Abstract
A 7-year-old boy developed a severe unilateral grand mal seizure at the age of 5 years (phenobarbitone therapy); 1.5 years later valproate (2-propylpentanoic acid, VPA) was added to the therapy. After a seizure-free period of 3 months the patient died from hepatic failure resembling Reye syndrome. Several plasma and urine samples from the final stage before and during peritoneal dialysis were analyzed by GC/MS.
The predominant feature was the abnormally increased formation of both 3 mono- and 4 double unsaturated metabolites of VPA amounting in plasma to 58%–71% of the sum of VPA plus all analyzed metabolites (controls maximal 15%) and in urine to 34%–61% (controls maximal 10%). The beta-oxidation pathway of VPA was shown to be suppressed (lack of 3-keto-VPA), whereas metabolites from the omega-oxidation pathway could still be measured (urinary 5-OH-VPA plus 2-propylglutaric acid ca. 1.6%, controls more than 10%). 4-en-VPA (2-propyl-4-pentenoic acid) (5%–21% in plasma) and 4,4′-dien-VPA (2(2-propenyl)-4-pentenoic acid) (4%–7%) have been found as abnormal unsaturated metabolites not detectable in controls. Additional typical findings were the high excretion of adipic acid, suberic acid, and 4-octen-1,8-dicarboxylic acid demonstrating the enhanced capacity of omega-oxidation in fatty acid oxidation.
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Dedicated to Prof. H. Bickel on the occasion of his 65th birthday
Supported by Deutsche Forschungsgemeinschaft (program “Research in Epilepsy”)
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Kochen, W., Schneider, A. & Ritz, A. Abnormal metabolism of valproic acid in fatal hepatic failure. Eur J Pediatr 141, 30–35 (1983). https://doi.org/10.1007/BF00445664
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DOI: https://doi.org/10.1007/BF00445664