Genetic Influences on Epilepsy

A hereditary component in the susceptibility to epilepsy has been suspected for many years, but only in the last few decades has progress been made in identification of specific genetic influences on epilepsy. Success has been hampered by methodological limitations, the multifactorial etiologies of epilepsy and the many different genetic factors involved.

Most forms of epilepsy are inconsistent with a simple Mendelian model of inheritance, and the degree of interaction between genetic and environmental factors is unclear. There is a higher risk for women with epilepsy to have children with seizures than for men with epilepsy. Consequently women with epilepsy and their physicians may have to deal with the complex issue of genetic influences on epilepsy.

Classification of Seizure Disorders

• Epilepsy: defined as recurrent (>2) unprovoked seizures. Unprovoked seizures occur in the absence of any immediate precipitating event, although injury to the central nervous system (CNS) may have occurred at some time in the past.
• Acute symptomatic seizures: seizures which only occur in association with acute structural, infectious, or metabolic insults to the CNS (the largest group in this category is febrile convulsions).
• Isolated unprovoked seizures: occurrence of a single unprovoked seizure.

Clinical Classification of Epilepsy

• By seizure type: includes generalized onset seizures (thought to involve the entire cerebral cortex from the outset) and partial onset seizures (which begin in a localized brain region).
• By epilepsy syndrome: includes information on seizure type, etiology, age at onset, clinical course, and electroencephalographic features. Results in identification as generalized epilepsies and localization-related (partial or focal) epilepsies.

Etiologic Classification of the Epilepsies

• Symptomatic: secondary to a previous CNS injury such as head trauma, stroke or infection.
• Idiopathic: unidentified cause, but presumed to be genetic in origin.
• Cryptogenic: presumed to be nongenetic, but cause unidentified.

Some researchers use combined term "idiopathic/cryptogenic" since etiologic factors in either category are often unclear and the specific genetic influence is largely unknown.

Significant Findings for Women with Epilepsy

• Early studies showed an increased risk of epilepsy in relatives of affected persons (probands), i.e., family aggregation, compared to the risk in the general population. Although this was a suggestive finding, it was not conclusive for a genetic etiology for epilepsy. Other explanations include common exposures to environmental factors or shared familial behavior patterns, in addition to genetic susceptibility.
• Other evidence more clearly supports a genetic basis for familial aggregation:
  1. higher concordance rate in monozygotic twins than in dizygotic twins.
  2. the association of Mendelian disorders with seizures (although these account for only a small proportion of epilepsy, ~ 1 percent, they illustrate that genetic mechanisms can raise susceptibility to seizures).
  3. identification of genes in experimental animals that raise seizure susceptibility.
  4. use of genetic linkage analysis to localize human epilepsy susceptibility genes to specific chromosomal regions (currently limited to a small number of epilepsy syndromes).
  5. identification of the causative genes in some of the above syndromes.
• The risk of epilepsy in relatives of probands with identified postnatal CNS injury is similar to that in the general population, thus suggesting that genetic influences on postnatal symptomatic epilepsy are minimal.
• Risks of epilepsy to children of women with epilepsy are approximately twice as high as that of children of men with epilepsy. This finding is not consistent with any conventional genetic model, including X-linkage (risks are about the same in sons and daughters of affected women). Also, research indicates that the finding cannot be explained by 1) intrauterine exposure to seizures or anti-epileptic drugs (AEDs) by children of women with epilepsy, 2) perinatal complications, although these occur with higher frequency in women with epilepsy, or 3) selective fertility patterns resulting in a higher proportion of mothers than fathers with familial forms of epilepsy. The cause for this increased risk is unknown.
• Relatives of probands whose epilepsy had early age onset (< 20 years) have a higher seizure risk than those whose epilepsy occurred at a later age (9 percent vs. 3 percent).
• Genetic influences seem to be somewhat greater for probands with generalized epilepsies as compared to localization-related epilepsies. However, recent studies have shown this difference to be less than previously recognized. The risk for having a child with epilepsy seems to be greater for probands with absence seizures than for probands with other forms of generalized epilepsy or partial epilepsy.
• Some studies suggest the possibility of a shared genetic susceptibility to epilepsy and cerebral palsy. There appears to be an increased risk of idiopathic/cryptogenic epilepsy in relatives of probands with epilepsy associated with cerebral palsy, and the converse also appears to be true. The risk of epilepsy associated with cerebral palsy was increased in the relatives of probands with idiopathic/cryptogenic epilepsy.

Therapeutic Interventions

• Ideally, implications of genetic influences on a specific type of epilepsy should be discussed by a woman with epilepsy and her physician prior to becoming pregnant.
• It is encouraging to recognize that even for patients in the highest risk groups (women with epilepsy, probands with absence seizures, or individuals with early age onset), the risk that an offspring will develop epilepsy is less than 10 percent.
• In addition to genetic counseling, it is important for physicians to discuss with women with epilepsy the potential adverse effects of AEDs on the developing fetus. See also Antiepileptic Drug Use in Women with Epilepsy and Epilepsy and Pregnancy.
  

CONTACT

For additional information, contact the Women and Epilepsy Initiative of the Epilepsy Foundation at (800) 332-4050.

REFERENCES

Bates L, Gardiner M. Genetics of inherited epilepsies. Epileptic Disorders. 1999;1(1):7-19

Buchhalter, JR. Genetics of epilepsy. In: Genetics in Neurology. Boston: American Academy of Neurology 49th Annual Meeting; 1997;244: 47-53.

Ottman R. Family studies. In: Engel J, Pedley TA, eds. Epilepsy. Philadelphia: Lippincott-Raven Publishers; 1997:177-183

Ottman R. Genetic epidemiology of epilepsy. Epidemiologic Reviews. Johns Hopkins University School of Hygiene and Public Health; 1997; 19(1):120-126

Ottman R, Lee JH, Risch N, Hauser WA, Susser M. Clinical indicators of genetic susceptibility to epilepsy. Epilepsia. 1996;37 (4):353-361.