Genetic factors play an important role in many types of epilepsy. Single gene mutations can cause monogenic forms of epilepsy, which are often inherited in an autosomal dominant or recessive pattern. These include mutations in ion channel genes like SCN1A, KCNQ2/3, GABRA1, and CLCN2. Non-ion channel gene mutations have also been linked to progressive myoclonic epilepsies. Chromosomal abnormalities, mitochondrial disorders, and inherited metabolic conditions additionally confer higher epilepsy risk. Environmental influences can also contribute to multifactorial, polygenic forms of epilepsy.

1. Genetic basis of
epilepsy
By Ahmed Abdelhady

2. 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.
• • 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.

3. What types of genetic disorders are there?
There are five types of genetic disorders:
• Single gene or Mendelian disorders (Monogenic). A single mutated gene is
sufficient to cause the phenotype. 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 (polygenic), 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.

4. • 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

5. SINGLE GENE MUTATION
(MONOGENIC)

6. Classification of Single gene mutation
(monogenic)
A-Ion channels implicated in human epilepsy
I. Autosomal dominant inheritance
1. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)
2. Benign familial neonatal convulsion (BFNC)
3. Generalized epilepsy with febrile seizures plus (GEFS+)
4. Juvenile myoclonic epilepsy (JME)
5. Autosomal dominant idiopathic generalized epilepsy

7. Classification of Single gene mutation
(monogenic)
II. Sporadic
1. Severe myoclonic epilepsy of infancy
III.Other ion channel gene implicated in epilepsy (mutation identified
in small number of patients, so role in epilepsy less clear)
1. Episodic ataxia type 1 and type 2

8. Classification of Single gene mutation
(monogenic)
• B- Single Non ion channel gene mutation implicated in epilepsy
1. Progressive myoclonic epilepsy (PME)
2. Autosomal dominant partial epilepsy with auditory features (ADPEAF)
• C- single gene mutation with high risk of developing epilepsy

9. Ion channels implicated in human epilepsy (AD)
• 1-Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)
• Feature:- characterized by childhood onset of clusters of sleep-related
seizures with predominant motor and dystonic features.
• Gene , locus and protein
CHRNA4 20q13 Ach receptor α4 subunit
CGRNB2 1q21 Ach receptor β2 subunit

10. The neuronal nicotinic acetylcholine receptors (nAChRs) (CHRNA4/CHRNB2) are pentamers, with each subunit containing four transmembrane
domains. At least ten nAChR subunits, which can assemble into heteromeric (α2–α6, β2–β4) or homomeric receptors ((α 7, (α 9), are expressed in the
human brain. The binding of two agonist molecules is required for channel opening. The channel itself shows little selectivity among monovalent cations

11. Ion channels implicated in human epilepsy (AD)
• 2- Benign familial neonatal convulsion (BFNC)
• Feature:- is a rare, highly penetrant, autosomal dominant disorder with short-lasting
multifocal or generalized seizures beginning between a few days of life and three
months of age. A few patients will manifest isolated seizures later in life.
• locus , Gene , and protein
• 20q13 KCNQ2 M-current potassium channel
• 8q24 KCNQ3 M-current potassium channel

12. Voltage-gated potassium channels (KCNQ2/KCNQ3) are tetramers made up from homologous subunits. Each subunit contains six transmembrane
domains. The fourth transmembrane domain carries several positively charged amino acids, which cause a conformational change on membrane
depolarization. The linker between transmembrane domains 5 and 6 contains the selectivity filter that lines the ion pore

13. Ion channels implicated in human epilepsy (AD)
• 3-Generalized epilepsy with febrile seizures plus (GEFS+)
• Feature:- GEFS+ encompasses a spectrum of childhood-onset epilepsy phenotypes including FS and
FS+ (when afebrile seizures occur and/or FS continue past age six years). Other less-common
phenotypes are FS+ with absence, myoclonic or atonic seizures, partial epilepsies, myoclonic astatic
epilepsy (MAE) and severe myoclonic epilepsy in infancy
• locus , Gene , and protein
• 2q24 SCN1A Voltage-gated sodium channel α1 subunit
19q13 SCN1B Voltage-gated sodium channel β1 subunit
2q23 SCN2A Voltage-gated sodium channel α2 subunit
5q31 GABRG2 GABAA receptor subunit (discuss in JME)

15. Voltage-gated sodium channels (SCN1A/SCN2A) are built from one α-subunit, which contains four tandem domains, each resembling the
structure of a voltage-gated potassium channel subunit. Sodium channels are associated with two accessory β subunits, which accelerate the
gating kinetics of the channel.

16. Ion channels implicated in human epilepsy (AD)
• 4-Juvenile myoclonic epilepsy (JME)
• Feature:- 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.
• locus , Gene , and protein
• 5q34-q35 GABRA1 GABA A receptor a1 subunit

18. The GABAA (γ-aminobutyric acid, subtype A) receptors (GABRG2/GABRA1) are ligand-gated ion channels that probably evolved from the same
ancient genes as the nAChRs, with whom they share several features, such as four transmembrane domains per subunit and a pentameric structure.
GABAA receptors are selective for small anions and allow both chloride and bicarbonate to permeate

19. Ion channels implicated in human epilepsy (AD)
5- autosomal dominant idiopathic generalized epilepsy
• locus , Gene , and protein
• 3q26 CLCN2 Chloride channels

20. Voltage-gated chloride channels of the CLCN type comprise a gene family with nine
mammalian members. They build homodimeric proteins, which probably contain two
separate pores. CLCN channels conduct chloride ions across cell membranes, governing the
electrical activity of cells.

21. Ion channels implicated in human epilepsy (sporadic)
1. Severe myoclonic epilepsy of infancy (Dravet’s syndrome)
• Feature:- Severe myoclonic epilepsy of infancy (SMEI) is an epileptic encephalopathy
beginning in infancy with prolonged clonic febrile and afebrile seizures and is
subsequently associated in most children with myoclonic, atypical absence and sometimes
focal seizures Sporadic SMEI has been associated with de novo SCN1A mutations in
30% of patients
• Gene , locus and protein
SCN1A 2q24 Sodium channel subunit

23. Voltage-gated sodium channels (SCN1A/SCN2A) are built from one α-subunit, which contains four tandem domains, each resembling the
structure of a voltage-gated potassium channel subunit. Sodium channels are associated with two accessory β subunits, which accelerate the
gating kinetics of the channel.

25. Other ion channel gene implicated in epilepsy (mutation identified in small number of
patients, so role in epilepsy less clear)
1- Episodic ataxia type 1 and 2 (EA1,2)
Gene , locus and protein
In EA1 KCNA1 12p13 Potassium channel subunit
In EA2 CACNA1A 19p13 Calcium channel subunit

26. Single Non ion channel gene mutation
implicated in epilepsy
1-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:
A- AD as
1. dentatorubral-pallidoluysian atrophy (DRPLA),
B- AR as
1. Unverricht-Lundborg disease
2. Sialidosis or cherry-red spot myoclonus
3. Lafora’s disease
4. Neuronal ceroid lipofuscinosis (NCL or Batten’s disease)

27. phenotype Mood of
inheritance
feature gene locus protein
dentatorubral-
pallidoluysian
atrophy
AD appears before age 30; affected
people have muscle twitches,
epilepsy, dementia, ataxia , and
choreoathetosis
CAG expansion in a gene on
12p13.31
Unverricht-
Lundborg disease
AR Usually presents in childhood
with stimulus sensitive and
spontaneous myoclonus, tonic-
clonic seizures, ataxia, and mild
cognitive decline
cystatin B
gene
21q22.3 protease
inhibitor
Sialidosis or cherry-
red spot myoclonus
AR Storage disese the sialidase gene on 6p21.3.

28. phenotype Mood of
inheritance
feature gene locus protein
Lafora’s disease AR Myoclonic epilepsy with onset in
the second decade, associated
with visual hallucinations and
cognitive decline. The
characteristic carbohydrate
accumulations (Lafora bodies)
EPM2A/
EPM2B
6q24 Laforin is
a tyrosine
phosphata
se
Neuronal ceroid
lipofuscinosis
(NCL or Batten’s
disease)
AR associated with early visual
impairment, cognitive decline,
and spasticity
1-palmitoyl-protein thioesterase gene
(1p32), causing either infantile or
juvenile-onset NCL
2- the tripeptidyl peptidase 1 gene
(11q15) and associated with late infantile
onset NCL
3- CLN3 gene on 16p associated with a
juvenile-onset form

29. Single Non ion channel gene mutation
implicated in epilepsy
2-Autosomal dominant partial epilepsy with auditory features (ADPEAF)
• Feature:- familial temporal lobe epilepsy (FTLE) includes mesial and lateral forms. The lateral
FTLE [autosomal dominant partial epilepsy with auditory features (ADPEAF)] begins in
childhood–adolescence with auditory hallucinations, alone or with other sensory (olfactory,
vertiginous, visual) symptoms. Mesial FTLE has childhood onset and seizures have mesial temporal
lobe auras, including de ´ja ` vu, perceptual changes or autonomic phenomena No loci have been
found.
• Gene , locus and protein
ADPEAF 10q24 LGI1 Leucine-rich glioma inactivated 1
Functional inactivation of one allele led to ADPEAF, whereas silencing of both alleles was observed
in several high-grade gliomas.

30. LGI1 is secreted from the presynapse and binds to postsynaptic ADAM22. Binding to ADAM22 results in altered
intracellular signalling in the postsynapse that decreases excitability, probably through subunit changes in
postsynaptic glutamate receptors. Mutations in LGI resulting in lack of ADAM22-mediated signalling therefore
result in a net increase in excitability.

31. Epitempin repeat in epilepsy-associated genes. The proteins encoded by both LGI1, the gene involved in autosomal
dominant lateral temporal lobe epilepsy, and the MASS1/VLGR1 gene, which is mutated in the Frings mouse model for
audiogenic seizures and in one family with febrile seizures, share the epitempin repeat. The MASS1/VLGR1 protein — one
of the largest membrane proteins and a member of the superfamily of seven-helix G-protein coupled receptors — contains
six complete and one degenerate copy of the epitempin repeat. MASS1/VLGR1 is expressed in the developing nervous
system rather than in the adult brain. Its overall structure shows homologies to large G protein coupled receptors from the
flamingo family, the latrophilins and the brain angiogenesis inhibitors. These receptors are mainly involved in neuronal
development. Furthermore, the leucine-rich repeat (LRR) domain subtype present in the LGI1 protein is also found in Slit, a
neurogenic protein involved in axonal guidance. It is therefore tempting to speculate that both MASS1/VLGR1 and LGI1
cause epilepsy by interference with normal brain development. aa, amino acid residues; TM, transmembrane domain

32. Other single gene disorders that can manifest
as epilepsy
• Tuberous sclerosis
• Tuberous sclerosis (TS) is a frequent cause of malignant childhood epilepsy, in particular
West syndrome (hypsarrhythmia, mental retardation, and infantile spasms). Approximately
half of patients with TS are familial cases, and the other half are sporadic. TS is caused by
dominant mutations of one or other of two tumour suppressor genes (TSC1 and TSC2
located on 9q34 and 16p13.3, respectively) Approximately 80% of people with tuberous
sclerosis develop epilepsy
• Neurofibromatosis 1 (NF-1)
• Approximately 3% to 13% of people with NF-1 develop epilepsy, although with a far better
prognosis than TS.

33. .
Fragile X syndrome
Fragile X syndrome is caused by a gene mutation on the X chromosome. It causes mild
to severe intellectual disability, 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.

35. 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 disability 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.

37. 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.

38. inherited metabolic conditions
A number of 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

39. Multifactorial disorders

40. 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.
• Among epilepsies with complex inheritance, IGEs seem very suitable for genetic
studies because they are common. BUT the unknown mode of inheritance, the
heterogeneity of the epilepsy phenotypes, the uncertainty of the genetic overlapping
of IGE sub-syndromes and the lack of large families are major obstacles to the
study of the genetic architecture of IGE

41. 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
myoclonicseizures 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.

42. 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.

43. Mitochondrial disorders

44. Mitochondrial disorders
• Myoclonus epilepsy and ragged-red fibres (MERRF)
Myoclonus epilepsy and ragged-red fibres (MERRF) is a progressive myoclonus
epilepsy that is caused by missense mutations in the mitochondrial gene coding
for lysine tRNA. 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.

45. Chromosomal disorders

46. Chromosomal disorders
1- 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.

47. 2- Wolf-Hirschhorn syndrome
Wolf-Hirschhorn syndrome occurs when part of chromosome 4 is deleted.
About 70% of people with this condition have epilepsy.

48. 3- 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.

49. 4- 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.