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Purpose: Epilepsy is a main manifestation in the autosomal dominant mental retardation syndrome caused by heterozygous variants in MEF2C. We aimed to delineate the electro-clinical features and refine the genotype-phenotype correlations in patients with MEF2C haploinsufficiency. Methods: We thoroughly investigated 25 patients with genetically confirmed MEF2C-syndrome across 12 different European Genetics and Epilepsy Centers, focusing on the epileptic phenotype. Clinical features (seizure types, onset, evolution, and response to therapy), EEG recordings during waking/sleep, and neuroimaging findings were analyzed. We also performed a detailed literature review using the terms “MEF2C”, “seizures”, and “epilepsy”. Results: Epilepsy was diagnosed in 19 out of 25 (~80%) subjects, with age at onset

Background Seizures in individuals affected by tuberous sclerosis complex (TSC) commonly develop in the first year of life, are often preceded by a progressive deterioration of the electroencephalogram (EEG), and likely influence developmental outcome. Although early diagnosis of TSC has offered a tremendous opportunity to monitor affected patients before seizure onset, reports of the neurological manifestations of TSC in infants before seizure onset are still scarce. Here we describe early EEG activity, clinical and genetic data and developmental assessment in a group of TSC infants, with the aim of identifying possible prognostic factors for neurodevelopmental outcome. Methods We report on six infants diagnosed with TSC pre- or perinatally, who underwent serial Video-EEG recordings during the first two years of life. EEGs were classified based on distribution and intensity of interictal epileptiform discharges, and Vigabatrin was introduced in case of ictal discharges. Psychomotor development, cognitive functioning and behavioral problems were assessed through standardized scales. Molecular testing included analysis for point mutations and deletions/duplications in TSC1 and TSC2. Results EEG abnormalities appeared at a mean age of 4 months. Four of the six patients developed seizures. EEG abnormalities preceded the onset of clinical seizures in all of them. The two individuals with good seizure control showed normal development, while the other two exhibited psychomotor delays. The patients who did not develop seizures had normal development. A pathogenic variant in the TSC2 gene was detected in all patients but one. The one without a mutation identified did not develop seizures and showed normal neurodevelopment. Of note, the two patients presenting with the worst outcome (that is, poor seizure control and intellectual/behavioral disability) both carried pathogenic variants in the GAP domain of TSC2. Conclusion Our report supports the importance of EEG monitoring before seizure onset in patients with TSC, and the correlation between prompt seizure control and positive neurodevelopmental outcome, regardless of seizure type. Our results also indicate a possible role of the genetic background in influencing the outcome.

Epilepsy is the most common neurological symptom in tuberous sclerosis complex (TSC), occurring in 72-85% of affected individuals. Despite the large number of patients reported, their electroclinical phenotype has been rarely described. We analyzed seizure semiology through ictal video-electroencephalography (V-EEG) recordings in a large series of patients. In this multicenter study, we reviewed V-EEGs of 51 patients: ictal recordings were analyzed in correlation with their clinical variables. The median age of epilepsy onset was six months (one day-16 years), with onset in the first year of life in 71% patients (36/51), in 10 of them during the neonatal period. Sixty-five percent of patients (33/51) experienced epileptic spasms in their life, with late-onset (>two years) in five; 42% of the epileptic spasms persisted after age two years, despite the onset in the first year of life. We identified four different electroclinical subsets: focal epilepsy (35%, 18/51), Lennox-Gastaut Syndrome evolution (27%, 14/51), focal seizures with persisting spasms (33%, 17/51), and spasms only (4%, 2/51). We reviewed 45 focal seizures, 13 clusters of epileptic spasms, and seven generalized seizures. In 12 patients, we recorded different seizure types. In 71% of the focal seizures (32/45), the ictal pattern was focal without diffusion. In 38% of the patients (5/13) epileptic spasms were related to typical diffuse slow wave pattern associated with superimposed fast activity, with focal predominance. Focal seizures and focal spasms resulted as the most frequent seizure types in TSC. Seizure onset was variable but showing a predominant involvement of the frontocentral regions (40%). Discrete clinical signs characterized the seizures, and behavioral arrest was the predominant first clinical objective sign. Epileptic spasms were a typical presentation at all ages, frequently asymmetrical and associated with lateralizing features, especially in older patients.

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystemic disorder caused by deregulation of the mTOR pathway, and represents one of the leading genetic causes of epilepsy. mTOR inhibitors (Sirolimus and Everolimus) are currently approved only for the treatment of growing subependymal giant cell astrocytomas, renal angiomyolipomas and lymphangioleiomyomatosis in TSC. However, preclinical and clinical evidence supports their potential role in effectively treating TSC-associated epilepsy, but no consensus on its use in seizures has been reached yet and there are few data on epilepsy outcome after the suspension of mTOR inhibitors treatment. We report for the first time on a patient in whom discontinuation of Everolimus (prescribed for growing subependymal giant cell astrocytomas) was associated with a relapse of seizures twice, and control of seizures was regained after reintroducing the medicine. This clinical report supports the promising potential of Everolimus in treating epilepsy in TSC, and specifically underlines the non-permanent effect on seizures after withdrawal.