INMED/TINS special issue
Human epilepsies: interaction of genetic and acquired factors

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Epilepsies, once regarded as due to demoniacal possession, can have both genetic and acquired causes, with interaction of these factors in many cases. To date, nearly all the genes discovered to be involved in human epilepsies encode subunits of ion channels, both voltage-gated and ligand-gated. Established acquired causes include serious brain trauma, stroke, tumours and infective lesions. Thus, in terms of exploring the neurobiology of ‘nature and nurture’ in disease, the epilepsies are an excellent paradigm. Here, we review the evidence and discuss the possibility that ion channels are a common biological substrate for both genetic and acquired epilepsies. This review is part of the INMED/TINS special issue Nature and nurture in brain development and neurological disorders, based on presentations at the annual INMED/TINS symposium (http://inmednet.com/).

Introduction

Epilepsies are a group of conditions (Box 1) characterized by recurrent and usually unpredictable seizures. They affect ∼3% of the population at some time in life, with the peak incidences in childhood and the elderly [1].

Section snippets

Genetic and acquired causes of epilepsies

Epilepsies can be caused by both genetic and acquired factors. Those epilepsies that are believed to be largely genetic are designated ‘idiopathic epilepsies’ and comprise ∼30% of all cases 1, 2. Epilepsies due to acquired factors are designated ‘symptomatic’ (Box 1) and account for about a quarter of patients. Acquired or environmental causes include head trauma, severe perinatal injury, stroke, developmental lesions, post-infectious lesions and tumours 1, 2.

It is generally believed that the

Brain development and epilepsy

To understand the neurobiology of epilepsies, both genetic and acquired, it is essential to consider developmental changes in the brain throughout life. This is because many epilepsies, especially idiopathic forms, have relatively specific ages of onset and offset [8]. In general, the immature brain is more susceptible to seizures than the adult brain. Developmental processes that might influence this include synaptic pruning, changing density of various neurotransmitter receptors,

How large is the genetic contribution to epilepsies?

Although at least 30% of patients with epilepsy are deemed to have ‘idiopathic’ syndromes [2], it is difficult to measure the genetic contribution to epilepsies definitively. This is because most idiopathic epilepsies are complex genetic disorders and, rather than showing simple Mendelian inheritance, which would enable easy classification of them as genetic or not, they are determined by multiple genes and can involve non-inherited factors. A guide to the importance of genes can be obtained

Interaction of genetic and acquired factors

The idea that genes and environment interact in human epilepsies is an old one and generally accepted for any complex disorder. The concept was first scientifically elucidated for epilepsy by William Lennox, in the mid-20th century [24]. He believed that in an individual patient with epilepsy there were multiple causative factors, including genetics, perinatal acquired factors and postnatal acquired factors, that conspired together to result in the particular phenotype. He emphasized that some

Mechanism of the interaction of genes and environment

Thus, there is good evidence that acquired epilepsies are influenced by genetic effects, and less powerful evidence that idiopathic epilepsies are modified by acquired factors. Consequently, the original idea of Lennox (Figure 1d) was modified, using clinical and experimental data, into a concept that idiopathic and symptomatic epilepsies represented a neurobiological continuum [30]. However, the biological basis of this interaction was unknown.

Regarding symptomatic epilepsies, there is an

Concluding remarks

Nature and nurture are clearly closely intertwined in the aetiology of the epilepsies. Ion channel dysfunction is central to the genetic human epilepsies. There is increasing evidence that changes in ion channels form a common pathway for diverse acquired causes of epilepsies. Our suggestion that ion channels might also be the substrate for the interaction of genetic and acquired factors can now be experimentally addressed. Ion channel biology will further unlock the secrets of this important

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