Rationale:
TBC1D24 gene proteins are involved in neuronal vesicular trafficking and oxidative stress resistance. Pathogenic mutations in TBC1D24 are associated with infantile onset focal and generalized epilepsy that is often drug-resistant and non-syndromic deafness. We report a novel pathogenic mutation, c.1481C >G(p.Thr494Ser) in the TBC1D24 gene that was identified in a case of noogenic epilepsy, otherwise known as reflex seizures triggered by thinking, in three siblings.Methods:
A 28-year-old woman (case A) with seizures since age 13 was followed in the epilepsy clinic. She had focal unaware seizures involving a “dream-like” state with unresponsiveness and amnesia followed by postictal confusion. These were triggered by recalling “items such as a fan or a plant from her old house”. She also had spontaneous nocturnal seizures. She required two antiseizure medications and was also evaluated for epilepsy surgery. Video EEG showed left temporal onset seizures (Image 1). MRI brain 3T with epilepsy protocol showed a left inferior frontal juxta-cortical T2/FLAIR hyperintense lesion concerning for a focal cortical dysplasia (Image 2). PET/CT brain showed possible area of hypometabolism in the region of focal cortical dysplasia (Image 2). In addition, the patient’s two sisters (Case B and C with ages 31 and 25 years, respectively) were also followed for focal epilepsy with the elder sister who had seizure onset at age of 26 showing left anterior temporal sharp waves on EEG (Image 1), while the younger sister with seizure onset at age 9 years had noogenic seizures similar to the patient (described as being triggered by “thinking of turning on the light switch in her house”) with EEG showing right anterior temporal onset seizures (Image 1). The sisters’ brain MRIs were both non-lesional. Her sisters both had focal unaware and focal to bilateral tonic-clonic seizures. Family members including the patient's brother and parents did not have epilepsy. There were no other seizure risk factors in the sisters.
Results:
All three sisters had seizures mostly controlled with two anti-seizure medications (ASMs). Breakthrough seizures occurred either with reflex triggers or ASM non-adherence. Epilepsy gene panels performed in her sisters showed a shared heterozygous c.1481C >G (p.Thr494Ser) mutation in TBC1D24 gene.Conclusions:
Patients with noogenic seizures should be considered for genetic testing to evaluate for a TBC1D24 mutation. Treatment of seizures may have therapeutic and prognostic implications. Noogenic seizures are suspected to have a genetic basis, and this is the first case of their association with a novel genetic mutation in TBC1D24 gene.
Funding: None