Carbamyl phosphate synthetase-l deficiency discovered after valproic acid-induced coma

Abstract

Valproic acid induced coma is presented in an adult patient without a history of metabolic disease. Liver biopsy revealed a reduction in activity of carbamyl phosphate synthetase-I, an enzyme obligated for transformation of ammonia to urea in the urea cycle. After recovery CT scan follow-up showed marked cerebral atrophy which did not exist prior to the state of coma. Risk factors are discussed.

Drug induced encephalopathy in six epileptic patients: topiramate? valproate? or both?

“…Accumulation of glutamine within the astrocyte can induce cerebral oedema as is observed in hepatic encephalopathy and Reye's syndrome (Hamer et al, 2000;Vossler et al, 2002;Bourrier et al, 1988). VPA-induced hyperammonaemia is mainly due to perturbations of the hepatic ornithine cycle: (1) inhibition of Nacetyl-glutamate synthetase, an activator of type-1 carbamyl-phosphatase-synthetase (CPS 1), either directly by inhibition of N-acetylglutamate synthetase, or indirectly via decreased production of acetyl-coenzyme-A (CoA) (Duarte et al, 1993;Marini et al, 1988;Bourrier et al, 1988), or inhibition of type 1 carbamyl phosphate synthetase (Verbiest et al, 1992) or ornithine transcarbamylase (Honeycutt et al, 1992;Oechsner et al, 1998); (2) VPA, which is a fatty acid, could also inhibit intramitochondrial -oxidation of long-chain fatty acids leading to activation of the cytosolic !-oxidation pathway, and a drop in free CoA and in acetyl CoA synthetase necessary for the ornithine cycle. The cytosolic !-oxidation pathway can also be enhanced by the presence of an enzyme inducer such as phenobarbital or PHT and perhaps TPM, thus inducing a drop in acetyl-CoA-synthetase (Duarte et al, 1993;Zaccara et al, 1987;Honeycutt et al, 1992;Murakami et al, 1996;Kossak et al, 1993).…”

Hyperammonemia from a Urea Cycle Disorder Presenting in Adulthood

“…Most patients present in infancy with seizures, irritability, and encephalopathy prompting medical investigation. When the diagnosis is made after the neonatal period, clinical features typically include nausea and vomiting, somnolence, seizures, and coma [2][3][4][5][6], but more subtle neurobehavioral disturbance and cognitive slowing are often dominant clinical features. Partial enzyme deficiencies may have delayed presentation as in our case.…”

“…Predisposing circumstances that may lead to a hyperammonemic crisis include high protein intake, post-surgical state, child birth, and any process that induces a catabolic state and excess protein breakdown [4,9]. Use of valproic acid, which inhibits the synthesis of urea, has also been reported to precipitate a crisis [3,4,10].…”

“…However, partial enzyme deficiencies may present in adolescence and adulthood [2]. Onset may be triggered with any stress resulting in acute catabolic state, such as surgery or childbirth, or use of valproic acid, as reported in several cases [3][4][5].…”

Antiepileptic Drugs in Pregnancy: Options for the Prevention of Congenital Abnormalities

“…Several publications suggest a genetic predisposition for hepatotoxicity associated with valproate use [69, 70, 71, 72, 73]. However, the biochemical mechanism of valproate teratogenicity seems to differ from that of valproate hepatotoxicity [74].…”