We sought to review the clinical presentation, testing results, treatments, and progression of disease in three male patients with Rett syndrome (RTT) due to a FOXG1 mutation. This work highlights the importance of individualized treatment plans for neurogenetic epileptic disorders.

Pathogenic mutations in FOXG1 disrupt normal brain development, resulting in a constellation of symptoms including postnatal microcephaly, structural brain abnormalities, severe global developmental delay, aphasia, stereotypies, and epilepsy refractory to anti-seizure medication. Ketogenic diet has emerged as a promising adjunct therapy to anti-seizure medications in cases of refractory epilepsy of genetic etiology.

Retrospective dual-site case series. Included male patients less than 18 years of age at time of diagnosis with genetically confirmed RTT with a FOXG1 mutation.

Our study revealed an age of diagnosis ranging from 13 months to 14 years of age. All three have developmental delays, abnormal movements, are non-verbal and non-ambulatory. Two of the three are known to be microcephalic. Two of three had electrographic seizures of more than one semiology before 14 months of age. The third has no confirmed seizures thus far but has abnormal movements with diffuse background slowing on electroencephalography. Of the two patients with seizures, one had up to 30 seizures daily and epileptic encephalopathy who was treated with anti-seizure medications (ASMs), Vagal Nerve Stimulator which was removed due to lack of efficacy, and Ketogenic Diet (KD). With a KD ratio of 4:1 and multiple ASMs, this patient had a reduction in seizure frequency to 3/day and fewer seizure-related hospitalizations. The other patient had a decrease in seizure frequency from three times daily to weekly on keppra and phenobarbital.

Our data highlights the difficulty in controlling seizures in 2/3 patients with FOXG1 RTT. We hypothesize that ketogenic diet can reduce the seizure burden in male patients with FOXG1 mutation.