Genetics of Familial Mesial Temporal Lobe Epilepsy

Summary and Comment |
December 21, 2010

Genetics of Familial Mesial Temporal Lobe Epilepsy

  1. Robert C. Knowlton, MD, MSPH

Analysis of an extended set of families suggests that this benign epilepsy syndrome has a complex inheritance pattern.

  1. Robert C. Knowlton, MD, MSPH

The genetic architecture and phenotype of familial mesial temporal lobe epilepsy (FMTLE) remain unclear. Some studies suggest dominant inheritance, but most families in these studies have been too small to allow exclusion of other inheritance modes. In addition, the severity of FMTLE in these studies has varied. To provide more-definitive data, researchers now report on 100 people with a benign form of FMTLE from 39 families, including 20 newly reported-on families with 51 affected members. The additional probands include one twin and 19 nontwins. The researchers assessed seizure-related symptomatology, response to treatment, and electroencephalography and magnetic resonance imaging (MRI) findings. The genetic architecture was assessed by testing goodness-of-fit to four simple dominant Mendelian models: 80% and 60% penetrance, both with and without allowing for epilepsies other than those involving the temporal lobe in first- or second-degree relatives.

In both the twin and nontwin families, segregation analysis revealed that the observed frequencies of TLE and other epilepsies were significantly lower than predicted by any of the models. The cardinal phenotypic features of TLE in these families were psychic and dysmnestic symptoms (e.g., déjà vu), successful antiseizure medication treatment (in all but one), and absence of mesial temporal sclerosis on MRI in those who underwent imaging. One patient had epilepsy surgery; hippocampal sclerosis was not apparent in this patient.

Comment

This report of a large number of families with familial mesial temporal lobe epilepsy provides strong support for polygenic rather than dominant inheritance for most affected families. The findings suggest that dominant inheritance of FMTLE is rare. The study also defines a relatively benign syndrome, in contrast to the common impression of medically refractory mesial temporal lobe epilepsy with hippocampal sclerosis, which was based on findings in another study population. These new findings help make sense of the dissonance between evidence for high heritability of FMTLE in twin studies and the absence of dominant segregation in most families. The authors accurately conclude that identifying most of the genes involved in mesial temporal lobe epilepsy will require genome-wide association studies to search for common genetic variants and deep resequencing methodologies, combined with copy-number variation screening, to identify rare causative variants.

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