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 giveexcessive anxiety to patients and their families and not to lead them to misunderstand the negative impact of the geneticfactor.
In some patients, family history reveals definite inheritance patterns (epilepsy syndrome) such as autosomal dominant andrecessive inheritance, or sex-linked inheritance. However, the inheritance pattern is undetermined in most of the patientswith 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 indescendants 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 casethat 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 nonfebrile 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)

138

Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 17-2

Current situation of genetic research and genetic testing forepilepsy
Summary
Various mutations have been identified in many epilepsy syndromes. However, genetic diagnosis has clinicalsignificance in only a few epilepsy syndromes. Identification of gene abnormalities leads to a definite diagnosis onlyfor 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 thefindings 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, evenwhen the genetic test result is negative, it does not exclude the possibility of having an unknown causative gene or a geneunidentifiable 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 NoAyumi. 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: applicationin 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)

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Table 1. Causative genes identified in various epilepsy syndromes.
Epilepsy syndrome
Benign familial neonatal seizures
Benign familial neonatal-infantileseizures
Benign infantile epilepsy
Ohtahara syndrome
Infantile spasms (atypical Rettsyndrome / West syndrome)
X-linked infantile spasms
Severe myoclonic epilepsy ofinfancy (Dravet syndrome)

Locus
20q13.3
8q24
2q23-q24.3

GeneKCNQ2
KCNQ3
SCN2A

Product
K V7.2(K channel)
K V7.3(K+ channel)
Na+ channel α2 subunit

16p11.2
9q34.1
Xp22.13
Xp22

PRRT2
STXBP1ARX
STK9/CDKL5

Proline-rich transmembrane protein 2
Syntaxin binding protein 1
Aristaless related homeobox
Cyclin-dependent kinase-like 5

Xp22.132q24
2q24.3
5q34-q35
9q34.1

Aristaless related homeobox
Na+ channel α1 subunit
GABA A receptor γ2 subunit
GABA A receptor α1 subunit
Chromodomain helicase DNA binding protein 2Syntaxin binding protein 1
Nav1.1(Na+ channel)
Na+ channel β1 subunit
GABA A receptor γ2 subunit
GABA A receptor δ subunit
Na+ channel α9 subunit
Syntaxin 1B
GABA A receptor γ2 subunit+

Genetic epilepsy with febrile
seizures plus (GEFS+)

2q24
19q13.1
5q34

Childhood absence epilepsy (withfebrile seizures plus)
PCDH19-related epilepsy limited
to females
Early-onset absence epilepsy(glucose transporter-1 deficiencysyndrome)
Juvenile myoclonic epilepsy

5q34

ARX
SCN1A
GABRG2GABRA1CHD2STXBP1SCN1ASCN1BGABRG2
GABRD
SCN9A
STX1B
GABRG2

Xq22

PCDH19Protocadherin 19

1p35-p31.1

SLC2A1GLUT1

5q34-q35
6p12-p11
20q13.2-q13.3
1q21
8p21
10q24

GABRA1EFHC1CHRNA4CHRNB2CHRNA2LGI1GABAA receptor α1 subunit
EF-hand domain-containing protein 1nACh receptor α4 subunitnACh receptor β2 subunitnACh receptor α2 subunit
Leucine rich glioma inactivated 110q22

KCNMA1

KCa1.1(K+ channel)

19p13

CACNA1A

Cav2.1(Ca 2+ channel)

12p13

KCNA1

Kv1.1(K+ channel)

1p21-23

ATP1A2

Sodium-potassium ATPase

15q11-13

Loss including
UBE3A
MECP2
FOXG1

(UBE3A)

Autosomal dominant nocturnal
frontal lobe epilepsy
Autosomal dominant lateral
temporal epilepsy (autosomal
dominant epilepsy with auditoryfeatures)
Generalized epilepsy andparoxysmal dyskinesia
Absence epilepsy and episodic
ataxia type 2
Focal epilepsy and episodic ataxia
type 1
Familial hemiplegic migraine andepilepsy
Angelman syndrome
Rett syndrome

Xp28
14q12

Methyl-CpG-binding protein-2
Forkhead box protein G1(Partially modified from: 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.)

140Part IThe Clinical Practice Guidelines for Epilepsy 2018

Table 2. Causative genes in progressive myoclonic epilepsy (PME).
Name of disease

Onset age(years)

Clinical symptoms

Locus

Gene

Neuronal ceroid lipofuscinosis (NCL)*
Infantile NCL0.5‒2Vision loss, microcephaly, epilepsy, regression

Late Infantile NCL)

2‒4Vision loss, epilepsy, myoclonus

Juvenile NCL

4‒10Vision loss, epilepsy

Adult NCL

12‒50

Epilepsy, ataxia, dementia

All ages

Myoclonus, cerebella ataxia, epilepsy

Dentatorubral-pallidoluysian atrophy(DRPLA)
Mitochondrial encephalomyopathy(MERRF)

Unverricht-Lundborg disease (ULD)

PME with K+ channel abnormality
Lafora disease

1p34.2
11p15.4
16p11.2
20q13.33
13q22.3
15q23
4q28.2
8p23.3
Not Mapped
11p15.5
17q21.31
11q13.2
7q11.21
12p13.31

5‒42
Short stature, hearing loss, cardiomyopathy mtDNA(mostly inmtDNAchildhood)
mtDNA
mtDNA
13q34
6‒16
Myoclonus, epilepsy, no or mild
21q22.3
intellectual disability
12q12
4q21.117q21.32
6‒149.5‒18

Resembling Unverricht-Lundborg disease
Epilepsy, myoclonus, regression

11p15.1
6q24.3
6p22.3

CNL1
CNL2
CNL3
CNL4
CNL5
CNL6
CNL7
CNL8
CNL9
CNL10
CNL11
CNL13
CNL14
ATN1
MT-TK
MT-TL1
MT-TF
MT-T1
CARS2
CSTB
PRICKLE1
SCARB2
GOSR2
KCNC1
EPM2A
EPM2B

* The loci and responsible genes for NCL are identified from all NCL, and does not correspond to each clinical subcategory.
(Partially modified from: Nakayama T. Molecular genetics of progressive myoclonic epilepsy. Igaku No Ayumi. 2015: 253(7); 584-588.)

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