital, Sapir Medical Center, Kfar-Saba and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
A 57-year-old woman was admitted because of dizziness, nausea and vomiting. From the age of 15, she had suffered from recurrent generalized tonic clonic seizures for which multiple antiepileptic drugs were prescribed. She was a withdrawn, apathetic individual with borderline mental retardation. She had been seizure free for the past 5 years prior to her present admission being maintained on carbamazepine 1200 mg, phenobarbital 200 mg and diazepam 30 mg, daily. On examination, she was haemodynamically stable. Laboratory data revealed a serum sodium of 129 mEq/l and carbamazepine level of 16.4 µg/ml (normal range: 412). Carbamazepine toxicity with mild water retention was diagnosed. A neurological consultant advised replacing carbamazepine with sodium valproate 1.5 g/day. Within 48 h, the patient's hyponatraemia was corrected and she was discharged only to be readmitted the same day following a generalized tonic-clonic seizure. Physical and neurological examination was unremarkable. Valproic acid (VPA) dosage was increased while phenobarbital and diazepam were tapered.
Over the next 4 days, the patient gradually went into stupor and eventual coma. Complete blood count, serum electrolytes, glucose, calcium, liver enzymes, urea and creatinine were all within normal limits. Blood gases analysis was without abnormality. Cerebrospinal fluid opening pressure and contents were normal. Computerized tomography of the brain showed cerebellar atrophy. An EEG tracing demonstrated diffuse slowing with triphasic waves compatible with a metabolic encephalopathy. Blood ammonia was 130 µmol/l (normal: 550). VPA was immediately discontinued and vigabatrine commenced. During the following week, the patient's condition gradually improved with a return to her pre-admission mental state. Concomitantly, blood ammonia levels decreased to normal values.
Questions
What is the cause of the patient's hyperammonaemia?
What is the link to the urea cycle?
What investigations would confirm your diagnosis?
Answers to quiz on preceding page
This patient developed a hyperammonaemic metabolic encephalopathy upon the administration of VPA. Although occasionally valproate may cause hepatic failure, secondary hyperammonaemia without hepatic dysfunction is a well documented side-effect of the drug [13]. Experiments performed in the intact functioning rat kidney have shown that VPA and its metabolite, sodium 2-propyl-4-pentenoate (4-en-VPA) stimulated the uptake of glutamine and glutamate and the production of ammonia by the kidney [4]. Furthermore, the renal uptake of ammoniagenesis inhibitors such as fatty acids, ketone bodies and -ketoglutarate was reduced [4]. The hyperammonaemia induced by VPA is for the most part asymptomatic. It is transient and completely reversible upon cessation of the drug.
Symptomatic hyperammonaemia during valproate therapy may indicate ornithine transcarbamoylase (OTC) deficiency [57]. This mitochondrial enzyme is one of the five involved in the urea cycle and catalyzes the reaction of carbamoyl phosphate with ornithine to form citrulline (Figure 1). In man, the urea cycle is the only known metabolic pathway of urea synthesis and the major one of ammonia detoxification. Genetic deficiencies of each of the urea cycle enzymes have been described with an overall prevalence estimated to be 1 in 30,000 live births. They are usually associated with hyperammonaemia, intolerance to protein ingestion and mental retardation.
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Discussion
OTC deficiency is an X-linked disorder and the most common inherited cause of hyperammonaemia [7]. The acute form of this enzyme deficiency usually occurs in neonatal males who present with fulminant encephalopathy. Most female carriers do not have episodes of encephalopathy although 30% report a history of dietary protein intolerance. The clinical presentation of manifesting females is very variable. Symptomatic hyperammonaemia may occur once or twice in a lifetime, may be chronic or frequently recurring. Symptoms may be non-specific (malaise, headache) or severe and life threatening (seizures, coma, permanent neurological deficit).
Misdiagnosis and diagnostic delays are common. Our patient is a case in point. She presented with an undefined neurological disorder consisting of relatively intractable epilepsy and borderline mental retardation. An increasing comatose state induced by VPA led to the establishment of the correct diagnosis. Apart from VPA, other precipitants of encephalopathy include parturition, catabolic states such as infection or trauma, concurrent liver disease, parenteral nutrition and/or a high protein intake. Age at diagnosis among heterozygous affected females may also be extremely divergent ranging from the neonatal period to middle life. In addition to the patient reported by Bogdanovic et al. [8], ours is probably the oldest documented case.
In summary, we suggest that serum ammonia levels be evaluated in all patients on VPA therapy who develop an altered mental status. In such conditions, in a patient with a history of previous encephalopathy, protein intolerance and mental deficit, OTC deficiency should be borne in mind.
References