Use of Perampanel and a Ketogenic Diet in Nonketotic Hyperglycinemia: A Case Report

Abstract

Background Nonketotic hyperglycinemia is a severe form of early onset epileptic encephalopathy caused by disturbances in the glycine cleavage system; the neurological damage is mainly attributed to overstimulation of the N-methyl-D-aspartate receptor. Case The patient presented with a severe form of nonketotic hyperglycinemia and experienced frequent epileptic spasms and focal seizures, which were resistant to vigabatrin, adrenocorticotropic hormone therapy, and combined dextromethorphan and sodium benzoate treatments. By 9 months of age, perampanel reduced epileptic spasms by >50%. At 14 months of age, the ketogenic diet markedly reduced focal seizures and glycine levels in the cerebrospinal fluid. Conclusion Perampanel reduced fast excitatory neuronal activity, which was induced by an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor, followed by prolonged electrical depolarizations due to an N-methyl-D-aspartate receptor. Furthermore, the ketogenic diet may have modulated the excessive neurotoxic cascade through the N-methyl-D-aspartate receptor. Perampanel and ketogenic diet were effective for seizure control in our patient.

Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels

“…We assume that this results from the use of endogenous glycine pools in gluconeogenesis (Fig. 1 A) [ 34 ] A lower cerebrospinal fluid (CSF) glycine level in an NKH patient on the KD has been reported once before [ 30 ]. The impact on brain glycine levels of the KD has not yet been documented.…”

“…Several case reports have described an ancillary effect of lowered plasma glycine levels with the ketogenic diet (KD), which was initiated for the treatment of refractory epilepsy in NKH patients [27][28][29][30][31][32][33]. We assume that this results from the use of endogenous glycine pools in gluconeogenesis (Fig.…”

“…It has previously been demonstrated that the KD may improve seizure control in patients with NKH, but its effect on other areas of neurodevelopment in patients with NKH has not yet been explored [27][28][29][30][31][32][33]. This question is of particular interest given that although a reduction of glycine levels, as traditionally accomplished via high dose benzoate therapy, leads to a decrease in seizures and improved levels of alertness and neurobehavioral profiles, its impact on neurodevelopmental outcomes in individuals with severe NKH is minimal even when initiated neonatally [19,20,[35][36][37].…”

Nonketotic Hyperglycinemia: Insight into Current Therapies

“…Attempts to use the above-mentioned therapy resulted in a different clinical response in patients or a complete lack of response, which raises doubts as to the validity of the therapy. In some patients with the classical variant of NKH, no clinical improvement was observed despite the early use of sodium benzoate and/or dextromethorphan, even if a reduction in glycine plasma concentration was temporarily achieved [ 3 , 16 , 17 ]. The wide variation in therapeutic effects may be influenced by the heterogeneity of NKH-inducing mutations, which has not always been considered [ 8 ].…”

“…An attempt to use perampanel, an antagonist of AMPA receptors, was reported in a patient for whom treatment with sodium benzoate and dextromethorphan was unsuccessful. By gradually increasing the dose to 0.65 mg/kg/day, an epileptic spasm reduction of50% was achieved [ 17 ].…”