"Conjugation with carnitine may result in its deficiency by diffusion out of the hepatocyte and renal loss, as well as inhibiting the carnitine uptake transporter. Sequestration of coenzyme A decreases fatty acid beta-oxidation and intra-mitochondrial acetyl-CoA, the latter of which is required not only for the function of the citric acid cycle (decreased ATP production) but also for the formation of N-acetylglutamate, which is a required cofactor in the rate-limiting step of urea formation from ammonium10. Metabolites of cytosolic omega oxidation may also contribute."
"T2/FLAIR: bilateral symmetric regions of high signal within the cerebral cortex (especially frontal and insular cortices) 4,5, cerebellar white matter 6, and globus pallidi 6"
"DWI: similar distribution of high diffusion signal to T2/FLAIR 5"
"MR spectroscopy: elevated glutamine/glutamate peak with decreased myoinositol and choline peaks on proton MR spectroscopy 6"
"Conjugation with carnitine may result in its deficiency by diffusion out of the hepatocyte and renal loss, as well as inhibiting the carnitine uptake transporter. Sequestration of coenzyme A decreases fatty acid beta-oxidation and intra-mitochondrial acetyl-CoA, the latter of which is required not only for the function of the citric acid cycle (decreased ATP production) but also for the formation of N-acetylglutamate, which is a required cofactor in the rate-limiting step of urea formation from ammonium10. Metabolites of cytosolic omega oxidation may also contribute."
"Conjugation with carnitine may result in its deficiency by diffusion out of the hepatocyte and renal loss, as well as inhibiting the carnitine uptake transporter. Sequestration of coenzyme A decreases fatty acid beta-oxidation and intra-mitochondrial acetyl-CoA, the latter of which is required not only for the function of the citric acid cycle (decreased ATP production) but also for the formation of N-acetylglutamate, which is a required cofactor in the rate-limiting step of urea formation from ammonium10. Metabolites of cytosolic omega oxidation may also contribute."
"patients with urea cycle disorders (e.g. ornithine transcarbamylase deficiency)"
"use of other drugs that interfere with the urea cycle (e.g. topiramate)"
"There are several proposed mechanisms regarding the development of hyperammonaemia during both therapeutic use and overdose with valproic acid, all of which converge on dysfunction of the urea cycle as the proximal cause 1-3."
"The metabolism of valproic acid is primarily hepatic, with less than 3% of the unchanged drug renally excreted. During therapeutic use, the primary means of metabolism occurs through (cytosolic) conjugation with glucuronide and (mitochondrial) beta oxidation; the latter is accomplished by cytosolic conjugation to carnitine, transport into the mitochondrion in exchange for free carnitine, conjugation to coenzyme A with subsequent oxidation in an analogous manner to long-chain fatty acid metabolism 9."