Familial mesial temporal lobe epilepsy: a benign epilepsy syndrome showing complex inheritance

Abstract

Temporal lobe epilepsy is the commonest partial epilepsy of adulthood. Although generally perceived as an acquired disorder, several forms of familial temporal lobe epilepsy, with mesial or lateral seizure semiology, have been described. Descriptions of familial mesial temporal lobe epilepsy have varied widely from a benign epilepsy syndrome with prominent déjà vu and without antecedent febrile seizures or magnetic resonance imaging abnormalities, to heterogeneous, but generally more refractory epilepsies, often with a history of febrile seizures and with frequent hippocampal atrophy and high T₂ signal on magnetic resonance imaging. Compelling evidence of a genetic aetiology (rather than chance aggregation) in familial mesial temporal lobe epilepsy has come from twin studies. Dominant inheritance has been reported in two large families, though the usual mode of inheritance is not known. Here, we describe clinical and neurophysiological features of 20 new mesial temporal lobe epilepsy families including 51 affected individuals. The epilepsies in these families were generally benign, and febrile seizure history was infrequent (9.8%). No evidence of hippocampal sclerosis or dysplasia was present on brain imaging. A single individual underwent anterior temporal lobectomy, with subsequent seizure freedom and histopathological evidence of hippocampal sclerosis was not found. Inheritance patterns in probands' relatives were analysed in these families, together with 19 other temporal lobe epilepsy families previously reported by us. Observed frequencies of epilepsies in relatives were lower than predicted by dominant Mendelian models, while only a minority (8/39) of families could be compatible with recessive inheritance. These findings strongly suggest that complex inheritance, similar to that widely accepted in the idiopathic generalized epilepsies, is the usual mode of inheritance in familial mesial temporal lobe epilepsy. This disorder, which appears to be relatively common, and not typically associated with hippocampal sclerosis, is an appropriate target for contemporary approaches to complex disorders such as genome-wide association studies for common genetic variants or deep sequencing for rare variants.

Genetics of epilepsy

“…27,28 The twin data support genetic influences in nonlesional TLEs; within this grouping, familial TLE is the most important. 29,30 A combination of twin and family data supports complex inheritance for most cases, 25 although there is the well-recognized exception of autosomal dominant FE with auditory features, often due to mutations in LGI1, 17,31 which was not identified in our twins.…”

“…This mixed group highlighted the potential flexibility of this system in an era of evolving understanding of the pathophysiology of epilepsies. For instance, for Nonlesional temporal lobe epilepsies (13,5) familial TLEs, our evolving understanding of the genetic influences based on twin and family data 25,29,30 suggests that this group would be better placed in the genetic group. Similarly, our evolving understanding of IPOE supports a genetic basis for this disorder.…”

“…24 FE were divided into idiopathic FE (IFE), idiopathic photosensitivity occipital epilepsy (IPOE), symptomatic FE, and unclassified FE. For temporal lobe epilepsy (TLE), because of emerging evidence of a major genetic component in cases without lesions, 25 we also used a specific category of nonlesional TLEs as these fall under the 1989 definition of IFE. We included cases with clinical or electrographic support for temporal lobe seizure origin, without structural abnormalities on MRI.…”

Multiplex families with epilepsy

“…In the absence of diagnostic EEG data, participants were classified as focal epilepsy where there was strong clinical evidence for focal onset of seizures (e.g., rising epigastric aura with intense déja vu for temporal lobe epilepsy). 20 Familial pedigree analysis. Pedigrees were constructed for each family, and relationships between affected family members recorded (i.e., sibling pairs or parent-child pairs).…”

Neuroimaging in Focal Epilepsies: An Update

“…TLE is frequently associated with structural abnormalities, but other forms of non-lesional TLEs have been described, such as some forms of familial temporal lobe epilepsy (Figure 4). [11][12][13] …”