AFG2A-related encephalopathy: Effectiveness of ketogenic diet in epilepsy and mitochondrial dynamics modulation

AFG2A-related encephalopathy (AFG2A-RE) is a neurodevelopmental disorder that may present with drug-resistant epilepsy (DRE). Our aims were: to evaluate the clinical response to a ketogenic diet (KD) in a series of patients with AFG2A-RE and DRE, and to describe the mitochondrial effects in patient's fibroblasts cultured in a KD mimicking medium (KD-MM). This was a collaborative, descriptive, and experimental study involving a total of five patients. The primary outcomes assessed following ketogenic diet (KD) treatment were the percentage of seizure reduction and the parents' global impression of change. Additionally, patient-derived fibroblasts (n = 3) were cultured in a KD-MM to evaluate effects on mitochondrial dynamics and metabolism. The mean age of the patients was 7.9 years, and four were males. All patients presented with developmental and epileptic encephalopathy with DRE, motor impairment, severe intellectual disability, deafness, and microcephaly. In all but one case, the initial epilepsy presentation was infantile epileptic spasms syndrome (IESS), with a mean age at onset of 13.6 months. Four patients received KD treatment for DRE, with seizure reduction rates of 0 %, 30 %, 70 % and 100 %, respectively. Improvement in social interaction improvement was observed in one patient, while improvements in attentional and motor function were noted in two. In vitro studies demonstrated that AFG2A-deficient fibroblasts exhibited altered mitochondrial morphology and dynamics, as well as reduced ATP production and ROS levels. These abnormalities were significantly reversed when the fibroblasts were cultured in KD-MM. In conclusion, this small series of patients with AFG2A-RE showed beneficial effects from KD treatment. Greater seizure control was achieved when the ketogenic diet was initiated during early childhood. These findings are preliminary and validation in multicenter prospective study is required.