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Genetics of Epilepsy

What role do genetics play in epilepsy?

Genetics play a part in many types of epilepsy. It seems likely that the seizure threshold, for example, is partly determined by genetics. Epilepsy often runs in families:

  • If a parent has idiopathic epilepsy, there is about a 9% to 12% chance that the child will also have epilepsy.
  • Although epilepsy that runs in families is uncommon, if a child has epilepsy, his brothers and sisters do have a higher risk of having epilepsy.
  • If one twin has idiopathic epilepsy, the identical twin is very likely to have it as well.
  • For some reason, children of women with epilepsy have a higher chance of having epilepsy than children of men with epilepsy.

Family studies have shown that some epilepsy syndromes are completely determined by genetics, and genes are a major factor in other syndromes. Some inherited metabolic conditions also raise the likelihood of having seizures, as do some chromosomal disorders.

What types of genetic disorders are there? 

There are five types of genetic disorders:

  • Single gene or Mendelian disorders. These result when a mutation causes a single gene to be altered or missing. Single gene disorders are typically described as inherited in families, since they are passed from one generation to the next.
  • Multifactorial or complex disorders. These are related to mutations in a number of genes, often coupled with an environmental influence. Environmental factors include things like alcohol or drug use, maternal infections, and exposure to hazardous materials. These disorders tend to run in families, although a pattern of inheritance is often difficult to identify.
  • Mitochondrial disorders. These disorders result from mutations in DNA found outside the cell nucleus in mitochondria. Mitochondria are structures that make energy for the cells. If there is a mitochondrial gene mutation, energy production is affected. The DNA in mitochondria is inherited only from the mother.
  • Chromosomal disorders. These disorders result when entire chromosomes or parts of chromosomes are missing or changed. Chromosomal disorders usually occur spontaneously, however, on rare occasions they are inherited.
  • Epigenetic disorders. These are disorders related to changes in the activity of genes, rather than a mutation in the structure of the DNA.

What epilepsy syndromes are tied to genetic disorders?

Genetic disorders can cause epilepsy alone, or can result in a syndrome with a number of different effects on the organs and functions of the body, including epilepsy.

The inheritance of epilepsy is often complex. Two children with mutations on different genes may develop the same epilepsy syndrome. Two members of the same family with the same gene mutation may both develop epilepsy, but the effects in each person may be very different. Some epilepsy syndromes are known to have a genetic basis, but the specific gene or genes that cause them have not been identified.

In addition, some genetic conditions are not inherited, but arise spontaneously through new mutations.

The following provides some examples of epilepsy syndromes that may result from genetic disorders. The field of epilepsy genetics is expanding rapidly, and new genes involved in epilepsy are identified frequently. For more detailed information on specific syndromes, please consult your doctor or a genetic counsellor.

Single gene disorders

At least 20 syndromes whose main feature is epilepsy have been mapped to specific genes, and many more single-gene disorders that cause brain abnormalities or metabolic disorders can have epilepsy as one of their manifestations.

Single gene epilepsy syndromes

Autosomal dominant partial epilepsy with variable foci

Autosomal dominant partial epilepsy with variable foci first appears at 14 years of age on average. People with the syndrome have complex partial seizures originating in the temporal, frontal, or parietal lobe and secondarily generalized seizures.

Autosomal dominant nocturnal frontal lobe epilepsy

Autosomal dominant nocturnal frontal lobe epilepsy  is a syndrome in which brief partial seizures arising from the frontal lobes of the brain occur in clusters at night. Different gene mutations cause different versions of this syndrome. This syndrome usually appears when the child is eight years old on average, and can be mistaken for night terrors. The syndrome can be mild or severe in different family members, which means that doctors and families often fail to realize that the syndrome runs in the family. In most patients, the syndrome is mild and responds well to medication. Some mutations may arise spontaneously.

Benign familial neonatal convulsions

Benign familial neonatal convulsions usually appear on the second or third day after birth. Children with this syndrome have generalized clonic or tonic seizures. The seizures usually disappear after about a week. Approximately 11% of children with this syndrome go on to have seizures later in life. This syndrome is caused by one of several possible gene mutations.

Benign infantile familial convulsions

Babies with benign infantile familial convulsions usually have clusters of partial seizures without fever, starting between the ages of four and eight months. The seizures are usually easy to control, and children do not generally have seizures later in life.

Familial temporal lobe epilepsy 

People with familial temporal lobe epilepsy usually have partial seizures with psychic or autonomic symptoms. Rarely, secondarily generalized partial seizures also occur. The average age of onset is 19 years. The epilepsy is usually mild and responds well to medication.

Generalized epilepsy with febrile seizures plus

Generalized epilepsy with febrile seizures plus is caused by mutations to any of several different genes that affect two different ion channels. The syndrome causes various childhood-onset disorders, which can include febrile seizures, seizures without fever, partial epilepsy, myoclonic-astatic epilepsy, and severe myoclonic epilepsy in infancy.

Progressive myoclonus epilepsies (PMEs)

The progressive myoclonus epilepsies (PMEs) are a group of rare disorders in which there is progressive neurological deterioration together with myoclonus (twitching) and epilepsy. Several PMEs have autosomal recessive inheritance, including:

  • Unverricht-Lundborg disease, which is caused by a recessive gene on chromosome 21. The affected gene, cystatin B, is responsible for protecting cells from the protein-degrading enzymes they produce. This disorder is also known as Baltic Myoclonus. This disease first appears between the ages of six and 15 years. People with this condition have severe myoclonic twitches, often stimulated by movement, tapping, light, or sound, and may also have tonic-clonic seizures and deterioration in movement. The jerks may interfere with walking, swallowing, and speaking.
  • dentatorubral-pallidoluysian atrophy (DRPLA), which is caused by a recessive gene on chromosome 12. The PME form of this condition usually appears before age 30; affected people have muscle twitches, epilepsy, dementia, ataxia (difficulty walking), and choreoathetosis (involuntary movements).
  • Lafora’s disease (progressive myoclonus epilepsy with Lafora bodies), which is caused by a recessive gene on chromosome 6. Lafora’s disease appears to be a storage disorder and people with the syndrome have microscopic deposits called Lafora bodies in various tissues throughout the body. The disease usually appears between the ages of 14 and 16, beginning with convulsive seizures. Shortly afterwards, muscle jerks begin to appear; these become worse and worse until they are nearly constant. Finally, people with the condition develop rapidly progressive dementia. The disease has a poor prognosis; affected people usually die within a decade after the first symptoms appear.

Other single gene disorders that can manifest as epilepsy

Neurofibromatosis 1 (NF-1)

Neurofibromatosis 1 (NF-1) is a condition in which benign tumours called neurofibromas grow along nerves in the brain, skin, and other parts of the body. There are two forms of neurofibromatosis caused by two different gene mutations; NF-1 is caused by a mutation on chromosome 17. If tumours or neuronal migration abnormalities develop in the brain, seizures may result. Approximately 3% to 13% of people with NF-1 develop epilepsy. People with NF-1 are born with one mutated copy of the gene in each cell. This copy is either inherited from an affected parent or, in about half the cases, mutated during fetal development or in the egg or sperm. Almost everyone who is born with one NF-1 mutation then develops a second mutation in the other copy of the gene in certain cells.

Tuberous sclerosis

Tuberous sclerosis is a complex condition in which growths develop in the skin, brain, kidney, and heart. Approximately 80% of people with tuberous sclerosis develop epilepsy. Mutations in one of two genes, TSC1 on chromosome 9 and TSC2 on chromosome 16, have been pinpointed as the cause of tuberous sclerosis. About two-thirds of the mutations arise spontaneously. However, if one parent carries an affected gene, there is a 50% chance that a child will inherit it.

Fragile X syndrome 

Fragile X syndrome is caused by a gene mutation on the X chromosome. It causes mild to severe mental retardation, and approximately 20% to 40% of people with the condition will also develop epilepsy. If a father has fragile X syndrome, he will pass a milder form of the disorder to his daughters but will not pass it to his sons. If a mother has fragile X syndrome, her children have a 50% chance of inheriting it. The gene is often passed down in a milder form, so that families may be unaware that they carry it.

Rett syndrome 

Rett syndrome is caused, in most cases, by a newly discovered mutation on the X chromosome. In a few families, the syndrome is inherited in an X-linked dominant pattern. It was initially believed that Rett syndrome affects only girls; however, it has recently been found to occur rarely in boys as well. The disorder usually develops between one and two years of age. Children with the disorder have epilepsy in 70% to 80% of cases, together with other problems such as constant hand-wringing, difficulty walking, developmental delay, and autism.

Acute intermittent porphyria

Acute intermittent porphyria is a rare disease caused by a gene mutation in the HMBS gene on chromosome 11, which controls a step in the production of hemoglobin. The symptoms of the condition consist of severe attacks of abdominal pain, vomiting, digestive problems, and seizures. The attacks are triggered by factors such as certain drugs, smoking, dieting, other illnesses, and stress.

Leukodystrophies

Leukodystrophies are disorders affecting the production or maintenance of the fatty covering of nerves. As a result, signals travel more slowly than normal through the nervous system. This disrupts the functioning of the nervous system, which can sometimes include seizures. Leukodystrophies can be caused by mutations in many different genes; their inheritance pattern depends on which gene is affected. In some cases, the mutation arises spontaneously. More than 30 leukodystrophies have been identified.  Some specific leukodystrophies are Alexander disease, Canavan disease, and Krabbe disease.

Mucopolysaccharidoses

Mucopolysaccharidoses are disorders of the enzymes that break down molecules called glycosaminoglycans into smaller components, which are needed to build connective tissue. Over time, the glycosaminoglycans build up in the body and cause permanent damage to cells, bone, skeletal structure, and organs. There are many different mucopolysaccharidoses, caused by many different gene mutations. Most of the mucopolysaccharidoses follow an autosomal recessive inheritance pattern; in general, if both parents have a copy of the affected gene, each child has a 25% chance of developing the syndrome. Sanfilippo syndrome, one of the mucopolysaccharidoses, frequently causes seizures.

Other inherited metabolic conditions

A number of other inherited metabolic conditions may cause seizures, including:

  • aminoacidopathies such as phenylketonuria (PKU) and maple syrup urine disease
  • galactosemia
  • lysosomal lipid storage diseases such as Tay-Sachs disease
  • peroxisomal disorders
  • pseudohypoparathyroidism
  • pyridoxine dependency

Multifactorial disorders

A number of epilepsy syndromes are thought to be multifactorial or complex disorders, in which genetic and environmental factors both seem to play a part.

Myoclonic-astatic epilepsy 

Myoclonic-astatic epilepsy usually appears between two and five years of age, with a variety of seizure types. The relatives of affected children often have other forms of epilepsy or febrile seizures, suggesting a strong genetic component. It is possible that several different genes are involved, as well as other modifying factors.

Benign epilepsy of childhood with centrotemporal spikes (BECTS)

Benign epilepsy of childhood with centrotemporal spikes (BECTS), also known as benign rolandic epilepsy, is one of the most common childhood epilepsy syndromes. It usually begins between ages five and 10 years and disappears in adolescence.

Benign myoclonic epilepsy of infancy

Benign myoclonic epilepsy of infancy is a rare condition that usually affects children between six months and three years old. Children with the syndrome have brief myoclonic seizures that are usually easy to control with medication. In about 30% of cases, other family members also have some form of epilepsy or febrile convulsions.

Juvenile myoclonic epilepsy

Juvenile myoclonic epilepsy usually appears in adolescents between 12 and 18 years old. People with this syndrome have myoclonic jerks, usually in the shoulders and arms, upon awakening or shortly afterward. Half of patients with this condition have relatives with epilepsy. The genetic basis of this syndrome is complex and the mechanism of transmission is unclear. It is possible that several different genes are responsible.

Childhood absence epilepsy

Childhood absence epilepsy begins between four and 10 years old, and involves severe and frequent absence seizures. In up to 44% of cases, other family members also have epilepsy. Some researchers have found links to chromosome 1 or chromosome 8. However, it seems likely that other factors besides genetics are involved.

Juvenile absence epilepsy

Juvenile absence epilepsy is similar to childhood absence epilepsy, but usually begins later in life, between 10 and 17 years old. Some children with this syndrome have family members with epilepsy.

Mitochondrial disorders

Mitochondrial disorders occur when the mitochondria fail and are not able to produce the energy a cell or tissue needs. These disorders appear to cause most damage to the brain, heart, liver, skeletal muscles, and kidney, which are tissues with the highest demands for energy. Mitochondrial disorders most often present as muscle weakness with neurological problems; other symptoms include poor growth, heart failure due to cardiomyopathy, gastrointestinal disorders, liver disease, and diabetes.

Myoclonus epilepsy and ragged-red fibres (MERRF)

Myoclonus epilepsy and ragged-red fibres (MERRF) is a progressive myoclonus epilepsy that is caused by a mutation in the mitochondrial DNA. People with this syndrome manifest it in a wide variety of ways; some are unaffected, some develop epilepsy later in life, and others develop severe, progressive epilepsy with dementia as children. The mutation is passed from mother to child.

Chromosomal disorders

Chromosomal mutations, damage, or faulty duplication are at the root of conditions like Down syndrome, Wolf-Hirschhorn syndrome, Angelman syndrome, and ring chromosome abnormalities.

Down syndrome

Down syndrome is caused by an additional copy of chromosome 21. This means that instead of the normal pair of chromosomes, there are 3 copies. This is called a trisomy. Down syndrome is also referred to as Trisomy 21. A trisomy is caused by an error that occurs during cell division. Approximately 2% to 15% of people with Down syndrome develop epilepsy.

Other trisomies

Other trisomies that can result in epilepsy in 20% to 25% of cases are trisomy 18 (Edwards syndrome), trisomy 13 (Patau syndrome), and trisomy 22.

Wolf-Hirschhorn syndrome

Wolf-Hirschhorn syndrome occurs when part of chromosome 4 is deleted. About 70% of people with this condition have epilepsy.

Angelman syndrome

Angelman syndrome is caused by a deletion on one arm of the copy of chromosome 15 that came from the person’s mother. More than 80% of people with this condition develop seizures, usually by age three.

Ring chromosome abnormalities

Ring chromosome abnormalities are rare disorders that occur when both ends of a chromosome are damaged and the chromosome reforms in a ring shape. Ring chromosome abnormalities, including ring chromosomes 6, 9, 14, 15, and 20, account for 2% to 3% of cases of epilepsy, although not all people with these conditions have seizures.

How are specific genes involved in brain development?

Many genes have an effect on brain development. Changes in even one of these genes can affect how the brain functions.

Mutations in certain genes have been identified as causes of brain malformations, which can lead to epilepsy. For instance, an abnormality in the doublecortin gene, which normally signals where brain cells should be located, creates an extra brain layer, a “double cortex.” Similarly, an abnormality in the ARFGEF2 gene can lead to a condition called periventricular heterotopia, in which brain cells which belong in the cortex are located along the ventricles. Both of these malformations can lead to seizures.

Many other genes are associated with specific ion channels. Mutations in these genes affect the function of nerve cells at a molecular level. For example, researchers have identified mutations in three different genes that affect sodium channel function in different families with the epilepsy syndrome known as generalized epilepsy with febrile seizures plus. Mutations in genes that control potassium or calcium channels can also cause epilepsy.

Berge Minassian, MD, FRCPC

2/4/2010




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