Genetic Aspects of Epilepsy

Abstract

Approximately 50 million people currently live with epilepsy worldwide. About 1% of children aged bellow 17 years have had a diagnosis of epilepsy or seizure disorder and about 0.6% of children of the same age group have active epilepsy. Different health problems are commonly seen in epileptic patients which could be related to the seizeres, whatever the cause of epilepsy or as a side effect of medications. There are many different causes of epilepsy, including genetic disorders, metabolic diseases, and structural brain abnormalities. However, in some cases, the cause of epilepsy is not known. A seizure occurs as a result of a sudden imbalance that occurs between the excitatory and inhibitory forces within the network of cortical neuronswith a sudden onset of net excitation. The paroxysmal depolarization shift (PDS) is the pathophysiological cellular phenomenon that underlies majority of types of epileptic seizuresand interictal epileptiform electroencephalography (EEG) abnormalities (“spikes”).The tendency of individual neurons to enter pathological states in which PDSs are generated can be based on intrinsic neuronal properties, such as dysfunctional ionophores in the genetically determined channelopathies, or on extrinsic mechanisms such as inadequate inhibitory neurotransmitter concentrations or exposure to excessive concentrations of excitatory amino acids or exogenous-excitotoxins. It is now thought that genetic factors account for about 40% of the etiologic causes of epilepsy. Multiple gene mutations have been discovered to be the cause of awide spectrum of genetic epilepsies.Causative gene mutations can either be in ion channel genes like sodium or potassium channel genes, in neurotransmitter receptor genes, in structural genes or in signal transduction pathway genes. Non syndromic genetic epilepsies may be classified based on age of onset of the seizures as follows: Epilepsies of neonatal onset, epilepsies of infantile onset, epilepsies of childhood onset, epilepsies of adolescent onset and epilepsies of variable age onset. Syndromic genetic epilepsies include entities where epilepsy is part of a constellation of manifestations that determine the clinical phenotype. Clinical history of affected individual and a family medical history should be obtained including any history of seizures and other neurodevelopmental disorders in relatives. Clinical, neurological examination and fundus examination are very important in evaluation of epilepsy. EEG is the most common neurodiagnostic test for distinguishing seizures from non epileptic paroxysmal disorderes. Theire are multipleavailable functional neuroimaging techniques, including computed tomography (CT), positron emission tomography (PET) scanning, single photon emission computerized tomography (SPECT) scanning, magnetic resonance spectroscopy (MRS), magnetic source imaging (MSI), and functional magnetic resonance imaging (fMRI), can be very helpful in the localization of theepileptogenic zone and for mapping functional areas of the brain, such as those for language and motor function. Geneticcounselingisimportantnotonlyafteradiagnosishasbeen madebutalsoduringthegenetictesting decision making process. The decision of starting treatment is multifactorial based and must consider the following: age, syndromic diagnosis, etiology, and acceptability of a further seizure. Treatable genetic causes of epilepsy typically include those involving inborn errors of metabolism. There are about 26 AEDs currently licensed for treatment of epilepsy in childhood. The choice of initial treatment should take into account the seizure type(s), epilepsy syndrome, age, etiology, co morbidities, and potential interactions with other medications. Surgical intervention is an established treatment for medically refractory partial (focal) epilepsies. However,surgical treatment is challenged by a consistent failure rate of 10-40% among selected patients.