A seizure is a sudden, uncontrolled electrical disturbance in the brain, which can cause changes in behavior, movements, feelings, or levels of consciousness. Epilepsy is a chronic neurological disorder defined by a tendency for recurrent, unprovoked seizures. Current research shows that genetics plays a significant role in susceptibility to epilepsy, contributing to the majority of cases either directly or by increasing vulnerability to other risk factors.
The Spectrum of Genetic Influence on Seizure Risk
The contribution of genetics to seizure risk exists on a broad continuum, ranging from being the sole cause to a minor predisposition. Approximately 70–80% of epilepsy cases are thought to have some genetic influence. The remaining cases are often classified as acquired, resulting from non-genetic causes like severe head trauma, stroke, or brain infections.
Genetic epilepsies are categorized based on the number of genes involved. Monogenic epilepsy is caused by a mutation in a single gene, often resulting in severe forms starting in early childhood. Conversely, polygenic or complex epilepsy is the most common form, where risk is influenced by the cumulative effect of many different genes, each contributing a small amount of risk.
These common genetic variants can be combined into a polygenic risk score (PRS), which helps estimate an individual’s overall susceptibility to developing the disorder. Even in cases of monogenic epilepsy, the severity of the condition can be modified by this polygenic background. This interplay explains why individuals with the same single-gene mutation can experience different degrees of seizure severity.
Mechanisms: How Gene Mutations Affect Brain Function
Genetic mutations cause seizures by disrupting the delicate balance of electrical activity within the brain’s neural networks. Neurons communicate through rapid electrical impulses that are tightly regulated by a balance between excitatory and inhibitory signals. A common mechanism involves defects in genes that produce ion channels, which are specialized proteins that act as tiny pores in the neuronal membrane.
These ion channels control the flow of charged particles, such as sodium, potassium, and calcium ions, into and out of the neuron, which generates the electrical signal. When a mutation occurs in a gene like SCN1A, KCNQ2, or GABRA1, the resulting ion channel protein can become dysfunctional. This leads to neuronal hyperexcitability, where cells are too easily triggered or fail to stop firing, causing the abnormal electrical storm that is a seizure.
Mutations often result in a “gain-of-function” or “loss-of-function” for the channel, altering its normal operation. For example, a defect in a sodium channel may cause it to stay open longer, increasing excitability. Genes that code for receptors of neurotransmitters like GABA (the brain’s primary inhibitory signal) can also be affected, reducing the dampening effect needed to prevent overstimulation. Other genetic syndromes can affect brain development, leading to structural abnormalities that disrupt neural circuits and increase seizure susceptibility.
Distinguishing Inherited and De Novo Genetic Changes
Genetic causes of epilepsy are further categorized by how the DNA change originates within the individual. An inherited, or familial, genetic change is a variant passed down from one or both parents. A parent may carry the mutation and have a history of seizures, a milder form of epilepsy, or sometimes no symptoms at all, making them an unaffected carrier.
The risk of a child inheriting epilepsy depends on the specific type, but children of a parent with epilepsy are generally two to ten times more likely to develop the disorder than the general population. These inherited patterns involve known modes of transmission, such as autosomal dominant or recessive inheritance, although the inheritance patterns are often non-Mendelian.
In contrast, a de novo mutation is a spontaneous genetic change that is not present in either parent’s DNA. This type of mutation occurs in the egg or sperm cell that formed the individual, or very early in the developing embryo. The person affected is the first in the family to carry the specific variant, and the family history is often negative for epilepsy. De novo mutations are common in severe, early-onset epilepsies and often imply a low risk for future siblings.
Genetic Counseling and Risk Assessment
Genetic testing is increasingly becoming a standard part of epilepsy care, particularly when the cause is unexplained or the condition is complex. Specialists may recommend testing for individuals with early-onset epilepsy, drug-resistant seizures, or those with additional neurodevelopmental symptoms like intellectual disability or autism spectrum disorder. The testing process typically involves analyzing a blood or saliva sample using techniques like gene panels or whole-exome sequencing to search for known gene variants.
Identifying a genetic cause can have immediate, practical implications for treatment, leading to precision medicine. For some genetic epilepsies, a specific diagnosis can guide the choice of anti-seizure medication, as certain drugs may work better or worse depending on the underlying genetic mutation. A genetic diagnosis can also offer prognostic information, such as whether seizures are expected to resolve by a certain age.
Genetic counseling is a service that helps individuals and families interpret complex test results and understand the implications of a genetic diagnosis. A counselor provides information about the recurrence risk for future children or siblings, which is important for reproductive decision-making. Counseling also helps families access support resources and provides a definitive answer that can end a long diagnostic journey.