Appendix 2

Three out of our five patients (cases 1-3) showed elevated ammonia serum levels. Very high ammonia levels have previously been described in patients with VE, even with normal liver function tests [21], and it has been hypothesised that the manifestations of VE are directly related to hyperammonaemia. VPA can increase the transport of glutamine across the mitochondrial membrane in the kidney, thereby increasing the production of ammonia [8]. Thus, hyperammonaemia may be due to increased renal ammonia production [22]. On the other hand, VPA inhibits carbamoylphosphatase synthase which reduces hepatic ammonia metabolism by decreasing carnitine availability. This suppresses fatty acid beta-oxidation [8, 23]. This theory is supported by the observation that VE seems to be more frequent in patients with carnitine deficiency or with congenital urea cycle enzymatic defects [8, 23]. It has also been shown that serum free carnitine concentrations are reduced in patients with VPA-associated hyperammonaemia. Serum ammonia concentrations correlate directly with serum concentrations of VPA whilst correlating inversely with serum concentrations of carnitine [23]. Based on this observation, it has been suggested that carnitine supplementation during VPA therapy could prevent VPA-induced hepatotoxicity in high-risk patients (especially in children with epilepsy < 2 years of age, anti-epileptic drug polytherapy, ketogenic diet, poor nutritional status) [23]. However, the value of L-carnitine therapy in VE and acute VPA overdose is not clear and there are no conclusive studies on the clinical value of such a therapy in adults with VPA-induced central nervous system side-effects, e. g. in VE. Nevertheless, carnitine supplementation seems to have no particular side-effects and could, theoretically, also be of benefit to adult patients with VPA-induced hyperammonaemia.