Some science behind the scenes

Epilepsy and genetics

Any mutations that affect the nerve cell itself may produce abnormal functioning of the nerve.

An obvious area where mutation may produce an odd result are the voltage gated and ligand gated ion channels.  Several genes that code for protein subunits of voltage-gated and ligand-gated ion channels have been associated with forms of epilepsy. Clearly, once the gene has been mutated it is passed on to any children and some forms of inherited epilepsy have been linked to the  genes that code for sodium channel proteins; these defective sodium channels stay open for too long, thus making the neuron hyper-excitable. There is research that also links epilepsy with gene malfunctions in calcium ion channels.  

Once one neuron is excited then subsequent neurons will excite and there will be a chain reaction of hyperexcitability that can be caused by perhaps only a few defective neurons, until the chain of neurons and their neurotransmitters reach the end of their range of operation.  So it does not take many defective neurons to produce an epileptic seizure.

The Voltage-Sensing Domain of K(v)7.2 Channels as a Molecular Target for Epilepsy-Causing Mutations and Anticonvulsants - Miceli F et al  - Division of Neurology, IRCCS Bambino Gesù Children's Hospital Rome, Italy.

Understanding the molecular mechanisms underlying voltage-dependent gating in voltage-gated ion channels (VGICs) has been a major effort over the last decades. In recent years, changes in the gating process have emerged as common denominators for several genetically determined channelopathies affecting heart rhythm (arrhythmias), neuronal excitability (epilepsy, pain), or skeletal muscle contraction (periodic paralysis). Moreover, gating changes appear as the main molecular mechanism by which several natural toxins from a variety of species affect ion channel function. ……..

[we find that ]…. genetically determined alterations in K(v)7.2 and K(v)7.3 genes are responsible for benign familial neonatal convulsions, a rare seizure disorder affecting newborns…. .

 Both mutation-triggered channel dysfunction and drug-induced channel activation can occur by impeding or facilitating, respectively, channel sensitivity to membrane voltage and can affect overlapping molecular sites within the voltage-sensing domain of these channels. Thus, understanding the molecular steps involved in voltage-sensing in K(v)7 channels will allow to better define the pathogenesis of rare human epilepsy, and to design innovative pharmacological strategies for the treatment of epilepsies and, possibly, other human diseases characterized by neuronal hyperexcitability.

NaV1.1 channels and epilepsy - Catterall WA, Kalume F, Oakley JC; University of Washington, Department of Pharmacology, Seattle, USA.

Voltage-gated sodium channels initiate action potentials in brain neurons, and sodium channel blockers are used in therapy of epilepsy. Mutations in sodium channels are responsible for genetic epilepsy syndromes with a wide range of severity, and the NaV1.1 channel encoded by the SCN1A gene is the most frequent target of mutations. Complete loss-of-function mutations in NaV1.1 cause severe myoclonic epilepsy of infancy (SMEI or Dravet's Syndrome), which includes severe, intractable epilepsy and comorbidities of ataxia and cognitive impairment. …….

 Generalized epilepsy with febrile seizures plus (GEFS+) is caused by missense mutations in NaV1.1 channels, which have variable biophysical effects on sodium channels expressed in non-neuronal cells, but may primarily cause loss of function …. Familial febrile seizures is caused by mild loss-of-function mutations in NaV1.1 channels; mutations in these channels are implicated in febrile seizures associated with vaccination; and impaired alternative splicing of the mRNA encoding these channels may also predispose some children to febrile seizures. We propose a unified loss-of-function hypothesis for the spectrum of epilepsy syndromes caused by genetic changes in NaV1.1 channels, in which mild impairment predisposes to febrile seizures, intermediate impairment leads to GEFS+ epilepsy, and severe or complete loss of function leads to the intractable seizures and comorbidities of SMEI.