Genetics of epilepsy

Genetics of epilepsy

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Is epilepsy genetically inheritable? If yes, is it dominant?


The causes of epilepsy are legion. There's a massive Wikipedia page listing various causes, and, wow, I get tired just reading the table of contents. None of those are genetic causes, but it should perhaps therefore be not surprising to learn that the genetic causes of epilepsy, although the minority of cases, are also quite varied. Apparently most of the causative genes involve ion channels (whether voltage- or ligand-gated), but there are a truly large number of genes that can be related to epilepsy.

This 2011 paper has quite a lot of information. Some facts it presents on the genetics of epilepsy:

  • Something like 1-2% of all mutations in mice present with epilepsy symptoms.
  • Concordance is around 50-60% for monozygotic twins, and 15% for dizygotic
    • The majority of twin concordance is likely from the same (genetic) cause
  • Monogenic causes (versus complex causes of epilepsy) account for around 1-2% of human cases.

In direct answer to your question, there is this paragraph (emphasis added) explaining the rough breakdwn:

Monogenic inheritance is suggested by the familial aggregation of cases that share a similar phenotype and are distributed in the pedigree according to a Mendelian mode of transmission: autosomal or sex-linked, dominant, or recessive. Autosomal recessive epilepsies are often associated with structural or metabolic abnormalities of the brain and with neurologic comorbidities, so most of them are not in the category of idiopathic epilepsies. Examples of these are pyridoxine-dependent epilepsy (PDE), several progressive myoclonic epilepsies (PMEs), and some malformations of cortical development (MCDs). Most of the monogenic idiopathic epilepsies follow the pattern of autosomal dominant inheritance, implying the presence of multiple cases in successive generations and male-to-male transmission.

In short:

  • If it's genetic, it's likely to be complicated and controlled by many genes
  • If it's controlled by one gene, it's likely to be dominant

The paper also presents the following table which may be of interest, listing monogenic causes of epilepsy:

Genetics of epilepsy - Biology

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Genetic Cause of Severe Epilepsy Identified

Severe infantile onset epilepsy is a highly debilitating and generally fatal brain hyperexcitability disorder with limited responsiveness to known anti-epileptic drugs. Mitch Goldfarb’s lab at Hunter College, collaborating with Gunnar Buyse and Peter de Witte’s his research teams at the University of Leuven in Belgium, has characterized a single genetic mutation responsible for this disorder in two children. The mutation, in a gene called FHF1, affects the interaction of FHF1 protein with nerve cell sodium channels in a manner that enhances channel activity to drive greater excitability of nerve cells. The discovery of a protein-protein binding site underlying severe epilepsy offers a potential target for future drug design and treatment. These studies are featured in the 2016 June 7th issue of the journal Neurology.

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Potential genetic link between epilepsy, neurodegenerative disorders

A recent scientific discovery showed that mutations in prickle genes cause epilepsy, which in humans is a brain disorder characterized by repeated seizures over time. However, the mechanism responsible for generating prickle-associated seizures was unknown.

A new University of Iowa study, published online July 14 in the Proceedings of the National Academy of Sciences, reveals a novel pathway in the pathophysiology of epilepsy. UI researchers have identified the basic cellular mechanism that goes awry in prickle mutant flies, leading to the epilepsy-like seizures.

"This is to our knowledge the first direct genetic evidence demonstrating that mutations in the fly version of a known human epilepsy gene produce seizures through altered vesicle transport," says John Manak, senior author and associate professor of biology in the College of Liberal Arts and Sciences and pediatrics in the Carver College of Medicine.

Seizure suppression in flies

A neuron has an axon (nerve fiber) that projects from the cell body to different neurons, muscles, and glands. Information is transmitted along the axon to help a neuron function properly.

Manak and his fellow researchers show that seizure-prone prickle mutant flies have behavioral defects (such as uncoordinated gait) and electrophysiological defects (problems in the electrical properties of biological cells) similar to other fly mutants used to study seizures. The researchers also show that altering the balance of two forms of the prickle gene disrupts neural information flow and causes epilepsy.

Further, they demonstrate that reducing either of two motor proteins responsible for directional movement of vesicles (small organelles within a cell that contain biologically important molecules) along tracks of structural proteins in axons can suppress the seizures.

"The reduction of either of two motor proteins, called Kinesins, fully suppressed the seizures in the prickle mutant flies," says Manak, faculty member in the Interdisciplinary Graduate Programs in Genetics, Molecular and Cellular Biology, and Health Informatics. "We were able to use two independent assays to show that we could suppress the seizures, effectively 'curing' the flies of their epileptic behaviors."

Genetic link between epilepsy and Alzheimer's

This new epilepsy pathway was previously shown to be involved in neurodegenerative diseases, including Alzheimer's and Parkinson's.

Manak and his colleagues note that two Alzheimer's-associated proteins, amyloid precursor protein and presenilin, are components of the same vesicle, and mutations in the genes encoding these proteins in flies affect vesicle transport in ways that are strikingly similar to how transport is impacted in prickle mutants.

"We are particularly excited because we may have stumbled upon one of the key genetic links between epilepsy and Alzheimer's, since both disorders are converging on the same pathway," Manak says. "This is not such a crazy idea. In fact, Dr. Jeff Noebels, a leading epilepsy researcher, has presented compelling evidence suggesting a link between these disorders. Indeed, patients with inherited forms of Alzheimer's disease also present with epilepsy, and this has been documented in a number of published studies."

Manak adds, "If this connection is real, then drugs that have been developed to treat neurodegenerative disorders could potentially be screened for anti-seizure properties, and vice versa."

Manak's future research will involve treating seizure-prone flies with such drugs to see if he can suppress their seizures.


Epilepsy, especially drug-refractory epilepsy, with ASD is a chronic neurologic disorder but also places a substantial burden on children, families and society (1). Previous research reported that the comorbidity rate varied widely, even in large samples including population-based studies, ranging from 2.4 to 63% (2, 3). In different epilepsy syndromes, such as in tuberous sclerosis complex (TSC), the incidence of ASD is 17�% (4). In Dravet syndrome (DS), the incidence of ASD is 24�% (5, 6), and in infantile spasms, it is 35% (7). Most published studies have primarily focused on clinical characteristics and outcomes of epilepsy with ASD (8). However, to date, there is still no comprehensive general description of both clinical features and the genetic etiology of these disorders.

In clinical work, we found large heterogeneity in behaviors and outcomes in epilepsy with ASD children, and the reasons are still unclear. In recent years, with whole exome sequencing (WES), neural panel data sequencing, copy number variant (CNV) analysis, and other molecular technologies, increasing numbers of epilepsy with ASD-related diseases have been recognized at the molecular level, such as Angelman syndrome, TSC, Fragile X syndrome, and Rett syndrome. To date, a small number of gene mutations, such as in SCN1A and TSC2, are known to cause epilepsy and ASD phenotypes simultaneously. Recently, several reviews described epilepsy with ASD genes from the perspectives of bioinformatics and genetics (9�). However, approximately 50% or more of the causes remain unknown. We therefore sought to expand the candidate genes for epilepsy with ASD and determine whether genetically pathogenic patients are more prone to drug-refractory epilepsy, severe ASD, and intellectual disability than non-pathogenic patients. Thus, in the current study, we conducted genetic testing on children with co-occurring epilepsy and ASD to identify causative genetic variants to determine a possible link between genotypes and phenotypes.

Learning the facts and understanding the risks of passing it along to your children can help.

If you have epilepsy, you may be afraid that your children will have epilepsy, too. However, it’s important to know the facts. The risk of passing epilepsy on to your children is usually low. Epilepsy shouldn’t be a reason not to have children. Medical testing may help people who have a known genetic form of epilepsy understand their risks.

If a child does develop epilepsy, remember that many children can get complete control of seizures. For some, the epilepsy may go away.

Most importantly, having seizures and epilepsy doesn’t mean you or your child are any different or less important than anyone else!

Pediatric Central Nervous System Vascular Malformations

Cavernous Malformations


A cavernous malformation is a discrete, well-circumscribed lesion with a reddish purple, multilobulated appearance similar to a cluster of mulberries. Microscopically, a cavernous malformation comprises sinusoidal spaces lined by a single layer of endothelium and separated by a collagenous stroma devoid of elastin, smooth muscle, or mature vascular wall elements. A characteristic marker is the lack of intervening neural parenchyma ( Fig. 16-7 ). 2 Venous malformations are commonly found in association with cavernous malformations. 50, 51

Cavernous malformations are found throughout the CNS, but are most common in the supratentorial compartment. They are frequently multiple and range in size from less than 0.1 to 9 cm. 52 The prevalence of cavernous malformations in the general population has been estimated to be 0.4% to 0.9%. 52 They are found equally in males and females. 52 Cavernous malformations are found sporadically and are inherited in an autosomal dominant fashion. 53


In young children, the most common presentation of a cavernous malformation is hemorrhage and acute neurologic deficit. 54, 55 Clinically significant intraparenchymal hemorrhage is heralded by an acute onset of headache, focal neurologic deficit based on the location of the lesion, and change in the level of consciousness. Subarachnoid hemorrhage is rare except when the cavernous malformation is located in the optic nerve, chiasm, or ventricle. Hemorrhage from a cavernous malformation is rarely life-threatening.

In older children and adults, the most common presentation of a cavernous malformation is epilepsy. The pathophysiology of epilepsy in cavernous malformations is postulated to be caused by irritation and compression from mass effect and multiple local hemorrhages with the exposure of the surrounding brain to blood breakdown products and subsequent local gliomatous reaction.

Acute or progressive focal neurologic deficit is another presentation of a cavernous malformation. Intralesional or perilesional hemorrhage is usually the culprit and can be documented with MRI. The neurologic deficit depends on the lesion location and size. The deficit may be fixed, transient, or recurrent.

Familial Occurrence

A familial form of cavernous malformations was first described in Mexican-Americans, but now has been documented in other nationalities as well. 53, 56 In 54% of patients with cavernous malformations, the trait is inherited in an autosomal dominant fashion. 53 Three genetic loci have been identified that predispose a patient to cavernous malformations. The CCM1 locus resides on chromosome 7q21-q22. The CCM1 locus has been identified as the KRIT1 gene. Many mutations in the KRIT1 gene have been identified. 57–59 The KRIT1 gene product interacts with RAP1A, which is a renin-angiotensin system guanosine triphosphatase hypothesized to function as a tumor suppressor gene. 59 The locus for CCM2 resides on chromosome 7p13-p15, and CCM3 resides on chromosome 3q25.2-q27. 60 The genes encoded by CCM2 and CCM3 have yet to be identified. It has been postulated that CCM1, CCM2, and CCM3 account for 40%, 20%, and 40% of the familial cases of cavernous malformations. 58

In a study of the natural history of familial cavernous malformations, it was noted that those patients were more likely to have multiple lesions, and it was common for new cavernous malformations to develop on MRI with follow-up. 61, 62 The calculated symptomatic spontaneous hemorrhage rate for familial cavernous malformations is 1.1% per lesion per year, which is higher than the hemorrhage rate seen with spontaneous cavernous malformations. 61


The CT appearance of cavernous malformations is a well-circumscribed, nodular lesion of uniform or variegated mixed density reflecting the calcification, hemorrhage, and cystic components of the lesion. Cavernous malformations may enhance faintly with contrast administration. Frequently, recent hemorrhage is seen as a homogeneous hyperdensity and obscures the lesion.

The MRI appearance of cavernous malformations is the most sensitive diagnostic test for cavernous malformations, and it is characteristic. 63 A cavernous malformation appears as a well-defined, lobulated lesion with a central core of reticulated mixed signal surrounded by a rim of signal hypointensity. The typical low T2 signal surrounding cavernous malformations is due to the ferritin from erythrocyte breakdown that is a consequence of intralesional and perilesional hemorrhages. The reticulated low T2 signal within the cavernous malformation reflects intralesional calcification. Areas of signal hyperintensity within the lesion represent acute and subacute hemorrhage in various stages of thrombus organization and resolution ( Fig. 16-8 ).

Natural History

The natural history of the cavernous malformation is still being elucidated. Cavernous malformations are dynamic lesions that have been shown to change in size and signal characteristics on neuroimaging studies. The appearance of new cavernous malformations has been documented in patients with existing lesions and patients with no history of cavernous malformations. 64 Cases of cavernous malformations forming de novo after radiation therapy for tumors have been reported in the literature. 65 The annual clinically significant hemorrhage risk has been estimated to be 0.6% to 1.1% per lesion per year, with the highest rates occurring with familial cavernous malformations. 61, 66 Cavernous malformations that bleed are at increased risk of hemorrhage in the future, and there is an association between female hormones and hemorrhage. 67


The goals of therapy are to control epilepsy, prevent or evacuate hemorrhage, and treat focal neurologic deficit. The treatment of epilepsy is typically medical. A patient with medically intractable epilepsy may benefit, however, from surgical extirpation of the cavernous malformation. 68 Before this procedure is undertaken, the patient must be thoroughly evaluated to identify the epileptogenic focus. During surgery, the grossly abnormal adjacent brain should be resected as well to ensure removal of the seizure focus. 68

Surgery also may be undertaken to extirpate the lesions that have shown repeated hemorrhage and focal neurologic problems. 52, 55, 69 This extirpation is particularly important with brainstem cavernous malformations because the brainstem does not tolerate mass effect from recurrent hemorrhage. 70–72 The resection of brainstem cavernous malformations should not be undertaken until the malformation presents to the surface to avoid injury to eloquent areas. 71, 72

Radiosurgery for cavernous malformations is a topic that is still under debate. Conflicting results are reported in the literature regarding its effectiveness. 73–77 The success of radiosurgery is difficult to ascertain because cavernous malformations are not visualized on angiogram, and the lesions frequently regress in size on MRI. Radiosurgery of cavernous malformations has shown higher complication rates of edema and radiation necrosis than for AVMs. 77 It has been postulated that the blood breakdown products present in cavernous malformations act as a radiopotentiator.

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Sacred disease secrets revealed : The genetics of human epilepsy. / Turnbull, Julie Lohi, Hannes Kearney, Jennifer A. Rouleau, Guy A. Delgado-Escueta, Antonio V. Meisler, Miriam H. Cossette, Patrick Minassian, Berge A.

In: Human molecular genetics , Vol. 14, No. 17, 01.09.2005, p. 2491-2500.

Research output : Contribution to journal › Review article › peer-review

T1 - Sacred disease secrets revealed

T2 - The genetics of human epilepsy

AU - Delgado-Escueta, Antonio V.

N2 - Neurons throughout the brain suddenly discharging synchronously and recurrently cause primarily generalized seizures. Discharges localized awhile in one part of the brain cause focal-onset seizures. A genetically determined generalized hyperexcitability had been predicted in primarily generalized seizures, but surprisingly the first epilepsy gene discovered, CHRNA4, was in a focal (frontal lobe)-onset syndrome. Another surprise with CHRNA4 was its encoding of an ion channel present throughout the brain. The reason why CHRNA4 causes focal-onset seizures is unknown. Recently, the second focal (temporal lobe)-onset epilepsy gene, LGI1 (unknown function), was discovered. CHRNA4 led the way to mutation identifications in 15 ion channel genes, most causing primarily generalized epilepsies. Potassium channel mutations cause benign familial neonatal convulsions. Sodium channel mutations cause generalized epilepsy with febrile seizures plus or, if more severe, severe myoclonic epilepsy of infancy. Chloride and calcium channel mutations are found in rare families with the common syndromes childhood absence epilepsy and juvenile myoclonic epilepsy (JME). Mutations in the EFHC1 gene (unknown function) occur in other rare JME families, and yet in other families, associations are present between JME (or other generalized epilepsies) and single nucleotide polymorphisms in the BRD2 gene (unknown function) and the malic enzyme 2 (ME2) gene. Hippocrates predicted the genetic nature of the 'sacred' disease. Genes underlying the 'malevolent' forces seizing 1% of humans have now been revealed. These, however, still account for a mere fraction of the genetic contribution to epilepsy. Exciting years are ahead, in which the genetics of this extremely common, and debilitating, neurological disorder will be solved.

AB - Neurons throughout the brain suddenly discharging synchronously and recurrently cause primarily generalized seizures. Discharges localized awhile in one part of the brain cause focal-onset seizures. A genetically determined generalized hyperexcitability had been predicted in primarily generalized seizures, but surprisingly the first epilepsy gene discovered, CHRNA4, was in a focal (frontal lobe)-onset syndrome. Another surprise with CHRNA4 was its encoding of an ion channel present throughout the brain. The reason why CHRNA4 causes focal-onset seizures is unknown. Recently, the second focal (temporal lobe)-onset epilepsy gene, LGI1 (unknown function), was discovered. CHRNA4 led the way to mutation identifications in 15 ion channel genes, most causing primarily generalized epilepsies. Potassium channel mutations cause benign familial neonatal convulsions. Sodium channel mutations cause generalized epilepsy with febrile seizures plus or, if more severe, severe myoclonic epilepsy of infancy. Chloride and calcium channel mutations are found in rare families with the common syndromes childhood absence epilepsy and juvenile myoclonic epilepsy (JME). Mutations in the EFHC1 gene (unknown function) occur in other rare JME families, and yet in other families, associations are present between JME (or other generalized epilepsies) and single nucleotide polymorphisms in the BRD2 gene (unknown function) and the malic enzyme 2 (ME2) gene. Hippocrates predicted the genetic nature of the 'sacred' disease. Genes underlying the 'malevolent' forces seizing 1% of humans have now been revealed. These, however, still account for a mere fraction of the genetic contribution to epilepsy. Exciting years are ahead, in which the genetics of this extremely common, and debilitating, neurological disorder will be solved.

Genetics of epilepsy - Biology

Molecular genetics of epilepsy: A clinician's perspective

Vikas Dhiman
Department of Neurology, Ivy Hospital, Panchkula, Haryana, India

Date of Web Publication8-May-2017

Correspondence Address:
Vikas Dhiman
House No. 54/2, Subhash Nagar, Manimajra, Chandigarh - 160 101

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aian.AIAN_447_16

Epilepsy is a common neurological problem, and there is a genetic basis in almost 50% of people with epilepsy. The diagnosis of genetic epilepsies makes the patient assured of the reasons of his/her seizures and avoids unnecessary, expensive, and invasive investigations. Last decade has shown tremendous growth in gene sequencing technologies, which have made genetic tests available at the bedside. Whole exome sequencing is now being routinely used in the clinical setting for making a genetic diagnosis. Genetic testing not only makes the diagnosis but also has an effect on the management of the patients, for example, the role of sodium channels blockers in SCN1A+ Dravet syndrome patients and usefulness of ketogenic diet therapy in SLC2A1+ generalized epilepsy patients. Many clinicians in our country have no or limited knowledge about the molecular genetics of epilepsies, types of genetic tests available, how to access them and how to interpret the results. The purpose of this review is to give an overview in this direction and encourage the clinicians to start considering genetic testing as an important investigation along with electroencephalogram and magnetic resonance imaging for better understanding and management of epilepsy in their patients.

Keywords: Clinical, epilepsy, genetics, molecular

How to cite this article:
Dhiman V. Molecular genetics of epilepsy: A clinician's perspective. Ann Indian Acad Neurol 201720:96-102

How to cite this URL:
Dhiman V. Molecular genetics of epilepsy: A clinician's perspective. Ann Indian Acad Neurol [serial online] 2017 [cited 2021 Jun 23]20:96-102. Available from:

Epilepsy is the most common serious neurological disorder, affecting around 65 million people in the world. [1] In more than 50% of people with epilepsy (PWE), the cause of seizures is not known. [2] These types of epilepsies were designated as “idiopathic” in the 1989 seizure classification. [3] With rapid advancements in the molecular genetic techniques, our understanding about idiopathic epilepsies has improved exponentially. More than half of all epilepsies are now known to have a genetic basis. This led the International League Against Epilepsy (ILAE) to replace the term idiopathic epilepsies with “genetic generalized epilepsies.” [4] Epilepsies due to structural lesions, such as focal cortical dysplasia, hippocampal sclerosis, and encephalopathies, were once thought to be solely due to structural pathology, but recently, more and more evidence supporting the genetic basis of these epilepsies is readily available in the literature. [1],[5] These rapid developments in the molecular genetics of epilepsy have changed the way we think about the causes of epilepsies, and it is bound to have an impact on the diagnosis and management of PWE. Whole exome sequencing (WES) is proving to be a highly effective method in identifying a causative gene in the clinical setting. [6] In the present times, everyone involved in the management of epilepsy patients, especially the clinician should have some grounding information about epilepsy genetics.

The main objectives of this review are to provide (a) clinically relevant aspects of molecular genetics of commonly encountered genetic epilepsies (b) the clinical implications of this knowledge in pharmacogenetics, clinical genetic testing, and the management of PWE and (c) the future prospects and challenges in the field.

The genetic epilepsies seen during the 1 st year of life are benign familial neonatal seizures (BFNS) (KCNQ2 and KCNQ3), benign familial neonatal-infantile seizures (SCN2A), and benign familial infantile seizures. [10] These are autosomal dominant epilepsy syndromes characterized by onset of seizures before first birthday and have a strong positive family history. [10],[11] Other epilepsies with more complex pattern of inheritance in this age group include Ohtahara syndrome (STXBPI and ARX), West syndrome, and Dravet syndrome (SCN1A). [6],[12] Febrile seizures affect 3% of children between age group of 6 months and 6 years. [13] Genetic epilepsy with febrile seizure plus (SCN1A, SCN1B, and GABRG2) and Dravet syndrome (SCN1A) form an important differential diagnosis, especially in a child with febrile seizures and developmental delay. [6],[12]

In childhood, classic generalized epilepsies, for example, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalized tonic–clonic seizures, which form about 20% of all epilepsies, are more common. [14] Although the genetic basis of most of these epilepsies remains elusive, early onset absence epilepsy (SLC2A1) and JME (GABRA1 and EFHC1) have a stronger genetic basis. [14] Partial epilepsies have long been associated with focal structural lesions. The genetic linkage analysis in multiplex families with partial epilepsies has identified various causative genes, for example, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) (CHRNA4, CHRNB2, and CHRNA2), [15] autosomal dominant epilepsy with auditory features (LGI1), [16] familial temporal lobe epilepsies (FTLE), and familial focal epilepsy with variable foci (FFEVF) (DEPDC5). [17] Progressive epileptic syndromes such as progressive myoclonus epilepsies (Unverricht–Lundborg disease, CSTB and Lafora body disease, EPM1 and EPM2) are also now known to have a strong genetic basis. [18] In the past few decades, genetics have also been implicated in various nonsyndromic epilepsies like those caused by structural and/or metabolic reasons, for example, malformations of cortical development (lissencephaly, PAFAH1B1, and DCX), neurocutaneous syndromes (tuberous sclerosis, TSC1 and TSC2), tumors, infections, brain trauma, and perinatal insults. [19],[20]

Clinically speaking, there are multiple indicators of genetic epilepsies. [21] On the one hand, genetic epilepsy should be suspected in a patient with early awakening seizures, normal neurological and imaging findings, 3 Hz spike and wave discharges on electroencephalogram, and a positive family history of seizures and when no underlying cause of seizures is demonstrable. [22] Various previously designated “idiopathic” generalized epilepsies such as JME, JAE, CAE, and epilepsy with generalized tonic–clonic seizures only, fall in this category. On the other hand, a genetic cause is strongly suspected in a patient with seizures with early age of onset (infantile or childhood), seizures associated with congenital anomaly, developmental delay, or autism spectrum disorder with or without positive family history of seizures. [21] Examples in this category included various epileptic encephalopathies (e.g., Ohtahara syndrome, West syndrome, and Dravet syndrome), cortical dysplasias, and neurocutaneous syndromes (e.g., tuberous sclerosis). There are separate sets of genetic tests available for these two groups (see genetic testing and implications).

The purpose of this section is to give a clinically relevant conceptual understanding of the underlying molecular basis of seizure occurrence rather enlisting every gene that has so far been linked to epilepsy. Every protein in our body is synthesized from their genes through the process of transcription (formation of messenger RNA, mRNA) and translation (synthesis of protein from mRNA). Factors which do not necessarily change the structure of the gene but do affect the process of transcription and translation are known as epigenetic factors. [23] Any perturbation in the transcription, translation, or epigenetic mechanisms can produce defective proteins leading to diseases. Seizures occur as a result of a complex interplay of altered gene expressions, increased neuronal excitability and disturbed intrinsic neuronal properties. [5],[24] Defects in epilepsy genes give a critical insight into the pathomechanisms of seizure generation and propagation, which has an impact on the management of the patients [25] as illustrated below.

Voltage-gated sodium channels are an important group of ions channels, which play an important role in generating action potential and depolarization of the neurons. Dravet syndrome, previously known as severe myoclonic epilepsy of infancy, is caused by mutations in the alpha 1 subunit of the voltage-gated sodium channel gene, SCN1A. [6] It is characterized by the onset of febrile seizures before 7 months of age, prolonged seizure episodes (ᡂ min), and developmental delay during 2 nd year of life. [6] About 70%󈞼% of patients with Dravet syndrome have mutations in SCN1A gene. This mutation in SCN1A gene causes defective gating in the sodium channel and thus causes hyperexcitability and seizures. [13] Different mutations (genotypes) produce different phenotypes (see below). SCN1A-positive Dravet syndrome patients have an important implication in the pharmacological management – all antiepileptic drugs (AEDs) with a dominant action on sodium channels (phenytoin, carbamazepine, oxcarbazepine, lamotrigine, and vigabatrin) can interfere with gating mechanism of the mutated channels and increase the frequency of seizures, especially myoclonic seizures in patients with Dravet syndrome, thus these AEDs can exacerbate seizures and thus should be avoided. [12]

Patients with early onset absence epilepsy, paroxysmal exertional dyskinesia, and encephalopathies are found to have mutations in SLC2A1 gene, which leads to GLUT1 deficiency. [26] GLUT1 protein transports glucose in the neurons from blood and surrounding cells. Mutations in SLC2A1 gene reduce or eliminate the function of the GLUT1 protein. It has been observed that patients with GLUT1 deficiency (SLC2A1 mutations) show a remarkable reduction in seizure frequency following ketogenic diet therapy. [27] Although the underlying mechanisms of how ketogenic diet ameliorates seizures are not known, knowing that less functional GLUT1 protein reduces the amount of glucose available to brain cells, ketogenic diet has a role to play in seizure termination in these patients. These findings have relegitimized ketogenic diet therapy in epilepsy patients. Hence, all patients with GLUT1 deficiency should be considered for early trials of ketogenic therapy. [27],[28]

Genotype–phenotype correlations always pose a problem for complex disorders such as epilepsy, diabetes, hypercholesterolemia, and hypertension. [2],[7] Due to complex genotype–phenotype correlations, classification and categorization of diseases become difficult. Epilepsy genes have been shown to carry all types of mutations, from missense to frameshift mutations to chromosomal aberrations and copy number variations, which account for phenotypic heterogeneity seen in epilepsy. [29] There are multiple tests available in the market, which can identify each of these mutations (see genetic testing and implication). It is general dictum is that the larger the mutation, the more severe is the phenotype, [12] but this does not hold true always. One of the important reasons for poor genotype–phenotype correlation in epilepsies is that most of the epilepsies have a complex pattern of inheritance with involvement of two or more genes and variable environmental effects even same type of mutation in two individuals can express disease with variable severity. [30] For example, the mutation of KCNQ2 can cause a benign BFNS in some neonates and severe epileptic encephalopathies in others. [31]

However, the entire scenario is not that gloomy too. It has been observed that many well-defined mutations cause a specific phenotype, for example, patients with truncating mutations in SCN1A gene lead to earlier onset of seizures in patients with Dravet syndrome than those with missense mutations. [30],[32] Furthermore, it has been noted that micro-chromosomal rearrangements involving SCN1A gene and contiguous genes are potentially associated with additional dysmorphic features in the affected patients. [32] It is interesting to note that in a patient in whom all sodium channels genes along with 49 contiguous genes were deleted, did not show any phenotype distinct from typical Dravet syndrome. [30] There are few important points, which a clinician should know when attempting a genotype–phenotype correlation in a case of epilepsy:

  1. The clinical profile (demography, clinical signs and symptoms, and investigation's results) should be clearly understood
  2. The genetic diagnosis, genetic technique employed, and its limitations should be understandable to the clinician
  3. A detailed family (at least three generation) should be drawn in case of positive family history
  4. The clinician should try to rule out any possible environmental effect, variable penetrance, and mosaicism
  5. Be open-minded and discuss with clinical geneticist, if required.

Pharmacogenetics deals with studying genetic variations among individuals, which affect the response to medications. With rapid advancements in the genomics and pharmacology, it is now possible to predict the differences in treatment outcomes in patients with apparently same disease and treatment by studying the genetic sequence variations between patients. These genetic sequence variations or polymorphisms have a profound effect on drug absorption, transport, metabolism, clearance, and site of action. [33] Furthermore, individuals with specific polymorphism are susceptible to adverse drug reactions. Pharmacogenetics has the potential to identify these susceptible individuals before treatment and selectively allow patients with low risk of adverse drug reactions for pharmacological management. [33]

In epilepsy, pharmacogenetics plays a very important role, especially in pharmacoresistance to seizures, unpredictability of AEDs response, and idiosyncratic drug reactions. [34],[35] Numerous genetic association studies have identified various genes, which are implicated in AED transport (Multidrug-resistant protein/adenosine triphosphate-binding cassette protein, MDR1/ABCB1, MDR2/ABCB2), metabolizing enzymes (cytochrome P450, CYP2D6, CYP3A4, CYP2C9, CYP2C19, and CYP2E1 glucuronosyltransferase, UGT1A6 and UGT1A9), ion channels (SCN1A), and immune system (HLA-DR, HLA-DQ, and HLA-B). [36],[37] P-glycoprotein is a drug efflux transporter, which is associated with MDR1/ABCB1 gene. Commonly used AEDs phenytoin and valproic acid are known to inhibit P-glycoprotein expression, making it a potential target for pharmacoresistance. [36] Cytochrome P450 liver enzymes metabolize most AEDs. Genetic variations in these enzymes can alter the metabolism and clearance of the AEDs from the body. For example, individuals with poor metabolizer allele of CYP2C9 or CYP2C19 genes need lower doses of phenytoin to achieve optimum serum level as compared to an individual with normal allele. The identification of such genotype can prevent unnecessary phenytoin toxicity in the patients. [38]

Many AEDs such as phenytoin, carbamazepine, and lamotrigine act through voltage-gated sodium channels (SCN1). Mutations in the alpha subunit of sodium channels (SCN1A) have been known to cause febrile seizures and Dravet syndrome in children. [30] It has been shown that patients with AA genotype in SCN1A gene required higher doses of phenytoin and carbamazepine for seizure control than those patients who had GG genotype. [32] Adverse drug reactions such as cutaneous hypersensitivity reactions are common with AEDs. Pharmacogenetics has the potential to reduce up to 50% of adverse drug reaction in PWE treated with AEDs. [34] This is best exemplified by HLA-B񦹾 allele on the major histocompatibility complex strong association with AED-induced Steven–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in Asian patients. [39] Similar association has also been seen with HLA-A񧒽 with carbamazepine-induced cutaneous reactions but the follow-up studies failed to show the results consistently. [40] As of now, testing HLA-B񦹾 allele before starting AED treatment in Asian patients is the only clinically relevant testing available.

It is important to take the advancements in epilepsy genetics from bench to bedside. As stated previously, the basis of most of the common genetic epilepsies is multifactorial with both genetic and environmental factors playing major roles, but nevertheless, there are multiple genetic tests available in the market to make diagnosis of specific type of epilepsy syndromes. Genetic testing in PWE is done mainly in two scenarios, first, where the patient is already known or suspected to have epilepsy and second, to predict the occurrence of epilepsy in a person with a family history of epilepsy. [22] The latter situation is commonly encountered, and the knowledge of percentage risk of manifesting a diseases in different modes of genetic inheritance would be useful for clinicians in day-to-day practice. In autosomal dominant epilepsies, for example, BFNS, BFIS, ADNFLE, FTLE, and FFEVF, there is a 50% chance of passing the mutated gene in each child. In autosomal recessive epilepsy syndromes such as Unverricht-Lundborg disease, Lafora disease, and dentatorubral-pallidoluysian atrophy, both parents with carrier mutation can pose a 25% risk of exhibiting the disease in every pregnancy. The chance of having an unaffected child but carrier of the disorder is 50%, and the chance that a child is both unaffected and not a carrier is 25%. The mode of inheritance of febrile seizures in children is more complex. Various family and twin studies have reported that the risk of siblings of the affected child is between 10% and 20%. [32],[41] Many epileptic encephalopathies have been recently found to have de novo mutations, wherein a new genetic mutation occurs in the individual with no history of disorder in either of parents. [42]

Genetic testing has important psychological, social, and financial implications. [22],[43] Knowing the genetic basis of their disease makes the patient relieved about the diagnosis and prevents them from undergoing unnecessary, laborious, invasive, and often expensive investigations. It is important to note that a positive genetic test can also cause psychological stress and fear among patients and family members, which sometimes lead to discrimination in employment and society. [2] Thus, it is important to have a pre- and post-genetic test counseling by a trained genetic counselor. [2] Another important clinical implication is in marriage and reproductive decisions. Genetic testing is usually advised in people where there is strong family history of genetic epilepsies, or parents share a common genetic pool (consanguineous marriage). [22] The chances of developing a recessive disorder are higher if both parents share a common ancestry. Therefore, it is important to get genetic counseling and testing done in such couples before marriage and conception. [22] Another aspect of genetic testing is the cost-effectiveness. [44] The high cost of genetic testing has some limitations in less developed countries like India, but with rapid progress in gene sequencing technologies and wider availability, the cost of genetic testing is going to reduce in the coming years. [45]

There have been multiple epilepsy genetics studies in India, focusing from pharmacogenomics to familial studies in JME and CAE. Contrary to multiple studies [46],[47],[48] showing association of ABCB1/MDR1 gene polymorphism in drug-resistant epilepsy, no such association is observed in the Indian population, [49] although significant involvement of CYP2C9, SCN2A, and GABRA genetic variants in modulation of epilepsy pharmacotherapy has been observed in the North Indian population. [50],[51] Association between polymorphism of a neuronal signaling molecule, namely, reelin (RELN) has also been seen with childhood epilepsy in Eastern Indian population from West Bengal. [52] Numerous family-based genetic association studies have been done in India, especially in JME. A locus for JME has been mapped to 2q33-q36 and 5q12-q14 in South Indian population. [53] Similarly, the absence of GABRA1 Ala 322Asp mutation has been noted in JME families from South India. [54] In addition, IGE syndrome is found to be linked to 3q13.3-q21 and missense mutation in the extracellular calcium-sensing receptor gene in the Indian population. [55] Another large family study showed a linkage of familial childhood absence seizures to chromosome 8q24. [56]

The advancements in molecular genetics of epilepsy have propelled the epilepsy research to an all-time high. Recent discoveries of epilepsy genes have definitely increased our understanding of epilepsies and their clinical management, but one important development that will guide future research is the role of molecular pathways that cause seizure disorders. This is best exemplified by recent advancement in the understanding of mammalian target of rapamycin pathway in the pathophysiology of epileptic encephalopathies and development of rapamycin as its therapeutic target. [24],[25] WES/whole genome sequencing has made genetic tests accessible at the bedside. Newer methods and techniques such as cerebral organoids, induced pluripotent stem cells, and gene editing (e.g., clustered regularly interspaced short palindromic repeats) will generate new data that will challenge our long-held concepts about pathomechanisms of epilepsies. [57],[58],[59] These newer approaches have the potential to unravel the most complex genetic mechanisms underlying epileptic seizures.

With a lot good holding in the future in epilepsy genetics, there are few challenges, which the epilepsy community has to work together and find solutions. Complex genotype–phenotype correlations will continue to haunt the epilepsy scientists. Large multinational consortium studies following uniform diagnostic guidelines will generate huge data, which will be more valid and acceptable and help in making more accurate genotype–phenotype predictions. In a less developed country like India, the genetic testing may not be easily available for every strata of society. It is expected that with further improvements in sequencing technologies, the cost of NGS for single gene/panel testing will reduce drastically, helping NGS to become a routinely employed diagnostic tool. The clinicians and resident doctors should be encouraged to take a detailed family history during patient evaluation, a lack of adequate family history leads to wrong diagnosis and management. Inadequate family history underestimates the utility of genetic testing in clinical practice. A professional, accurate, and effective counseling by a trained genetic counselor is an important cornerstone in the management of patients with genetic epilepsies unfortunately, there is an acute shortage of genetic counselors in the country. With genetic tests going to become a routine laboratory investigation in coming times, this shortage of genetic counselors should be promptly dealt with.

Common epilepsies share genetic overlap with rare types

An international study led by Columbia University Medical Center (CUMC) and NewYork-Presbyterian researchers has found that several genes previously implicated only in rare, severe forms of pediatric epilepsy also contribute to common forms of the disorder.

"Our findings raise hopes that the emerging paradigm for the treatment of rare epilepsies, where therapies are targeted to the precise genetic cause of disease, may also extend to a proportion of common epilepsy syndromes," said study leader David B. Goldstein, PhD, director of the Institute for Genomic Medicine and professor in the Departments of Genetics and Development and Neurology at CUMC.

The findings were published online in The Lancet Neurology.

In recent years, researchers have uncovered dozens of genes that, alone or in combination with other factors, cause rare pediatric epilepsies. These discoveries have led to the use of targeted therapies for some seizure disorders, such as the ketogenic (high-fat, low-carbohydrate) diet in patients with Dravet syndrome or a GLUT-1 deficiency. Other therapies such as quinidine, a medication to treat heart arrhythmias, and memantine, an Alzheimer's disease treatment, have been tried in children with certain gene mutations. These attempts have not proved universally effective for all patients with these mutations, but suggest the potential to repurpose existing medicines to treat rare genetic forms of epilepsy.

"Unlike very rare types epilepsies, previous studies had shed little light on the genetic underpinnings of common epilepsies, which suggested that this precision medicine paradigm may have a very narrow application," said Dr. Goldstein.

To learn more about the genetics of epilepsy, Dr. Goldstein and his colleagues conducted a study to identify the genetic contributions to more common forms of epilepsy. In the study, the first of its kind, researchers compared the exomes (protein-coding genes) of 1,140 individuals with two of the most common types of epilepsy with the exomes of 3,877 unrelated epilepsy-free controls. The analyses were conducted at CUMC's Institute for Genomic Medicine, in collaboration with NewYork-Presbyterian, as part of Epi4K, an international consortium of epilepsy clinicians and researchers. Most of the patients were recruited through the Epilepsy Phenome/Genome Project.

The researchers found a significant excess of mutations in five genes, previously implicated only in rare forms of epilepsy, in some of the individuals with familial non-acquired focal epilepsy, one of the more common types. "We estimate that these five genes contribute to epilepsy risk in approximately 8 percent of people with this common form of the disorder," said Erin Heinzen Cox, PhD, assistant professor in the Department of Pathology and Cell Biology and Deputy Director of the Institute for Genomic Medicine at CUMC. A similar pattern was also observed for another common type of epilepsy, genetic generalized epilepsy.

The findings have important implications for clinical practice and for research. "At present, all common epilepsies are treated the same way, with the same group of medications," said Dr. Goldstein. "But as we identify more of these epilepsy genes that span a much wider range of types of epilepsy than previously thought, we can begin to try targeted therapies across these patient populations. As this genetically driven treatment paradigm becomes more established, our field, which is accustomed to undertaking large clinical trials in broad patient populations, will need to take a new approach to clinical research, focusing on patients based on their genetic subtype."

"This is a very exciting breakthrough in the treatment of epilepsy, in which current treatment is based on whether a child has focal seizures, which begin in one area of the brain, or generalized seizures," said James J. Riviello, MD, the Sergievsky Family Professor of Neurology and Pediatrics and Chief of Child Neurology at NewYork-Presbyterian Morgan Stanley Children's Hospital. "Genetic testing for epilepsy may allow us to identify the specific anticonvulsant medication that potentially works best for an individual patient. We have already identified children in whom knowing the underlying genetic basis of the epilepsy has guided our treatment choices."Additional studies, analyzing 10,000 to 12,000 samples, are planned for the coming year.

"With a larger analysis, we expect to find additional genetic variations that contribute to common epilepsies," said Dr. Goldstein.


This work was funded by the National Natural Science Foundation of China (81271921 and 81101339), Sheng Hua Scholars Program of Central South University, China (H.D.), Research Fund for the Doctoral Program of Higher Education of China(20110162110026), Natural Science Foundation of Hunan Province, China (10JJ5029), Construction Fund for Key Subjects of the Third Xiangya Hospital, Central South University, and Students Innovative Pilot Scheme of Central South University (CL11280, DL11446, and DL11447), China.

Conflict of Interest

The authors declare that they have no conflict of interest.

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