Chapter 17
Epilepsy and Genetics
CQ 17-1
Relation between epilepsy and genetics
Summary
When a parent has epilepsy, the frequency of the patient’s children developing epilepsy is 4–6%, which is 2–3 times higher than that in the general population. However, the frequency varies depending on the cause of epilepsy. There is no clear pattern of inheritance for epilepsy in general.
Comment
The genetic factor plays a small role in the pathogenesis of epilepsy in general1). Therefore, we should take care not to give excessive anxiety to patients and their families and not to lead them to misunderstand the negative impact of the genetic factor.
In some patients, family history reveals definite inheritance patterns (epilepsy syndrome) such as autosomal dominant and recessive inheritance, or sex-linked inheritance. However, the inheritance pattern is undetermined in most of the patients with epilepsy. The familial prevalence and the rate of EEG abnormalities differ even for the same epilepsy syndrome, suggesting multifactorial inheritance pattern involving many overlapping factors. The incidence rate of epilepsy in descendants of the patients is 6%, which is clearly higher than the incidence for people aged up to 20 years in the general population (1‒2%). When the mother has epilepsy or when one of the parents has absence seizures, the incidence rate is further increased to 8–9%2). In addition, epilepsy occurs relatively frequently in siblings of patients with epilepsy. In the case that the onset age of the proband is under 15 years, the incidence rate of epilepsy in siblings by 20 years of age is 3‒5%2). Moreover, the incidence rate increases to 5‒15% in the proband’s siblings when the EEG of the proband shows generalized spike-and-wave complex, or when the proband’s parent is (or both parents are) affected by epilepsy2).
Regarding febrile convulsion, while the prevalence in children is 7‒11% (4% in other countries), the prevalence increases to 20‒25% in siblings of patients with febrile convulsion. Also, children with febrile convulsion will eventually have non-febrile convulsion (epilepsy) at a higher rate when their parents are affected by epilepsy3, 4).
▪ References
1) Genetics Commission of International League Against Epilepsy. Things you want to know. https://www.ilae.org/files/dmfile/GeneticsPamphlet-2013.pdf
2) Hauser WA, Hesdorffer DC. Facts about epilepsy. New York: Demos press, 1999. p.1-16.
3) Granstrom ML, Gaily E, Beck-Mannagetta G. Febrile convulsions, epileptic seizures and EEG abnormalities in offspring of epileptic mothers. In: Beck-Mannagetta G, Anderson VE, Doose H, Janz D eds. Genetics of epilepsies, Berlin: Springer-Verlag, 1989. p.137-141.
4) Clinical Practice Guideline for Febrile Convulsion Development Committee (ed.), The Japanese Society of Child Neurology (supervision). Clinical Practice Guideline for Febrile Convulsion 2015. Tokyo: Shindan To Chiryou Sha, Inc. 2015 (in Japanese).
▪ Search formula and secondary sources for reference
PubMed search: June 28, 2015
No. of references 63 “epilepsy/genetics [majr] AND heredity [mesh] Sort by: Relevance Filters: Publication date from 2008/01/01 to 2015/12/31; Humans; English; Japanese”
Ichushi search: June 28, 2015
No. of references 100, ((epilepsy/MTH) and ((genetic test/TH or genetic test/AL))) and (PT = excluding proceedings)
CQ 17-2
Current situation of genetic research and genetic testing for epilepsy
Summary
Various mutations have been identified in many epilepsy syndromes. However, genetic diagnosis has clinical significance in only a few epilepsy syndromes. Identification of gene abnormalities leads to a definite diagnosis only for progressive myoclonic epilepsy, Angelman syndrome, Rett syndrome, and Dravet syndrome.
Comment
The causative genetic abnormalities for various epilepsy syndromes are shown in Table 11, 2), and those for progressive myoclonic epilepsy (PME) are shown in Table 23). When Dravet syndrome is suspected, gene testing is useful because the findings from the SCN1A genetic test may help us determine the treatment strategy and provide genetic counseling at an earlier stage than when diagnosis is obtained from only clinical symptoms4).
On the other hand, based on the current knowledge about genetic research on epilepsy, genetic results cannot accurately predict the prognosis (for example, patients with the same SCN1A mutation may have different phenotypes). Moreover, even when the genetic test result is negative, it does not exclude the possibility of having an unknown causative gene or a gene unidentifiable by conventional sequence analyses such as copy-number polymorphisms. It should be noted that genetic tests have only limited usefulness for exclusion diagnosis.
Furthermore, many genetic tests are not covered by medical insurance at present, making it difficult to be used as a routine test in the clinical practice.
▪ References
1) Ottman R, Hirose S, Jain S, et al. Genetic testing in the epilepsies—report of the ILAE Genetics Commission. Epilepsia. 2010; 51(4): 655-670.
2) Ishii A. Molecular genetics of Dravet syndrome and GEFS+ : The spectrum of epilepsies caused by mutations of SCN1A and other genes. Igaku No Ayumi. 2015: 253(7); 561-567 (in Japanese).
3) Nakayama T. Molecular genetics of progressive myoclonic epilepsy. Igaku No Ayumi. 2015: 253(7); 584-588 (in Japanese).
4) Hirose S, Scheffer IE, Marini C, et al. Genetics Commission of the International League Against Epilepsy. SCN1A testing for epilepsy: application in clinical practice. Epilepsia. 2013; 54(5): 946-952.
▪ Search formula and secondary sources for reference
PubMed search: June 28, 2015
No. of references: 21, “epilepsy/genetics [majr] AND genes [mesh] Filters: Review; Publication date from 2008/01/01 to 2015/12/31; Humans; English; Japanese”
Ichushi search: June 28, 2015
No. of references: 27, ((epilepsy/MTH) and ((gene/TH or gene/AL))) and (PT = review)
Table 1. Causative genes identified in various epilepsy syndromes.
Table 2. Causative genes in progressive myoclonic epilepsy (PME).
