Genetic analysis of tuberous-sclerosis genes 1 and 2 in nonlesional focal epilepsy

Germline mutations of TSC1 (harmartin) and TSC2 (tuberin) are known to cause tuberous sclerosis (TSC), an autosomal dominant disorder with severe neurological and systemic manifestations. In addition, increasing data indicate aberrant patterns of allelic variants in patients with lesion-associated epilepsy, but absence of other stigmata of TSC. Animal models of TSC suggested that mutations in the TSC2 gene, even in absence of manifest neuropathological changes, induce aberrant neuronal activity. On this basis, we have carried out a mutational analysis of TSC1 and TSC2 in patients with pharmarcoresistant focal epilepsy without evidence of epileptogenic lesions on neuroradiological and histopathological examination (n = 10). SSCP analysis revealed an allelic variant of TSC2 to be significantly increased (exon 41: 50.0% vs controls 14%, P = 0.0132), which previously was reported to be increased in gangliogliomas and mineralized focal cortical dysplasia as well. Our data suggest allelic imbalances of TSC2 in nonlesional focal epileptic tissue.

Research Highlights► Patients with nonlesional focal epilepsy have rather poor clinical outcome. ► Relevant TSC2 alterations are not necessarily associated with morphological changes. ► TSC2 sequence analysis shows allelic imbalances in nonlesional focal epileptic tissue. ► Respective changes overlap with those in other patients groups with focal epilepsy. ► These data may point to a more general role for TSC2 in epileptogenic brain foci.