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Genetics of Epilepsy
ISSN: 2155-9562

Journal of Neurology & Neurophysiology
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  • Review Article   
  • J Neurol Neurophysiol 2019, Vol 10(3): 488

Genetics of Epilepsy

Oluwayemi Joshua Bamikole*, Miles-Dei Benedict Olufeagba, Samuel Temitope Soge, Noah Olamide Bukoye, Taiwo Habeeb Olajide, Subulade Abigail Ademola and Olukemi Kehinde Amodu
Institute of Child Health, University of Ibadan, Nigeria
*Corresponding Author: Oluwayemi Joshua Bamikole, Institute of Child Health, University of Ibadan, Nigeria, Tel: +2347068505498, Email: [email protected]

Received Date: Feb 06, 2019 / Accepted Date: Mar 27, 2019 / Published Date: Aug 09, 2019

Abstract

Genetics is a branch of the human biology which provides insights about basic and vital processes which arises from birth till death, development to Apoptosis (cell death), and in disease aetiology and therapies or better methods in use of available treatments to solve human health conditions because gene functions in all biological process.

Epilepsy is a seizure that occurs without identifiable justification with a great chance of further seizures which is almost the same to the global recurrence risk of 60% after two unjustified seizures, happening over a ten years’ span. Fifty million people globally present with epilepsy ranging from about 20 to 70 cases per 100,000 in a year and Over 85% of the epilepsy cases are present in underdeveloped and even developing countries with low or middle income. Two out of three of all epilepsy occurrences are genetic, with one percent familial and ninety-nine percent sporadic. A total of about Seventy-six genes has been associated with epilepsy and the variants in these genes are usually new or inherited.

Literatures were gotten mainly from Public Medline with the use of search terms like “genetics of epilepsy”, “epilepsy”, “genetics and epilepsy”, “genetics”, epilepsy associated websites, and the NCBI.

Genetics has changed the clinical understanding of epilepsy and the reward is the provision of useful and vital information to the public at large and this has brought about interventions and breakthrough in the handling, care, treatment, diagnosis and control of epilepsy. Therefore, it is expedient that research on genetic mechanisms involved in epilepsy and the occurrence is encouraged and promoted as it will aid improvement in the knowledge of epilepsy and increase the ability to correctly diagnose the disease, and developing better treatment options.

Keywords: Genetics; Epilepsy; Seizure

Introduction

Genetics is a branch across the human biology which provides information about basic processes which arises from birth till death, development to programmed cell death, and also in providing insight about disease aetiology and therapies or much better use of available treatments to solve underline human health conditions because gene activity is involved with all biological process [1].

According to ILAE [2], epilepsy, a common non-infectious neurologic disease remains a public burden. History wise, epilepsy was known to be a disease caused by the wrath from a higher being usually a god, devil, witch craft or an angry ancestral spirit [3]. The belief was that powerful entity such as gods, devil, witches, spirits could strip a man of his good and perfect health state, by propelling him up and down the ground, convulsing him and then restoring him to his former good state of health in a short while [3,4]. This historical knowledge has perpetually influenced the mind-set of the general public to epilepsy making it a feared disease as `lunatic' was a term previously used to identify epilepsy patients.

According to St Mark 9 (KJV), A foul spirit sent out of a man with fits and in Matthew’s account, the word epileptic was used to describe the boy. It is important to note that Jesus casted it out as he did to other demons, however the Bible eventually mentioned epilepsy as a condition different to demon possession in Matthew 4:24. These beliefs and different understanding of the bible have caused patients with epilepsy (PWE) to be castigated, ostracized and stigmatized. The social importance is negligible, for instance, in Madagascar, epileptics are refused burial in their different family allocated graves sites and even in some places in Nigeria [5].

In African countries, people with epilepsies are out-cast, as Africans have a deep and strong believe in history, and history according to Ogunrin [3], says the disease resulted from visitation from either of the devil, witch-craft, ancestral spirit or consumption of dangerous substances. Epileptic individuals are likely to become drop outs, become jobless, find it impossible to marry, and becomes inflicted to the extent of becoming a wanderer [3,5] hence, suicide is common among epileptic individuals [2,3,5].

The WHO dictionary defined epilepsies as reoccurring disorder of the central nervous system (CNS) of different aetiologies which has a typical feature of recurrent seizures (the clinical manifestation of an abnormal and immoderate synchronization of a population of cortical neurons leading to electrical activities in the brain) due to unconscionable discharge of cerebral neurons.

Epilepsy can be defined with any of the following conditions:

1. A minimum of two unjustifiable seizures happening more than twenty-four hours apart [6]

2. One reflex seizure with a chance of more seizures similar to the general recurrence risk of at least 60% after two unprovoked seizures, occurring over a span of 10 years [6]

3. Presence of epilepsy syndrome [6]

There are many forms of epilepsy that can be distinguished by various characteristics including age of onset, predominant seizure type(s), and etiology [7]. Many Factors can lower the threshold and trigger seizures such as Flashing/bright lights, Inadequate sleep, Stress, Over stimulation, Certain medications, Hyperventilation, Alcohol consumption, fever among others [8].

Approximately 4% of individuals will develop epilepsy during their lifetime, making epilepsies one of the most common neurological conditions [9]. Given the relatively high prevalence and adverse effects on quality of life, epilepsies represent a substantial health and economic burden to the patients and the society [10]. The manifestation of epilepsy may be motor, sensory, psychic or autonomic, epilepsies Exclude Single afebrile episodes, Febrile seizures, Seizures due to altered metabolic states, Seizure due to alcohol or drug withdrawal, Other transient cerebral insults [11]. According to ILAE [12], three are three distinctive classes of epilepsies; which include Genetic classes, structural/metabolic classes and the unknown/ uncategorized. It is important to note that genetic factors underline 70% of all epilepsy cases [8].

Prevalence of Epilepsy

According to WHO [13], reported that 50 million people globally have epilepsy with a yearly incidence which ranges from 20 to 70 cases per 100,000. Over 85% of the cases are found in low and middle income nations. This incidence rates occurs more within ages 15 and 65 years, and raises again the elderly [13]. The prevalence is specifically high in countries such as the underdeveloped and developing nations (Latin America and several African countries, such as Liberia and Nigeria) [2,3]. Most epileptic patients in African countries prefer to remain silent and are reluctant in opening up about the disease because of the stigma attached to the disease, this factor affects the prevalence rates hence a likelihood that most of the reported prevalence rates represent a just a few as the chances of underreporting are definitely high [12].

Reported epilepsy prevalence rates in Africa are based on selected communities and hospital admissions which ranges from 2.2 to 58 per 1000 [13]. Most African studies reported a high case of epilepsy among males, this may be due to the fact that in most parts of Africa, males more readily go to the hospital for socio-economic reasons and hence predominate in the hospital populations and also, a higher prevalence of epilepsy among rural dwellers [3],

Figure 1 shows the commuted prevalence rate of epilepsy from 1988-2003 among various African countries, with lowest recorded prevalence of 3.5 in congo, highest prevalence of 58 in Cameroon and an average of 15.83 per 1000 in the selected African countries.

neurology-neurophysiology-Epilepsy-prevalence

Figure 1: Epilepsy prevalence among some selected African countries between 1988-2003 [16].

One of the foremost publications on Nigerian epilepsy reported a prevalence of between 8 and 1.3 per 100 people dwelling in the Lagos urban community; Osuntokun et al. [14] reported a prevalence rate of 0.53 per 100 people among Igbo-ora inhabitants. The prevalence rate is usually lower compared to rural African communities, and this low prevalence rate is due to the improvement in health functions and facilities. Another community-based study by Longe and Osuntokun [15] reported a prevalence rate of 0.62 per 100 among a rural Community of Udo, Nigeria. However, based on reported communities, the prevalence of epilepsy varies from 0.2 to 1.3 per 100 but with a approximated rate of 3.1 per 1000 [3]. These reports are vital as they show that, improved social health, General sensitization/ awareness concerning epilepsy will reduce the incidence burden.

Considering the fact that, epilepsies were long regarded as magical or divine disease and are not a single clinical entity but rather, a group of conditions with seizures being the unifying symptom [17], It is necessary to note that symptoms are not limited to seizures in many epileptic syndromes. The effect of the underlying causal factors is not often restricted exclusively on mechanisms regulating seizure activity but also other aspects of development and central nervous system (CNS) functions and other tissues can be affected [18]. Therefore, individuals with epilepsy may have other neurological symptoms, dysmorphic features, muscular disorders or other defects in any tissue. Seizures are also a common comorbidity of various other neurological and neurodevelopmental disorders where epilepsy is not the primary phenotype [17]. These include, for instance, autism spectrum disorders, migraine and intellectual disability, as well as many other genetic syndromes [19,20].

It is worthy to note that genetic studies on epilepsies has discovered a high number of gene involved with epilepsy [19].

Pathomechanism of Epilepsy

The nervous system is the part of the animal that cordinatates its actions by transmitting signals to and from different parts of the body other via synaptic connections, this process is called synaptic transmission, which can be either excitatory or inhibitory [18]. The nervous system consists of two part which include the (a) Central Nervous System which consist of the brain and the spinal cord (b) Peripheral nervous system (PNS) which according to Bourdenx M, et al. [21] mainly consist of nerves. The nervous system is defined by presence of a special cell type Neuron, which is also known as nerve cell [22]. Neurons have special structures that allow them to send signals rapidly and precisely to other cells, these structures ae known as dendrites [21]. Dendrites are a branched structure of a neuron, where synapses are located (Figure 2). Synapses can be chemical or electrical, of which chemical synapses are most prevalent. They send this signals in form of electrochemical waves traveling along thin fibers called axons, which causes chemicals called neurotransmitter to be released at junction called synapses [19]. According to Myers and Mefford and McTague et al. [19,22], thousands of synapses, either excitatory or inhibitory, can be present in each dendrite and they can originate from multiple presynaptic neurons. Dendrites are responsible for processing of these synaptic inputs. Postsynaptic potentials are changes in the membrane potential at the synaptic terminal of the neuron that receives the signal. Postsynaptic potential generated by each active synapse is small, these excitatory and inhibitory postsynaptic potentials are, however, added together and if the sum exceeds a threshold, action potential is triggered.

neurology-neurophysiology-Neuron

Figure 2: Neuron [18].

Action potential is the electric signal that travels along the axon and sends information to other neurons [18]. In chemical synapses, the neurotransmitter that is released from the presynapse to the postsynapse via the synaptic cleft determines the nature of the synaptic potential. Gammaaminobutyric acid (GABA) is the most common inhibitory neurotransmitter where there is an inward flow of CI- and outward flow of K+ currents, while glutamate, aspartate is an example of a neurotransmitter in excitatory synapses where there is an inward flow of Na+ and an outward flow of Ca2 + currents. Other major neurotransmitters in the brain according to the American Epilepsy society, include acetylcholine, dopamine, serotonin, histamine, other modulators such as neuropeptides, hormones.

A unified pathomechanism for epileptic seizures can be described as the imbalance of the above described process which is the inhibition and excitation in the nervous system. This imbalance can result from having too little inhibition (disinhibition) or too much excitation, thus, seizure activity may arise when the mechanisms inhibiting neuronal firing are impaired or the system facilitating excitation is promoted [23,24].

Initially, the many genes known to be linked to epilepsies encode proteins with a large variety of functions and many of them do not have any obvious association with potential mechanisms controlling the balance of inhibition and excitation, however, when first genes associated with epilepsies were identified, the functional connection of the epilepsy genes and the imbalance between excitation and disinhibition was more evident [25], many of these genes encode neuronal ion channels, which have an important role in regulation of neuronal excitability, for example, some of these proteins included voltage-gated potassium or sodium channels genes, whose function is to generate and propagate action potentials [25]. Depending on the type of neurons in which the ion channels are expressed and type of the mutation (gain-of-function, loss-of-function), dysfunction of these epilepsy associated ion channel causes either too much excitation or too little inhibition, for example, if a missense or nonsense variant disrupts sodium channel function in an inhibitory neuron, it leads to decreased inhibition an hyperexcitability of a neuronal network causing seizure [26]. Given the strong link of ion channel genes and epilepsies, epilepsies have been considered as ‘channelopathies’, i.e., diseases where ion channel function is impaired [18].

Classification of Epilepsy

Classification in epilepsy is primarily for clinical purposes. It influences every clinical consultation, yet its impact stretches far beyond the clinical domain to clinical and basic epilepsy research and to the development of novel therapies [27]. In 2017, The world's main scientific body devoted to the study of epilepsy revised the classification of Epilepsy and Figure 3 is a Framework for epilepsy classification according of international league of epilepsy.

neurology-neurophysiology-Framework-epilepsy

Figure 3: Framework for epilepsy classification [28].

According to the international league against epilepsy (ILAE) [12], three are three distinctive aetiological classes of epilepsies; Genetic, Structural/metabolic and Unknown [17].

According to Hildebrand et al., [8], Genetic category was formerly referred to as idiopathic, implying that the underlying cause of the disease is unknown, He concluded by estimating that genetic factors causing epilepsies are 70%. A report by Panayiotopoulos [29] shows that genetic generalised epilepsies (GGE) constitute the most frequent form of genetic epilepsies and it accounts for approximately 30% of all cases.

Epileptic encephalopathies (EE) are another subgroup of genetic epilepsies. They are individually rare but collectively account for an important fraction of epilepsies. EEs are early-onset and severe forms of epilepsies where epileptic brain activity contribute to cognitive and behavioural defects [17]. According to Khan and Al Baradie [30], epileptic encephalopathies do not respond well to antiepileptic drugs and they are associated with developmental delay or regression and poor prognosis. Genetic epilepsies can be further divided into epilepsy syndromes with distinctive electroclinical features and these can be arranged based on their onset (neonatal, infancy, childhood, adolescence-adult) and characteristics findings in electroencephalogram (EEG) [17].

The second aetiological category includes epilepsies that are caused by structural lesions or metabolic conditions [17] also known as symptomatic. Structural defects, which increase the risk of epileptic activity, may arise due to acquired disorders such as trauma, stroke and infection. Notably, this category can also include genetic disorders, when the underlying genetic variants result in structural lesions or other defects causing seizures. Tuberous sclerosis is one example of such disorders. It is useful to note that symptoms are not always limited to seizures in many epileptic syndromes. The effect of the underlying causal factors is not often restricted exclusively on mechanisms regulating seizure activity but also other aspects of development and function of the central nervous system (CNS) and other tissues can be affected. Therefore, individuals with epilepsy may have other neurological symptoms, dysmorphic features, muscular disorders or other defects in any tissue (Figure 4) [17].

neurology-neurophysiology-Pictorial-representation

Figure 4: Pictorial representation of classes of epilepsy according to ILAE 2013.

The third aetiological category include epilepsies that are caused by unknown/uncategorized causes which can’t be categorically stated as having a genetic or symptomatic backbone [17].

The classification of epilepsy according to seizures

• Seizures beginning in the brain (Figure 5)

neurology-neurophysiology-seizure-types

Figure 5: Classification of seizure types [34].

focal seizures previously referred to as partial seizures

Generalized previously referred to as primary generalized

• Seizures describing awareness

Focal aware

focal impaired awareness

• Describing motor and other symptoms in focal seizures

Focal motor seizure

Focal non-motor seizure

• Unknown onset seizures description

According to to Brodie MJ, et al. [33], when the beginning of a seizure is not known, the classification still gives a way to describe whether the features are motor or non-motor.

Diagnosis of Epilepsy

According to [3], Epilepsy diagnosis is still depenent on clinical information, and the evaluation epileptic patients requires the use of investigative modalities such as Electroencephalography (EEG) and Neuroimaging facilities such as Plain Radiography, Computerized Tomography, MRI, Positron emission tomography. Other diagnosis method reported by DNA diagnostic experts [35] include physical examination, family history and genetic testing [36].

Electroencephalography as an electrophysiological technique that is used in monitoring and recording electrical activity of the brain. It is majorly non-invasive, and it uses a small metal discs known as electrodes attached to the scalp. It is mostly often use in epilepsy diagnosis. Despite limited spatial resolution EEG continues to be a valuable tool for research and diagnosis of epilepsy.

Plain radiology generally refers to projectional radiography (without the use of more advanced techniques), it is also referred to as radiography that generates single static images as contrasted to fluoroscopy. Plain skull x-ray still has a place in developing countries although the development of advanced imaging techniques has made it almost irrelevant, although It is still very cheap, widely available and relatively innocuous despite its inferiority in both sensitivity and specificity to newer techniques). It is useful in the detection of bony changes (as seen in raised intracranial pressure and some tumours) and abnormal calcification (commonly associated with cerebral tumours, arteriovenous malformations and infections like cysticercosis, toxoplasmosis and cytomegalovirus) [3].

Computerized Tomography is also called CT scan and it makes use of computer processed combinations of so many x-ray measurements taken from various angles to produce many cross sectional (tomographic) images of a scanned area of an object, allowing the user to have inside view of the object without cutting. It is also useful in detecting structural lesions and in determining the exact location of such lesions [36]. It is also useful in determining cerebral atrophy, a common abnormality demonstrated in epileptic patients [3].

Magnetic Resonance Imaging (MRI) makes use of magnetic field and pulses of radio wave energy in making pictures of organs and structures inside of the body and this technique is much superior to CT scan [37].

Single Photon Emission Computerized Tomography (SPECT) is an imaging technique that uses gamma rays. It is not commonly used in the diagnosis of epilepsy [38]. It is both a structural and functional neuro radiological investigation as it reveals the presence of structural lesions and metabolism disturbances. It makes use of radioisotope scanning to describe structural abnormalities and cerebral perfusion [3].

Positron Emission Tomography (PET) is a nuclear medicine imaging technique that is generally used to monitor metabolic processes in the body. It detects gamma rays indirectly emitted by a positron emitting tracer which is introduced into the body on a biologically active molecule [39].

Other diagnosis method includes:

Clinical and family history: According to the DNA diagnostic experts [37], detailed information on clinical history gives insight to know whether seizure events are truly epileptic seizures, rather than non-epileptic events such as fainting, breath-holding, transient ischemic attacks, strokes, arrhythmias, or hypoglycemia, all of which shows similarity to epileptic seizures

Genetic testing: The information obtained from other diagnostic methods helps a clinician in determining if genetic testing should be offered to a patient with epilepsy and the particular genetic test (s) that is required or appropriate [35]. According to Ottman [40] the outcome of a genetic test includes; positive, negative result, or a variant of unknown significance

- A positive result shows the presence of the disease-causing mutation in the tested individual [40].

-A negative result does not necessary rule out a genetically inherited epilepsy syndrome in an epileptic patient [40].

- When there is indication that the pathogenic role of the variant cannot be clearly established, variance of unknown significance is reported [40].

- Research on genetic mechanisms underlying epilepsy is essential for improving the knowledge, ability to correctly diagnose the disease, and also predict who will or will not end with epilepsy.

Management and Treatment of Epilepsy

Dietary management research has shown that ketogenic diets are strongly linked with the management of intractable epilepsy. The classical diet is based on an estimated daily requirement of 75 kilocalories per body weight; 50% of calories are given as fat, the remainder as protein and carbohydrates [12]. The fats are mainly long chain fats such as butter and cream [41]

Drug therapy: Epilepsy diagnosis has a great implication to the sufferer, not least of which is the fact that the patient might likely have to be on medication for the rest of his or her life. According to [42] the administered drug can cause harmful side effects, and it do require continual medical supervision, therefore the decision to begin drug treatment requires rightly diagnosis of epilepsy, chance estimate of seizure recurrence, the extent to which anticonvulsant therapy will improve these chances be considered [3]. The most suitable drug for a particular type of seizure is selected and administered in a dose high enough to bring the plasma drug concentration into a therapeutic range without unacceptable side effects [32]. It is quite usual to find epileptic patients seeking alternative treatment methods in Nigeria [3,5,31] and this probably could explain late presentation in the hospital.

Surgical Management: According to the World Health Organization (WHO) [32], Patients with frequent seizures despite good compliance with drug usage, good dietary management may require the surgical option. According to a report by Mohamed et al., [43] the less seizures a patient has, the more easier it is to control the epilepsy, hence, seizures may beget seizures has been hypothesized for more than a century.

Genetic Epilepsy

First gene discoveries in epilepsies were done in the 1990s. In 1990, the genetic defect underlying myoclonic epilepsy and ragged-red fibre disease, a syndromic form of epilepsy involving myopathy and spasticity in addition to myoclonic seizures, was identified in the mitochondrial genome [44]. In epilepsy syndromes where seizures are clearly the predominant clinical feature, the first causal variant was identified in CHRNA4, encoding a nicotinic acetylcholine receptor subunit [24]. This particular variant causes autosomal dominant nocturnal frontal lobe epilepsy. One of the most important gene discovered in epilepsy were variants in KCNQ2 and SCN1A, the former encoding a neuronal potassium channel and the latter a neuronal sodium channel [45,46].

International league against epilepsy [34] reported 76 epilepsy genes in total that has been identified and are all associated with different age groups (some identified with more than one age group) {49 genes identified among infants (0-12months), 31 genes identified among childhood (13 months-12yrs), 13 genes identified with adolescents (13yrs-28yrs) and 9 genes identified among adults (over 18yrs)}, the types of seizures, and other associated features (Figure 6).

neurology-neurophysiology-genetic-epilepsy

Figure 6: Representation of genetic epilepsy [18].

Genetic generalised epilepsies (GGE) constitute the most common form of genetic epilepsies and it accounts for approximately 30% of all cases [29]. GGEs emerge typically in the childhood or adolescence and they are generally not associated with cognitive dysfunction or developmental delay. Seizures are generally well controlled with appropriate antiepileptic drugs in GGEs [29]. Epileptic encephalopathies (EE) are another subgroup of genetic epilepsies. They are individually rare but collectively account for an important fraction of epilepsies [30]. EEs are early-onset and severe forms of epilepsies where epileptic brain activity contribute to cognitive and behavioural defects [17].

Genetic epilepsies can be further divided into epilepsy syndromes with distinctive electroclinical features and these can be arranged based on their onset (neonatal, infancy, childhood, adolescence-adult) and characteristics findings in electroencephalogram (EEG) [17].

As mentioned earlier and illustrated in Figure 4, genetic factors underlie majority of epilepsies. The role of genetic factors in epilepsies has been formally demonstrated in family-based studies showing that relatives of affected individuals are in higher risk to have epilepsy and in twin studies showing that monozygotic twins have higher concordance of epilepsy compared to dizygotic twins [17].

Classification of genetic epilepsies

Mendelian or simple epilepsies: Mendelian epilepsies causes a single gene to be missing or changed in which a single major locus accounts for segregation of the disease trait in a family and each is associated with a different age that the seizures start, the types of seizures, and other associated features [47,48]. According to Robinson and Gardiner [39], there few numbers of “idiopathic” mendelian epilepsies, such as benign familial neonatal convulsions and benign familial infantile convulsions, autosomal dominant nocturnal frontal lobe epilepsy, and generalised epilepsy with febrile seizures plus. Epilepsies with mendelian epilepsies are rare but the risk to relatives are quite high.

Non-mendelian or “complex” epilepsies: This mutation occurs in a number of genes often coupled with environmental influence such as juvenile myoclonic epilepsy, where the pattern of familial clustering is accounted for by the interaction between several susceptibility loci and environmental factors. Example include entities such as childhood absence epilepsy and juvenile myoclonic epilepsy. This is futher divided into Mitochondrial disorders which result from mutations in DNA found outside the cell nucleus and – Epigenetic disorders; this disorders are related to changes in activity of genes in relation to the environment [48]. Common examples of complex epilepsies include juvenile myoclonic epilepsy [47]. Inheritance in most epilepsies are usually non mendelian hence, risks to relatives are considerably lower.

Chromosomal disorders: Chromosomal disorder causes the presence of a gross cytogenetic abnormality [47].

The family and beyond

If genetic factors are so important, why do most patients with epilepsy seem to lack an obvious family history of the disorder? At least two major scientific reasons account for this apparent paradox according to Thomas and Berkovic [49]. First, in complex disorders the proportion of affected relatives is much lower than is observed in Mendelian disorders. For example, in fully penetrant, autosomal dominant disorders (Figure 7), 50% of first-degree relatives are affected; whereas in complex disorders, typically less than 5–10% of first-degree relatives have the disease phenotype. Second, for epilep¬sies caused by de novo mutations, which are increasingly recognized to be important, no family history of epilepsy can be present by definition. However, a number of additional barriers can prevent us from fully appreciat¬ing the importance of genetic factors in people with epi¬lepsy [49]. These obstacles, for the most part, are created by failing to adequately ascertain the family history and by not appreciating the complexity of epilepsy genetics [38,49]. Obviously, inadequate inquiry into the wider family history will result in incomplete understanding; however, several potential pitfalls can be avoided. Failure to routinely ask about seizures in all family members of patients with epilepsy is often driven by underappreciation of the role of genetic factors in certain epilepsies, such as adult-onset focal epilepsy.

neurology-neurophysiology-epilepsy-transmission

Figure 7: Pedigree showing patterns of epilepsy transmission [49].

Epilepsy, because of its intermittent nature and psychosocial consequences, is often covert. Seizures in the patient’s older relatives might not be disclosed, at least in part because of excessive social stigma [3]. This situation can be circumvented by asking about the family history at repeated intervals, and specifically asking the individual to speak to aunts and grandparents. Inheritance patterns are easiest to establish in excep¬tionally large pedigrees [46,49]. However, over-reliance on these rare examples, despite their being a valuable and neces¬sary research tool, can discourage us from recognizing the existence of a familial history in a more modestly sized family (Table 1) [24,48,49].

Epilepsy syndrome Inheritance Gene location Gene
Mendelian inheritance
Benign familial neonatal convulsions AD 20q (EBN1) KCNQ
8q24 (EBN2) KCNQ
Benign familial infantile convulsions AD 19q Unknown
Autosomal dominant nocturnal frontal lobe epilepsy AD 20q12.2 CHRNA
Generalised epilepsy with febrile seizures plus AD1 9q13 SCN1B
2 Unknown
Non-mendelian inheritance
Juvenile myoclinic epilepsy Complex 15q14 CHRNA
6p (EJMI) Unknown
Childhood absence epilepsy (and/or EEG trait) Complex 8q24 Unknown
Juvenile absence epilepsy Complex 21q22.1 GRIK1
Benign epilepsy with centrotemporal spikes Complex 15q14 Unknown

Table 1: Major genes implicated in genetic epilepsies [48].

Genes involved in epilepsy

As of date, 76 epilepsy genes in total has been identified and are all associated with different age groups (some identified with more than one age group) {49 genes identified among infants (0-12 months), 31 genes identified among childhood (13 months-12yrs), 13 genes identified with adolescents (13yrs-28yrs) and 9 genes identified among adults (over 18yrs)}, the types of seizures, and other associated features [50].

Six ion channels were identified with all the genes associated with the genes involved in epilepsy, this include; Sodium ion channel, Potassium ion channel, Chloride ion channel, Calcium ion channel, Acetylcholine receptor ion channel, GABA receptor ion channel [34]. The 76 genes that are identified with epilepsy are in one of the group of the above six mentioned ion channels, according to the ILAE [50], the various genes include;

Childhood genes: ASAH1, CHD2, CHRNA2, CHRNA4, CHRNB2, CNTNAP2, CPA6, CSTB, DEPDC5, EPM2A

GABRA1, GABRB3, GABRG2, GOSR2, GRIN1, GRIN2A, KCNC1, KCNMA1, KCNT1 KCTD7, LGI1, NHLRC1, PCDH19, PRICKLE1, PRICKLE2, SCN1A, SCN1B, SCN9A, SLC6A1, SRPX2, STX1B, SYN1, SYNGAP1

Infantile genes: ALHD7A1, ALG13, ARHGEF9, ARX CDKL5 CLN8 DNM1 EEF1A2 DEPDC5, KCNMA1 KCNQ2 KCNB1 KCNA2 IER3IP1 HCN1 GRIN2B GNA01 GABRG2 GABRA1 KCNQ3, KCNT1 KCTD7 MEF2C PCDH19 PLCB1 PNKP PNPO PRRT2, RELN SCN1A SCN1B SCN2A SCN8A SCN9A SIAT9, SIK1 SLC25A22 SLC2A1 SLC35A2 SNIP1 SPTAN1 ST3GAL3 STRADA, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, WWOX

Adult genes: LGI1, SCARB2, SCN1A, SCN1B, SCN9A, SYN1, CPA6, DEPDC5, GABRG2

Ion Channel Gene Inheritance Chromosome
Sodium SCN1B Single-gene 19q19.1
SCN1A Single-gene 2q24.3
SCN2A Single-gene 2q24.3
Potassium KCNQ2 Single-gene 20q13.3
KCNQ3 Single-gene 8q24
KCND2 Not known 9q34.3
Chloride CLCN2 Single-gene 3q27.1
Calcium CACNA1A Single-gene 19p13
CACNA1H Complex 19p13
CACNB4 Complex 2q22-q23
Acetlcholine receptor CHRNA4 Single-gene 20q13.2-q13.3
CHRNA2 Single-gene 8p21
CHRNB2 Single-gene 1q21.3
GABA receptor GABRG2 Single-gene 5q34
GABRA1 Single-gene 5q34

Table 2: Common genes associated with the major ion channel.

Adolescent genes: DEPDC5, EPM2A, GABRA1, GABRG2, KCNT1, LGI1, NHLRC1, PRICKLE2, SCARB2

SCN1A, SCN1B, SCN9A, SYN1

Childhood genes: ASAH1, CHD2, CHRNA2, CHRNA4, CHRNB2, CNTNAP2, CPA6, CSTB, DEPDC5, EPM2A

GABRA1, GABRB3, GABRG2, GOSR2, GRIN1, GRIN2A, KCNC1, KCNMA1, KCNT1

KCTD7, LGI1, NHLRC1, PCDH19, PRICKLE1, PRICKLE2, SCN1A, SCN1B, SCN9A,, SLC6A1, SRPX2, STX1B, SYN1, SYNGAP1

Infantile genes: ALHD7A1, ALG13, ARHGEF9, ARX, CDKL5, CLN8, DNM1, EEF1A2, DEPDC5, KCNMA1 KCNQ2, KCNB1, KCNA2, IER3IP1, HCN1, GRIN2B, GNA01, GABRG2, GABRA1, KCNQ3, KCNT1, KCTD7, MEF2C, PCDH19, PLCB1 PNKP PNPO PRRT2, RELN SCN1A SCN1B SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC25A22, SLC2A1, SLC35A2, SNIP1, SPTAN1, ST3GAL3, STRADA, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, WWOX.

Adult genes: LGI1, SCARB2, SCN1A, SCN1B, SCN9A, SYN1, CPA6, DEPDC5, GABRG2

Adolescent genes: DEPDC5, EPM2A, GABRA1, GABRG2, KCNT1, LGI1, NHLRC1, PRICKLE2, SCARB2 SCN1A, SCN1B, SCN9A, SYN1

The different modes of inheritance can be found in the genes of epilepsy listed above, which includes Autosomal, x-chromosomal, mitochondrial and complex inheritance. According to Thomas and Berkovic [49], family studies show that the age of onset, as well as the severity of the phenotype and the penetrance of these mutations is often less than 100%, and it varies within families.

Conclusion

Genetics is transforming clinical practice in epilepsy especially in children. The effect of the thorough understanding of the genetics of epilepsy that underpin both common and rare epilepsy have started to cascade into the clinical domain. Useful and beneficial information is hence being provided to individuals and the public, this benefit has led to breakthrough in the correct management, treatment, diagnosis, control and solutions to frequently asked questions on epilepsy such as I am pregnant with a male baby and am epileptic, will my baby be epileptic?

Recommendation

1. There is need for participation in genetic research on epilepsy as it is critical and essential for bridging the knowledge gap in epilepsy.

2. There is need for effective enlightenment and genetic screening and counselling centres for epileptic patients and their respective family members and even the public in general.

References

Citation: Bamikole OJ, Olufeagba MDB, Soge ST, Bukoye NO, Olajide T, et al. (2019) Genetics of Epilepsy. J Neurol Neurophysiol 10:488.

Copyright: © 2019 Bamikole OJ, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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