multi-generation family

Is epilepsy genetic?

Advances in science and medicine over the last decade have led to a better understanding of the ways genetic factors contribute to epilepsy.

  • Some types of epilepsy run in families, passed down from one generation to the next. These epilepsies are both inherited and genetic.
  • Other types of epilepsy may be due to genetic changes that were inherited or happened for the first time in an individual. In such instances, there may not have been any family history of epilepsy. Thus, not all epilepsies that are due to genetic causes are inherited.
  • Some forms of epilepsy are due to acquired (happen for another reason) causes, like in the case of a head injury, and are neither genetic nor inherited.
Not all epilepsies that are due to genetic causes are inherited.

The genetics of epilepsy is a new and emerging field. For some individuals, it is not yet possible to determine whether their seizures are due to genetic factors.

condition affecting members of a family
 

What are the chances of inheriting epilepsy?

In general, if a person has a first-degree relative (mother, father, sibling) with epilepsy, the risk of developing epilepsy by the age of 40 is less than 1 in 20 (Peljto et al. 2014). The risk differs somewhat between focal and generalized epilepsy. There is an increased risk of developing epilepsy if the first-degree relative has a generalized epilepsy rather than focal epilepsy (Peljto et al. 2014; Helbig et al. 2016). These estimates come from population-based studies, meaning they are based on the average across a large group and may not apply for all individuals.

The likelihood of inheriting epilepsy may differ significantly if a person has a relative with a known genetic epilepsy diagnosis. In this case, the chance of developing epilepsy depends on the specific gene and inheritance pattern involved.

Basic Genetic Terms

To fully appreciate this, we first need to review a few basic genetic terms.

Gene

Genes are sequences of DNA (deoxyribonucleic acid) that determine different proteins made in the body. These proteins have a variety of functions and ultimately determine how we develop, grow and function. There are about 20,000 genes in the human genome. With a few exceptions, humans have two copies of every gene: one inherited from each parent.

Genetic Variant

A genetic variant is a change in the DNA sequence, which can cause the gene not to work properly and ultimately can affect how the gene (protein) functions.

De novo Variant

A de novo genetic variant arises for the first time in one individual. Usually, this is caused by a random change in the DNA of the egg or the sperm cell of the parent but is not otherwise present in either parent.

Incomplete Penetrance

For some genetic conditions, not everyone with a disease-causing variant will develop the symptoms of the disease. This phenomenon is called incomplete penetrance.

Autosomal Recessive Inheritance

  • Recessive inheritance means that to develop the condition, both copies of the gene (one gene from each parent) have a disease-causing variant.
  • If a person has an autosomal recessive genetic condition causing epilepsy, it means that both copies of the gene have a disease-causing variant.
  • In these cases, the mother and father are typically carriers of the condition, meaning that only one of their genes has a disease-causing variant.
  • Usually carriers do not have any symptoms of the disease. In this scenario, the mother and father would have a 1 in 4 chance with each pregnancy of having another child with this condition.
  • A person with an autosomal recessive disease can have a child with the same diagnosis, but only if their partner is also a carrier of the same recessive disease.
autosomal recessive
 

Autosomal Dominant Inheritance

  • Dominant inheritance means that to develop the condition, only one copy of the gene has a disease-causing variant.
  • If a person has a mother or father with an autosomal dominant genetic condition, the person has a 50% chance of inheriting the gene.
  • The chance of developing epilepsy will depend on the specific gene involved due to incomplete penetrance (not everybody with the variant will have symptoms).
  • For genes that have incomplete penetrance, the risk of inheriting the disease causing variant will still be 50%, but the likelihood of actually developing the symptoms may be lower.
autosomal dominant
 

X-linked Inheritance

  • X-linked inheritance occurs when the DNA change is present in a gene on the X chromosome.
  • X-linked inheritance can be either recessive or dominant.
  • Often with X-linked inheritance, a female with the genetic variant may be unaffected or mildly affected whereas a male would be much more significantly impacted. However, this is not always the case and depends on the specific gene.
  • There are some genetic epilepsies, for example, in which males are unaffected carriers, whereas females are typically significantly impacted.
X-linked recessive genes
 
X-linked dominant genes
 

Are certain types of epilepsy associated with genetic changes?

Certain types of epilepsy are associated with specific genetic changes, including changes in an individual gene or changes in a chromosome.

  • In some cases, the specific genetic change and type of epilepsy are well described in the medical literature.
  • For instance, individuals with a clinical diagnosis of Dravet syndrome are likely to have a variant in a gene called SCN1A. Usually, the variant in SCN1A is a de novo variant. This means the variant arose in either the egg or the sperm cell and the parents do not have the SCN1A variant.
  • However, it is important to note that the field of epilepsy genetics is in the early stages. In many cases, researchers are just beginning to learn about specific genes and the types of epilepsy associated with them.
  • In many instances, it may be hard to predict an individual’s epilepsy prognosis because more research is needed.

Are there epilepsy-related genes?

  • The first few epilepsy-related genes were identified in the late 1990s. Advances in DNA sequencing now have identified hundreds of genes that play a role in epilepsy.
  • New genes are being identified on a regular basis.
  • Some of the genes identified to date seem to be specific to epilepsy.
  • Other genes are associated with epilepsy and other issues, such as
    • Developmental delay
    • Autism spectrum disorder
    • Intellectual disability
  • There are many different types of genetic tests that may be used to detect epilepsies with a genetic cause.
  • Individuals with epilepsy should speak with their healthcare providers about genetic testing options.

What types of research are being done to understand the role of genetics in epilepsy?

Research is currently ongoing in many medical centers and laboratories around the world to help understand the role of genetics in the development of epilepsy. One long term goal of this research is precision medicine. This means individuals with genetic epilepsies would be treated with approaches specifically targeted to their genetic diagnosis.

Although there are many types of research studies, three main types relate to the field of epilepsy genetics:

  • Natural History Studies
  • Clinical Trials
  • Functional Studies

Natural History Studies

  • This is observational research that collects specific information about individuals to understand the various features and progression of a specific condition.
  • There are currently many ongoing natural history studies for specific genetic epilepsy syndromes.
  • These types of studies are important to help families and clinicians better understand the prognosis for all the different genetic epilepsies.
  • The data generated from studies can be extremely useful for future clinical trials to help identify whether a therapy is effective.
  • Participating in a natural history study usually involves

Clinical Trials

  • These research studies are aimed at evaluating the safety and benefit (efficacy) of a specific intervention (such as, a medication, surgery, or device).
  • Typically, the intervention has been extensively tested in animal and cell models before a clinical trial takes place in humans.
  • Clinical trials require approval from the U.S. Food and Drug Administration (FDA) before they can begin.
  • They usually have four stages, each with a specific goal related to safety and benefit (efficacy).
  • The gold standard in medical research is called a randomized controlled trial.
  • When participating in a clinical trial, it is important to discuss the risks and benefits of participating with your physician and the researchers.
  • Usually, there are criteria to participate in a clinical trial (study).
    • You can only enroll if you meet all of the inclusion (characteristics someone must have to participate) and none of the exclusion (characteristics that make a person unable to participate) criteria.
    • One example of a criteria that might be used in a clinical trial could relate to a person’s age. If the inclusion criteria said, “A person must be over age 18 to participate,” then anyone under 18 would be excluded from the study.
  • The research team will review the informed consent document in detail and discuss the specific risks and potential benefits involved with the clinical trial.
  • Sometimes there may not be a direct benefit to a subject participating in a clinical trial. However, the research study may add to the scientific body of knowledge about the disease. This is especially important for rare diseases, such as the genetic epilepsies.

Learn More

Functional Studies

  • Sometimes a variant is seen in a gene, but it is difficult to know whether the variant causes a disease or not.
  • Functional (how something works) studies are very important in the field of genetics. They help to determine if a variant in a gene influences the function of the resulting protein.
  • The laboratory uses a variety of techniques on biological samples to assess the effect of the genetic variant.
  • Sometimes, the researchers need a sample (such as a blood, urine, or skin biopsy) directly from an individual with the specific genetic variant to complete the test. In these cases, the researcher may need to get informed consent from the person.

What clinical trials are available to families with a genetic diagnosis in epilepsy?

There are currently a limited number of clinical trials available to individuals and families with some forms of genetic epilepsies, but we anticipate the number of trials will continue to increase. The following links are a good place to start for information about currently available trials for genetic epilepsies:

References

Helbig I, Heinzen EL, Mefford HC, and Ilae Genetics Commission. Primer Part 1-The building blocks of epilepsy genetics. Epilepsia, 57 (2016): 861-8.

Peljto AL, Barker-Cummings, Vasoli VM, Leibson CL, Hauser WA, Buchhalter JR, and Ottman R. Familial risk of epilepsy: a population-based study. Brain, 137 (2014): 795-805.

Illustrations

National Library of Medicine (US). Adapted from Genetics Home Reference [Internet]: ghr.nlm.nih.gov. Bethesda (MD): The Library; 2013 Sep 16.

Authored By: 
Natalie Lippa MS, CGC
Authored Date: 
12/2019
Reviewed By: 
Beth Rosen Sheidley MS, CGC
Annapurna Poduri MD, MPH
Elaine Kiriakopoulos MD, MSc
Elaine Wirrell MD
Epilepsy Foundation Digital Strategies & Engagement
on: 
Thursday, April 23, 2020