Epilepsy is a chronic noncommunicable brain condition that affects approximately 50 million people worldwide. Its main symptom is recurrent seizures, which can be brief bursts of involuntary movement impacting a specific part of the body (partial) or the entire body (generalized).
Seizure episodes occur due to excessive electrical discharges in clusters of brain cells. These discharges can originate from various brain areas. Seizures can range from minor muscular twitches or lapses in concentration to more severe convulsions lasting an extended period. The frequency of seizures varies, from infrequent occurrences (less than one per year) to frequent episodes (many per day).
A person is considered to have epilepsy if they meet any of the symptoms below:
To identify the source of the seizures and to diagnose epilepsy, patients undergo a number of tests. The assessment can consist of:
Genetic tests will be explored further in the sections of each disease. You also may have one or more brain imaging tests and scans that detect brain changes:
Treatment aims to reduce the frequency of seizure episodes or even eliminate them entirely for individuals diagnosed with epilepsy. Various treatment options are available:
Medication: Anti-seizure medications, such as...
Surgery: Epilepsy surgery involves removing the brain area responsible for generating seizures. It is particularly effective when seizures are localized in a specific region of the brain.
Vagus Nerve Stimulator: This device is attached to the vagus nerve in the neck and implanted beneath the chest skin. It can reduce seizures by approximately 20-40%.
Responsive Neurostimulation: Implantable devices analyze brain activity patterns to deliver medication or electrical charges.
Deep Brain Stimulation: Electrodes implanted in targeted brain areas, usually the thalamus, are connected to a chest generator that sends electric signals to the brain.
Idiopathic (genetic) generalized epilepsy is a subtype of generalized epilepsy characterized by standalone generalised tonic-clonic seizures, which encompass both tonic (stiffening) and clonic (twitching or jerking) phases of muscle activity. It also includes specific conditions like childhood absence epilepsy, adolescent absence epilepsy, and juvenile myoclonic epilepsy.
On the other hand, symptomatic epilepsy emerges following a brain injury that carries the potential to trigger the condition. Examples of such injuries encompass severe head trauma, brain tumors, strokes, and more.
Historically, a wide array of epileptic disorders were categorized as symptomatic to differentiate them from idiopathic epilepsy, which is driven by hereditary factors. However, with the progression of genetic research, the clear demarcation between these two forms of epilepsy has become less distinct. Advances such as the identification of SCN1A mutations underlying severe myoclonic epilepsy of infancy (SMEI), a condition formerly categorized as symptomatic, have cast doubt on the strict classification between symptomatic and idiopathic cases. Additionally, the absence of major genes for common idiopathic epilepsies like juvenile myoclonic epilepsy challenges this classification.
Although hereditary epilepsies account for only a small proportion of seizure disorders, the etiology of most epilepsies is a complex interplay between acquired and inherited factors. This underscores the need for a more nuanced understanding of epilepsy classifications beyond the traditional idiopathic and symptomatic categories. (Andrade & Minassian, 2007).
Idiopathic epilepsies, at least in the uncommon hereditary types, have been demonstrated to be mostly caused by malfunctions of mutant voltage- or ligand-gated ion channels. Ion-channel mutations are suspected of being a key factor in more prevalent epilepsies such juvenile myoclonic epilepsy and childhood and adolescent absence epilepsies, which are uncommon monogenic idiopathic epilepsies (Avanzini et al., 2007).
Summary of all the CHRNA4 mutations found in ADNFLE. The second transmembrane domain (M2) is where all of the mutations are found. CpG dinucleotide sites are underlined, and affected nucleotides are show n in bigger italic font. (Source)
Structure and mutation locations of the channel protein KCNQ2 (K V 7.2). The structure of K V 7.2 is typical of voltage-gated potassium channel subunits; it consists of six transmembrane segments (S1–S6), an intracellular N- and C-termini, a voltage-sensing domain (VSD) composed by S1–S4, and a pore-loop between S5 and S6. The sites of KCNQ2 mutations in epilepsy that is easily managed are shown by red dots. The sites of KCNQ2 mutations in intractable epilepsy are shown by blue dots. (Source)
DNA vs phenotype. SCN2A-related phenotypes can be roughly divided into three groups: (1) mutations leading to Ohtahara Syndrome, unclassified epileptic encephalopathies with or without dystonia, Infantile Spasms, or Lennox-Gastaut Syndrome; (2) mutations leading to Benign Familial Neonatal-Infantile Seizures (BFNIS); and (3) mutations leading to autism and intellectual disability (ID). (Source)
Numerous ion channels or proteins that influence ion-channel function are encoded by the majority of the epilepsy genes thus far listed (such as accessory channel subunits). The conclusion that idiopathic epilepsies are a category of channelopathies resulted from this. Non-ion channel genes, however, were shown to be at least marginally involved in the aetiology of idiopathic epilepsies.
Postsynaptic ADAM22 is bound by LGI1, which is released from the presynapse. When ADAM22 is bound, the postsynapse experiences modified intracellular signalling that reduces excitability. This is most likely caused by subunit alterations in postsynaptic glutamate receptors. Hence, a net increase in excitability is caused by mutations in LGI that prevent ADAM22-mediated signalling. (Source)
Myoclonus, a sudden, brief involuntary twitching or jerking of a muscle or group of muscles, generalised epilepsy, and progressive neurological deterioration, including dementia and ataxia (loss of muscle control and coordination), are characteristics of the uncommon clinically and genetically heterogeneous disorders known as PMEs (primarily autosomal recessive ).
Unverricht-Lundborg disease (Baltic myoclonus), myoclonic epilepsy and ragged-red fibre disease (MERRF), neuronal ceroid lipofuscinosis (CLN), dentatorubropallidoluysian atrophy, etc. are examples of the diverse mechanisms that may underlie various neurogenetic syndromes characterised primarily by seizures and cognitive decline.
Patients with EPM1 epilepsy are affected by mutations in the cystatin B (CSTB) gene. In the mouse cortex and human cerebral organoids (hCOs), CSTB release stimulates the recruitment of migratory interneurons and fosters the expansion of progenitor cells. EPM1-derived hCOs have impairments in both roles. The overexpression of CSTB leads to the growth of progenitor cells in both the developing mouse brain and hCOs.
When migratory interneurons are recruited, CSTB is secreted. In the developing mouse cortex, there are fewer progenitors and migratory interneurons as a result of downregulating Cstb and overexpressing R68X. Cell non-autonomous reduction of proliferation occurs in cerebral organoids generated from EPM1. Cerebral organoids generated from EPM1 show early differentiation. (Source)
Although the number of epilepsy genes that are now identified is outstanding; they likely just represent the very top of the iceberg. A rough estimate is that 50% of all genes are expressed in the brain at least during foetal development and may thus be considered seizure disorder possibilities. Aside from that, past studies suggest that variations in genomic DNA copy number and gene regulatory elements are likely to be just as significant for human illnesses as gene-related abnormalities (Ooi & Wood, 2007). Right now, whole-genome screening methods such as array-based comparative genomic hybridization (aCGH) or genome-wide single nucleotide polymorphism (SNP) analysis became important tools for the identification of genetic alterations with potential application to common forms of human epilepsy. The current generation of whole-genome screening techniques have emerged as crucial instruments for the detection of genetic changes that may have implications for the prevalent types of human epilepsy. It is also evident that, even with so much existing data and research about epilepsy, there's still a long way to go.
Hello, I’m Adina/Kai, from the mighty land of Kazakhstan! My project was a blend of both genetics and neurobiology respectively, carrying the name “Genetics of Epilepsy”. In it, I wanted to research the genetic basis for a widely researched, yet still greatly unknown neurological disease of epilepsy. With millions of people suffering from some form of an epileptic disorder, the etiology of this disease is especially important. Thanks to modern research, epilepsy has a lot of classifications regarding different aspects of epileptic symptoms. However, some epileptic disorders caused by genetic mutations are still a topic of further research. With Elio Academy’s help, I gained a new sense of community with people throughout the world. It motivated me to learn and represent a better world with my intentions. I hope that by sharing my project and what I’ve researched so far, I’ll help spark interest in groups of like-minded people who can change future medicine!
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