Genes and Seizures: A Complicated Interaction

Advancing genetic research has begun to unlock some of the secrets of epilepsy.

By Beryl Lieff Benderly
Special to EpilepsyUSA
Posted: June 1, 2006

At least as far back as Hippocrates, observers have suggested epilepsy is inherited. About 400 B.C., the Greek physician who is said to have founded Western medicine wrote that epilepsy's "origin is hereditary."

In recent years, modern genetic research has proven that his basic conclusion about heredity was right, at least for several types of epilepsy. Researchers have also begun mapping out a molecular basis for understanding how some epilepsies are transmitted and how they may some day be treated.

A specific epileptic syndrome was first mapped to a chromosome location in 1989. About a dozen genes known to relate to epilepsy have been found. But scientists have long known numerous forms of epilepsy appear to run in families, strongly suggesting genetic influence.

As research advances, the picture of the relationship between genes and epilepsy is becoming more complex because epilepsy is not one condition but an array of different disorders of the brain with a variety of causes. Genetic research has already produced major new insights into the processes underlying some kinds of seizures, as well as promising new approaches in treatment that could lead to important advances.

Origins of Risk

Genetics cannot explain all types of epilepsy. Experts classify about 25 percent of cases as symptomatic, or resulting from known damage to the brain. Common causes include traumatic accidents, mishaps during pregnancy or birth, infectious diseases (such as meningitis), abnormal blood sugar levels (such as hypoglycemia), tumors, strokes, and certain types of brain malformations. Although the effects of some infectious diseases can include seizures, epilepsy is not, in itself, contagious.

A number of symptomatic epilepsies occur as a result of disorders that cause widespread abnormalities of the brain. Seizures are only one symptom of these larger syndromes affecting many aspects of the individual's cognitive or neurological functions.

Gene abnormalities already identified, though very important scientifically, account for under 1 percent of epilepsy cases. The causes of the remaining three-quarters of cases remain unknown, but experts believe genetics play a role in many of them.

Some experts divide these undetermined cases into two categories: idiopathic, or resulting from an unknown cause, often thought to be genetic; and cryptogenic, or resulting from a hidden cause, often thought to be related to some underlying condition. Other authorities reject this distinction as being of little use.

The risk to an affected person's family members varies markedly depending on the epilepsy's cause. Relatives of those with symptomatic epilepsies caused by known trauma, such as an accident or stroke, are no more likely to develop epilepsy than are members of the general population, who face a risk of only about 1 to 2 percent.

When the cause of a primary epilepsy cannot be pinned down to a particular injury, the risk of relatives developing epilepsy is higher than that of the general public. Still, in more than 90 percent of such cases, no one in the family has the disorder; in this case, the epilepsy is called sporadic. When multiple family members have epilepsy, it is called familial. The risk to relatives is generally higher in familial rather than sporadic epilepsies.

Children of parents with epilepsy generally have a 10 to 12 percent risk of developing epilepsy; the risk is higher when the affected parent is the mother. Siblings of persons with epilepsy of unknown origin run a 4 to 8 percent risk, except for identical twins, whose risks are much higher. The more closely related the family members with epilepsy are, the greater the risk that other close relatives will develop it, too.

Relatives face a much lower risk if the onset of the seizures occurs after age 35 than in childhood or adolescence. If the seizures are generalized, immediate family members run a higher risk than if the seizures are partial or focal.

Understanding the Genetics

Several factors further complicate the genetic picture. Epilepsy is not a single disorder but a collection of syndromes and conditions that involve seizures of various types and doubtlessly arise from a number of different causes. One expert, Ruth Ottman, Ph.D., a professor of epidemiology at Columbia University and a member of the Epilepsy Foundation's professional advisory board, described a seizure as "a very general manifestation… like sneezing." Just as sneezes can result from allergies, air pollution, a mild cold or a grave disease, "a lot of things could cause you to have a seizure." In the great majority of cases thought to result at least in part from inheritance, researchers have not yet found the specific gene or genes responsible.

A second complication is that among the genes found, the effects on various individuals can vary considerably. Epilepsies of the same type may be more or less severe. Nor is the correspondence between genetics and symptoms necessarily exact. People with the same genetic abnormality may have different types of seizures. People with the same form of epilepsy may have different genetics.

The two major categories of apparently genetic epilepsies correspond to different patterns of inheritance. The 1 percent associated with currently known genes generally follow a pattern called simple or Mendelian inheritance. An abnormality in a single gene is responsible for a disorder passed by either parent to some or all of their children in a clearly discernible way. The other category follows a pattern known as complex inheritance. The disorder results from abnormalities in a number of genes from either parent, as well as environmental factors. The patterns are often obscure.

A third category of genetic disorders results from defects in genes contained in structures within the cells called mitochondria. Individuals inherit mitochondrial genes from their mothers only. Disorders can also result from changes that affect the chromosomes, the cellular structures that contain the genes. Types of epilepsy can also occur from genetic changes that take place on their own (or de novo) within affected individuals themselves.

How Genetics Work

The genetic instructions for the structure and function of the human body are contained in the chromosomes, thread-like structures composed of a material called DNA. At conception, each human being normally inherits 23 pairs of chromosomes, one member of each pair from each parent. The original cell arising from the fertilized egg multiplies into the body's billions of cells, each containing a copy of the chromosomes.

Along each chromosome are arrayed sections called genes which contain the specific instructions for particular proteins. Except for the special chromosome pair that determines the individual's sex, the chromosomes in each pair are the same length and contain versions of the same genes. The differing versions of each gene are known as its alleles.

Some traits are determined by a single gene transmitted in Mendelian inheritance, named after Gregor Mendel, discoverer of the principles of genetic transmission. In the pea plants that Mendel studied, whether the pea is smooth or wrinkled is an example of such a single-cell trait. In human beings, a number of rare genetic epilepsies are Mendelian traits caused by abnormal alleles of a single gene. Normal copies of the gene lack the abnormality and do not cause epilepsy.

Mendelian genes may be either dominant or recessive. If dominant, a single copy of the abnormal allele will cause the disorder. If recessive, two copies of the abnormal allele are needed to produce the disorder.

In dominant Mendelian epilepsy, an individual who inherits one epilepsy allele develops epilepsy. Because each parent passes to each child only one chromosome from each of the 23 pairs, on average half of his or her children will receive the epilepsy allele and develop epilepsy. Individuals who receive the abnormal allele also pass it to an average of half of their offspring. Individuals who do not receive the epilepsy allele will not develop epilepsy and cannot pass it on to their descendents.

In a recessive Mendelian syndrome, an individual needs two epilepsy alleles to develop the disorder and must inherit one from each parent. Such individuals will also pass the epilepsy allele for it to each of their children. If both parents have two epilepsy alleles, then so will all their children. If one parent lacks the epilepsy gene, however, the children will receive only one epilepsy gene and not develop epilepsy.

Individuals with one recessive epilepsy allele do not develop the disorder, but still pass it, on average, to half of their offspring. They are known as carriers. If one parent has the disorder and the other is a carrier, on average, half of the children will receive two epilepsy genes and develop the disorder. The other half will be carriers.

If both parents are carriers, each will, on average, transmit the epilepsy gene to half their children. On average, a fourth of the children will receive two normal genes, a half will receive one defective and one normal gene and be carriers, and a fourth will receive two epilepsy genes and both develop the disorder and transmit the defective gene.

A number of very rare primary epilepsy syndromes have been identified as involving Mendelian inheritance. These include benign familial neonatal convulsions, autosomal dominant nocturnal frontal lobe epilepsies, generalized epilepsy with febrile seizures, autosomal dominant juvenile myoclonic epilepsies, and autosomal dominant partial epilepsy with auditory features. Affected families often have multiple members with epilepsy.

Mendelian inheritance also explains a number of severe degenerative disorders that have epilepsy as one of many features. These include the progressive cyclone epilepsies, such as Unverrict-Lundborg disease (also known as Baltic myoclonus) and Lafora's disease. Both are recessive syndromes.

Strikingly, however, the specific mutations causing a number of the Mendelian epilepsy syndromes are not identical from family-to-family, nor are the effects of given mutations always the same.

Non-Mendelian Inheritance

Mendelian inheritance gives insight into the role of certain genes, but does not explain why the majority of persons have epilepsy.

Many of these people are sporadic cases with no affected relatives or family history of the disorder. Others belong to families with histories of epilepsy that do not follow Mendelian patterns. Experts suspect that these much more common cases involve complex inheritance of multiple genes, along with environmental factors.

No one knows how many of the 30,000 human genes may potentially contribute to epilepsy, but the number is much larger than the dozen thus far identified. Some scientists believe it may reach as high as 500.

In complex inheritance, multiple genes appear to make relatively small contributions towards raising the person's susceptibility to seizures. When these genetic effects, probably also combined with environmental factors, push the individual's susceptibility over a certain threshold, seizures are the result. Without precipitating environmental factors, the individual may remain free of epilepsy.

Isolating the genes involved in complex inheritance is difficult because affected families often have several different forms of epilepsy. A given gene may be related to different types of epilepsy and persons with the same form of epilepsy may have different genes or mutations. Juvenile myoclonic epilepsy is one form known to have a genetic component but a pattern of transmission that remains obscure.

Two specific epilepsy syndromes have been tied to mutations in mitochondrial genes. The mitochondria's main function is providing energy to power the cell. Mutations in these genes can severely disrupt the cell. Among the disorders that mitochondrial mutations cause are two rare degenerative diseases that cause seizures: myoclonic epilepsy with ragged-red fibers and mitochondrial encephalopathy lactic-acidosis and stroke-like episodes. Epilepsy syndromes caused by mitochondrial mutations suggests a possible explanation for why mothers are more likely to transmit epilepsy than fathers.

Epilepsies caused by chromosomal abnormalities are generally parts of larger syndromes, such as Down syndrome and Wolf-Hirshhorn syndrome. An epilepsy type caused by a de novo single mutation occurring in the individual is severe myoclonic epilepsy of infancy, a rare and grave syndrome.

Future Directions

The epilepsy genes thus far identified have a special significance to science. Finding the functions they serve in the brain has provided new insights into mechanisms that can produce seizures. Some of the known genes affect the ability of cells to migrate to the proper locations during early brain development. Others affect the form of structures known as ion channels that act as gates and have a vital role in passing signals among the cells of the brain. Each known ion channel mutation creates a particular defect in a specific type of channel without harming the structure of the rest of the cell. Abnormal functioning of these molecular portals is therefore fundamental to certain epilepsies. Genes have been identified relating to sodium, calcium and potassium channels in the brain.

Other cellular abnormalities, such as errors in breaking down certain proteins and carbohydrates, have also been related to certain epilepsies through identification of the particular gene mutations that cause them.

In addition to increasing researchers' understanding of the processes that produce seizures, genetics may lead to better treatments by revealing defects that are promising targets for new or improved treatments. More than 2,000 years after Hippocrates, the hope of understanding the various types of epilepsy is beginning to come true.

Editor's Note: Beryl Lieff Benderly is a prize-winning scientific writer specializing in genetics and genetic technology. She has a Master of Science degree in anthropology and used to teach at Fisk University and the University of Puerto Rico. She also used to teach science writing at the University of Maryland.