In recent years, there has been a spectacular change in research and knowledge of the genetic bases of epilepsy, determining with increasing precision the cellular, subcellular and molecular mechanisms of the seizure phenomenon, as well as its possible alterations based on gene mutations, interrelated with environmental factors, ultimately lead to a seizure phenotype.
All of this must be analyzed remembering that epilepsy can appear as a consequence of a cerebral alteration, with a structural and/or metabolic basis, or as an expression of an inherited susceptibility to cortical hyperexcitability, which, as is well known, are the conceptual limits between symptomatic epilepsy and idiopathic.
It is accepted that between 40% and 50% of epilepsies belong to the group of generalized idiopathic epilepsies, in which the existence of a genetic basis is considered, an origin also assumed in hereditary partial epilepsies, as will be discussed later.
Ultimately, modern epileptology cannot be understood without a clinical understanding of the aetiological significance of these genetic considerations.
Epilepsies can be inherited through any of the forms of human inheritance, from traditional inheritance, which is carried out through a single gene (Mendelian) with a different trait (autosomal dominant, recessive or X-linked), to more complex form by polygenic or multifactorial inheritance.
But they can also appear as a consequence of an alteration of part or all of a chromosome, or through non-traditional inheritance, such as mutation of the mitochondrial genome, or abnormal repetition of a DNA sequence
INHERITANCE BY DEFECT OF A GENE: They have been determined in different epilepsies and epileptic syndromes that will be mentioned later, but it is necessary to make some considerations about the existing dilemma between the phenotype and genotype of the various epilepsies and epileptic syndromes, which do not have on many occasions a coincident clinical translation, which can lead to misconceptions.
* In some epilepsies in which a responsible gene has been identified, such as Juvenile Myoclonic Epilepsy and Benign Familial Neonatal Seizures, locus involvement has evident heterogeneity in its clinical expression, that is, in the convulsive phenotype, among affected individuals, even if they belong to the same family.
* Likewise, in the aforementioned examples, it has been shown that mutations in different loci can produce a similar epileptic phenotype. Circumstance that is also seen in Progressive Myoclonic Epilepsies, where by various pathophysiological pathways, due to different mutations, the same epileptic phenotype is reached (myoclonic epilepsy). On other occasions, allelic variations within the same locus can in turn condition different phenotypes.
* Some idiopathic epileptic syndromes are polygenic, that is, resulting from the sum of multiple genetic mutations.
* Sometimes there is a clear interaction between genetic and environmental factors, so that the former are responsible for susceptibility to epilepsy, while the latter are necessary for there to be clinical expression, examples are photosensitive epilepsies or febrile seizures.
* Some epilepsies occur when a genetic defect is “unmasked” as a result of an acquired brain injury, the example is found in post-traumatic onset epilepsies that develop more easily in individuals with a family history of epilepsy.
CHROMOSOME ANOMALIES: This section includes trisomies, deletions, duplications, inversions, translocations, etc., which usually condition somatic alterations of various locations, but which may also be responsible for a certain electroclinical epileptic phenotype, as occurs, for example, in Angelman syndrome.
NON-MENDElian MECHANISMS: Within this section it is necessary to highlight the concept known as genomic “imprinting”, which defines a non-Mendelian pattern of inheritance, which can give rise to a different phenotype depending on whether the anomaly comes from the father or of the mother, being a characteristic example the Angelman Syndrome and the Prader Willi Syndrome that will be commented on later.
In direct relation with the development of the pathology that concerns us, two mechanisms of great significance stand out and that currently must be analyzed as one more possibility in the inheritance of certain epilepsies and epileptic syndromes: mitochondrial inheritance and the processes derived from an abnormal triplet repetition of nucleotides.
Finally, epilepsy has sometimes been related to the inheritance of stable DNA expansions, which are called minisatellite sequences (tandem repeats), and this possibility is considered to be involved in progressive myoclonic epilepsy of the Unverricht-Lundborg type.
Mapping of epilepsy genes
It should be kept in mind that the search for the genetic bases of epilepsy collides head-on, on many occasions, with the existing classifications of epileptic seizures, epilepsies and epileptic syndromes. We currently use classification criteria that relate age-dependent factors, electroencephalogram (EEG) findings, and even the age at which seizures may disappear.