Valproate and cytochromec oxidase deficiency

Adult-onset of Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) Syndrome Presenting as Acute Meningoencephalitis: A Case Report

“…It has previously been shown that valproic acid inhibits oxidative phosphorylation in hepatic and cerebral mitochondria and impairs the proton pumping activity of complex IV (cytochrome c oxidase) in the respiratory chain, which precipitates more severe symptomatology of MELAS (including exacerbation of seizures) in 50% of MELAS patients (17)(18)(19)(20)(21). Therefore, valproic acid is contraindicated for the treatment of seizures in patients diagnosed with a mitochondrial disorder (e.g., MELAS syndrome).…”

Paradoxical effect of sodium valproate that aggravates epilepsy of MELAS in a patient with A3243G mutation of the mitochondrial DNA

“…Enhancement of glutamic acid decarboxylation and inhibition of GABA transamination play dual roles. In animal studies, VPA have been reported to cause seizure [13][14][15][16]. The mechanism of this paradoxical effect is not known.…”

“…Altrup et al [13] reported that VPA changes the structure of the mitochondrial membrane, and Chabrol et al [14] demonstrated that VPA alters the activity of cytochrome c oxidase, a mitochondrial enzyme. Furthermore, measurements of the respiratory enzyme activities in even intact mitochondria of patients with MELAS, revealed that more than a half have associated with some degree of complex I, or complexes I and IV deficiency [13][14][15][16][17]. Therefore, we propose that in patients with mitochondrial diseases such as MELAS, a defective oxidative and phosphorylation (OX-PHOS) due to complex I or complex IV or both might predispose the patient to the unfavorable pharmacological effects of VPA on the mitochondrial machinery toward the paradoxical epileptogenicity.…”

“…Other supportive evidence gives clue to the explaination of this paradoxical cellular event. First, the papers by Ponchaut et al [15,16] demonstrated that the activity of complex IV of the respiratory chain is jeopardized by VPA. Second, Lam et al [17] suggested that there is an inborn error of mitochondrial system in patients whose seizures worsen by use of VPA.…”

“…A pre-existing hepatic mitochondrial dysfunction in MELAS per se may also contribute to a decrease in the capacity of hepatic elimination of VPA and its metabolite. The toxicity of accumulated VPA and its metabolites in turn accelerates the development of the mitochondrial "encephalopathy", changes of the mitochondrial membrane stability, and thus the paroxysmal depolarization shift (PDS) [13], and the subsequent seizures [12][13][14][15][16][17]. Finally, the threshold of PDS may be greatly altered and reduced by the regional brain acidic milleau (elevated H + concentration) associated with lactic acidosis.…”