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GENETIC MECHANISMS THAT
UNDERLIE EPILEPSY
Ortrud K. Steinlein
Genetic factors can cause recurrent abnormal synchronization and episodic hyperexcitability of
neuronal networks through various mechanisms. Many of the genes that have been implicated in
idiopathic epilepsies code for ion channels, whereas syndromes with epilepsy as a main feature
are caused by genes that are involved in functions as diverse as cortical development,
mitochondrial function and cell metabolism. Each ‘epilepsy gene’ that is identified provides new
and fascinating insights into the molecular basis of neuronal excitability and brain function.
ABSENCE EPILEPSY
A non-convulsive form of
epilepsy that is characterized by
a sudden, brief impairment of
consciousness.
MYOCLONUS
Brief, involuntary twitching of a
muscle or a group of muscles.
Familiar examples of normal
myoclonus include hiccups and
jerks experienced when drifting
off to sleep.
FRAGILE X SYNDROME
A genetic condition, commonly
transmitted from mother to son,
that is associated with mental
retardation, abnormal facial
features and enlarged testicles.
Institute of Human Genetics,
Friedrich-WilhelmsUniversity Bonn,
School of Medicine,
Wilhelmstrasse 31,
53111 Bonn, Germany.
e-mail:
[email protected]
doi:10.1038/nrn1388
400
Epilepsies are characterized by recurrent seizures,
which can cause motor, sensory, cognitive, psychic or
autonomic disturbances. The seizures themselves are
the clinical manifestation of an underlying transient
abnormality of cortical neuronal activity, and the phenotypic expression of each seizure is determined by the
point of origin of the hyperexcitability and its degree of
spread in the brain. By convention, the diagnosis
of epilepsy requires that the patient has had at least two
unprovoked seizures. The seizures, which can last
between a few seconds and a few minutes, can either be
isolated or occur in series.
Although its most basic manifestation starts at the
single neuron level, epilepsy is fundamentally a circuit
phenomenon, and seizures are only possible because the
brain is organized in a series of interconnected neuronal
networks. The initially localized hyperexcitability
spreads into surrounding neuronal networks, where it
might be either counterbalanced by inhibitory mechanisms, or, after involving more and more neurons,
cause a clinically visible seizure. A related but different
mechanism is found in absence seizures, where abnormal synchronization of the thalamocortical network,
rather than an excessive recruitment of neurons, causes
the seizures. Recurrent seizures can lead to permanent
alterations of neuronal networks, paving the way for
future seizures.
The causes of sporadic or recurrent seizures are
numerous, and they include acquired structural brain
damage, altered metabolic states and inborn brain malformations. However, about 1% of all people develop
| MAY 2004 | VOLUME 5
recurrent unprovoked seizures for no obvious reason
and without any other neurological abnormalities.
These are named ‘idiopathic epilepsies’, and they are
assumed to be mainly genetic in origin. In some cases,
the genetic point of origin has already been shown by
successful cloning of the mutated gene1–15, but for most
idiopathic epilepsies, especially the common forms like
juvenile myoclonic epilepsy, or childhood and juvenile
ABSENCE EPILEPSY, the genes that are involved in epileptogenesis remain unknown. In addition to the large
group of idiopathic epilepsies, more than 200 single
gene disorders are known in which epilepsy is a more
or less important part of the phenotype. These include
syndromes as diverse as neurodegenerative disorders
from the group of progressive MYOCLONUS epilepsies,
mental retardation syndromes like FRAGILE X SYNDROME or
ANGELMAN’S SYNDROME, neuronal migration disorders
or mitochondrial encephalomyopathies.
Modes of inheritance for epilepsies
All possible modes of inheritance are found in epilepsies,
including AUTOSOMAL, X-chromosomal, mitochondrial
and complex inheritance. Autosomal recessive inheritance is a common finding in epilepsies with an early age
of onset and a progressive course. A recessive allele that
causes early disablement or death in a homozygous state
can be passed through the generations by healthy carriers. Monogenic idiopathic epilepsies, with their mostly
benign course, are usually of autosomal dominant inheritance. Under a strict model of autosomal dominance,
the mutant alleles of these genes should be expected to
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Box 1 | Modes of inheritance
Monogenic: a single mutated gene is sufficient to cause the phenotype.
Major gene effect: a highly penetrant mutation, which becames phenotypically manifest
only if the genetic background of the patient provides additional minor mutations in
other genes.
Oligogenic: the phenotype is caused by mutations in a few genes.
Polygenic: mutations in several genes are needed to generate the phenotype.
The number of genes involved in different idiopathic epilepsies determines the mode of
inheritance that underlies each syndrome. Epilepsies with oligogenic or polygenic
inheritance are much more common than monogenic forms. The impact of any given
mutation on the phenotype is determined by the effect the mutation has on the function
of the gene, the importance of the gene for normal brain function and the existence of
parallel pathways that might be able to compensate the defect. The impact of mutations
is further modified by environmental factors, epigenetic effects and the genetic
background of the patient.
cause epilepsy in each of their carriers. However, family
studies show that the penetrance of these mutations is
often less than 100%, and that the age of onset, as well as
the severity of the phenotype, varies within families16,17.
This indicates that the clinical expression of genes that
have been implicated in epilepsy can be modified by
additional genes that have yet to be identified, and possibly by environmental factors. Monogenic epilepsies, and
those with a more complex mode of inheritance, cannot
be distinguished on the basis of their clinical features.
One example of an idiopathic epilepsy with more than
one possible form of inheritance is the syndrome of
generalized epilepsy with febrile seizures plus (GEFS+),
which is discussed below18. The spectrum of possible
inheritance models in the common forms of idiopathic
epilepsy extends from major gene effects, through
oligogenic inheritance, to polygenic models (BOX 1). In the
common forms of idiopathic epilepsies, the involvement
of different genes probably explains why several epilepsy
subtypes can occur within the same family or even the
same patient.
the coming years. The channels that are involved in idiopathic epilepsy belong to either the class of voltage-gated
ion channels, which are important for action potential
generation and control, or the class of ligand-gated ion
channels, which are mainly involved in synaptic transmission. Mutations in voltage-gated potassium, sodium and
chloride channels, as well as in ligand-gated acetylcholine
and GABAA (γ-aminobutyric acid, subunit A) receptors,
are known to cause different forms of idiopathic
epilepsy1–15 (FIG. 2, TABLE 1). So far, most of the mutations
have been found in families with rare epilepsies that
follow monogenetic inheritance patterns, but ion channels are probably involved in the more common forms of
idiopathic epilepsy too.
Ion channels are directly linked to membrane
excitability and to neurotransmitter release, and have
been found to be responsible for various other inherited
paroxysmal disorders, like hyper- and hypokalaemic
periodic paralysis, PARAMYOTONIA CONGENITA, episodic
ataxia and familial hemiplegic migraine19. The normal
functioning of the cortex relies on a finely tuned balance
between excitatory and inhibitory input, so any disturbance of this balance carries with it the possibility of
uncontrolled hyperexcitability. Seizures can be induced
either by the enhancement of excitatory stimuli or by
impairment of inhibitory mechanisms. For example,
inhibitory input can be disturbed directly by a mutated
GABAA receptor, or indirectly by a mutation in a
voltage-gated chloride channel that normally provides
the chloride-efflux pathway, which is important for the
inhibitory GABAA response9,10,15. A loss-of-function
mutation in a voltage-gated sodium channel accessory
β-subunit decreases the channel’s rate of inactivation
Normal
nAChR
GABAA
SCN
K+ Ca2+
Na+
Cl–
Na+
Neuronal excitability and communication
ANGELMAN’S SYNDROME
A genetic disorder that is caused
by deletion or disruption of
UBE3A (E6-AP). The symptoms
of Angelman’s syndrome include
hyperactivity, ataxia, problems
with speech and language, and
an unusually happy demeanour.
AUTOSOMAL
A term that refers to any
chromosome in a cell that is not
a sex chromosome.
PARAMYOTONIA CONGENITA
A rare autosomal dominant
disorder in which muscle fibres
are slow to relax after
contraction.
The excitability of neurons and their communications
with each other depend on the action of various
ion channels. The main structural feature that all ion
channels share is the transmembrane pore, which shows
distinct ion selectivity in different channel subtypes. The
channel pore not only controls the type of ion that
passes through it, but also the direction of ion flow (FIG. 1).
Ion channels can rapidly alter the permeability of the
membrane for certain ions, and this might, for example,
change the resting potential to an action potential, or
vice versa. It is therefore not surprising that ion channels
have a key role in various disorders that are associated
with hyper- or hypoexcitability of the affected tissue.
Idiopathic epilepsies as channelopathies
Idiopathic epilepsies are caused predominantly by
mutations in genes that code for ion channels or their
accessory subunits. So far, mutations in ten different ion
channel subunit genes have been found in human idiopathic epilepsies, and this number is set to increase in
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K+ Ca2+
Na+
Cl–
KCNQ
CLC
K+
Cl–
K+
Cl–
LOF
GOF
Na+
Mutant
Type of
mutation: GOF
LOF
LOF
Figure 1 | Gain- and loss-of-function in mutated ion
channels. Simplified model demonstrating gain-of-function
(GOF) and loss-of-function (LOF) effects caused by mutations
in various channels that are associated with idiopathic
epilepsy. From left to right: neuronal nicotinic acetylcholine
receptor (nAChR) (genes: CHRNA4 and CHRNB2), GABAA
(γ-aminobutyric acid, subtype A) receptor (genes: GABRG2
and GABRA1), voltage-gated sodium channel (SCN) (genes:
SCN1A, SCN2A and SCN1B), voltage-gated potassium
channel (KCNQ) (genes: KCNQ2 and KCNQ3) and voltagegated chloride channel (CLC) (gene: CLCN2). For each
channel, the model presents only one of several possible
pathogenetic mechanisms. The main ion currents are
indicated by arrows.
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and causes hyperexcitability by increasing the transmembrane sodium influx6. Mutations in specific
subtypes of potassium channels that are responsible for
membrane repolarization lead to prolonged neuronal
depolarization and therefore to spontaneous series of
action potentials3–5 (FIG. 1).
a CHRNA4/CHRNB2
b GABRG2/GABRA1
N
N
C
C
1
2
3
1
4
2
3
4
c SCN1A/SCN2A
1 2 3 4 5 P 6
1 2 3 4 5 P 6
1 2 3 4 5 P 6
1 2 3 4 5 P 6
N
C
d KCNQ2/KCNQ3
e CLCN2
4
1
2
3
4
5
6
1 2 3
5 6 7 8
9–12
N
N
13
C
C
Figure 2 | Subunit structures of ion channels involved in epileptogenesis. a | 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 (α7, α9), 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. b | 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. c | 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. d | 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. e | 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.
402
| MAY 2004 | VOLUME 5
These examples demonstrate that mutated channels
can cause neuronal hyperexcitability through numerous
pathogenic mechanisms. In the following sections,
some of the idiopathic epilepsies that are caused by
mutated ion channels will be discussed in more detail.
Familial nocturnal frontal lobe epilepsy. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a rare
partial epilepsy that is characterized by clusters of brief
motor seizures, which occur mostly during non-REM
(rapid eye movement) sleep. ADNFLE shows considerable intrafamilial variation in terms of age of onset and
severity. The motor features consist of thrashing hyperkinetic activity or tonic stiffening with superimposed
clonic jerking. Secondary generalization with loss of consciousness can occur, but most patients remain conscious
throughout their seizures20.
In most ADNFLE families, the pathway that finally
leads to partial seizures starts with a mutation in either
the α4-subunit (CHRNA4) or the β2-subunit (CHRNB2)
gene of the neuronal nicotinic acetylcholine receptor
(nAChR)1,2. The nAChRs, like glycine, GABAA and
serotonin receptors, are part of the superfamily of
homo- and heteropentameric ligand-gated ion channels.
One of the most common nAChRs in the mammalian
brain assembles from α4- and β2-subunits, so it was not
surprising to discover that both subunits are associated
with the same type of epilepsy. However, it was surprising to find that a nAChR subtype that is ubiquitously
present in the brain causes a partial type of epilepsy
instead of a generalized one, and the reasons for this
phenomenon are poorly understood.
The first CHRNA4 mutation — a S248F amino-acid
exchange within the second transmembrane region —
was identified in 1995 (REF. 1). This was followed by
several other descriptions of new mutations, either in
CHRNA4 or in CHRNB2 (REFS 2,21–24). All of the known
ADNFLE mutations are located within or close to the
second or third transmembrane domain. Both transmembrane domains contribute to the walls of the ion
channel, so it seems that only mutations that have a
direct effect on the ion pore can cause ADNFLE.
Reconstitution experiments in Xenopus laevis oocytes or
human embryonic kidney (HEK) cells and PATCH CLAMP
characterization of the known ADNFLE mutations
revealed different electrophysiological and pharmacological profiles. Some mutations (α4S248F, α4776ins3)
led to a reduction in calcium permeability, whereas other
mutations (α4S252L) did not change the ionic selectivity
of the channel. An increase in receptor desensitization
was seen for only one of the known ADNFLE mutations
(α4S248F). Furthermore, mutations α4S248F, α4776ins3
and β2V287M were effectively blocked by the
anti-epileptic drug carbamazepine, whereas the drug
response that was observed for some of the other
mutants did not differ from that seen for the wild-type
receptor25. These different functional properties might
explain why some of the nAChR mutations seem to be
associated with specific clinical features. For example,
carriers of the α4776ins3 mutation are often affected
by psychiatric disorders, whereas families with the
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Table 1 | Some of the genes that are involved in epilepsy
Subtypes
Gene symbol
Phenotype
Ion channel genes in idiopathic epilepsy
Nicotinic acetylcholine receptors
CHRNA4/CHRNB2
ADNFLE
Potassium channels
KCNQ2/KCNQ3
BFNC
Sodium channels
SCN1A/SCN2A/SCN1B
GEFS+
Chloride channels
CLCN2
IGE
GABAA receptors
GABRG2/GABRA1
GEFS+/IGE
Non-ion channel genes in idiopathic epilepsy
Function unknown
LGI1
ADLTE
G-protein coupled receptors
MASS1/VLGR1
FS
Polyglucosan metabolism
EPM2A/EPM2B(NHLRC1)
Lafora disease
Cysteine protease inhibition
CSTB
Unverricht–
Lundborg disease
Respiratory chain
MTTK/MTTL1
MERRF
Lipidoses
PPT
Infantile NCL
CLN2
Late infantile NCL
CLN3
Juvenile NCL
CLN5
Late infantile NCL,
Finnish variant
CLN6
Late infantile NCL,
Indian variant
CLN8
Northern epilepsy
NEU1
Sialidosis
metabolism
Progressive myoclonus epilepsies
Glycopeptide/oligosaccharide
ADLTE, autosomal dominant lateral temporal lobe epilepsy; ADNFLE, autosomal dominant
nocturnal frontal lobe epilepsy; BFNC, benign familial neonatal convulsions; FS, febrile seizures;
GEFS+, generalized epilepsy with febrile seizures plus; IGE, idiopathic generalized epilepsies;
MERRF, myoclonic epilepsy with ragged red fibres; NCL, neuronal ceroid lipofuscinosis.
α4Ser252Leu mutation might have an increased risk for
mental retardation26,27. The one characteristic that all
mutations have in common is that they increase the
acetylcholine sensitivity of nAChRs, indicating that a
gain-of-function effect underlies this type of epilepsy.
The mechanism by which the increased ACh sensitivity
results in seizures is still speculative, but one attractive
hypothesis is that the mutated nAChR alters the activity
level of the thalamocortical loop in favour of oscillation
by reinforcing the input from the thalamus25 (FIG. 3).
PATCH CLAMP
Technique whereby a very small
electrode tip is sealed onto a
patch of cell membrane, making
it possible to record the flow of
current through individual ion
channels or pores within the
patch.
MISSENSE MUTATION
A mutation that results in the
substitution of an amino acid in
a protein.
Benign familial neonatal convulsions. The syndrome of
benign familial neonatal convulsions (BFNC) — a rare
autosomal, dominantly inherited epilepsy of the newborn
— is characterized by unprovoked, generalized or multifocal seizures, typically starting within the first few days of
life. The course of the disorder is usually benign and selflimiting, and, with or without pharmacotherapy, the
seizures remit spontaneously within a few weeks or
months28,29. Later seizures might occur in up to 15% of
the patients, but they tend to occur infrequently. Recently,
several patients with BFNC have been described in which
the seizures did not respond well to anti-epileptic drugs
and resulted in delayed development or psychomotor
retardation30. It remains unclear whether these patients
have a second unrecognized condition, or whether certain
risk factors in combination with the BFNC mutation are
responsible for the unfavourable outcome.
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BFNC can be caused by mutations in the voltagegated potassium channel genes KCNQ2 or KCNQ3
(located on chromosome 20q13.3 and 8q24, respectively)3–5. The KCNQ2 and -3 genes encode subunits of
the M-channel, a very slowly opening and closing potassium channel that is found ubiquitously in the brain31.
The M-channel, which was first discovered some 20 years
ago32, is a powerful controller of neuronal repetitive firing.
It regulates the number of action potentials of individual
neurons by opposing sustained membrane depolarization. All but two of the known BFNC mutations have
been found in KCNQ2. Most of these mutations are truncating and are located in the large carboxy (C)-terminal
portion that lies downstream of the six transmembrane
domains. However, several MISSENSE MUTATIONS within
the transmembrane domains have also been described.
Most BFNC mutations cause only modest reductions
(20–30%) in potassium currents in reconstitution experiments, indicating that even a slight alteration of
M-channel activity is sufficient to cause epilepsy3. An
exception to this haploinsufficiency concept is the
KCNQ2/R207W mutation, which neutralizes a charged
amino-acid residue within the channel’s voltage sensor in
transmembrane domain 4. This mutation causes a more
severe change in potassium channel properties by drastically slowing the voltage-dependent activation. At the
clinical level, this results not only in BFNC, but also in
myokymia — a spontaneous and repetitive involuntary
contraction of muscle fibre groups33.
In mice, Kcnq2 knockout experiments resulted in early
post-natal lethality in homozygous animals, whereas
heterozygous mice developed and behaved normally but
showed an increased sensitivity to the chemoconvulsant
pentylenetetrazole34. Nevertheless, they did not develop
spontaneous seizures, which might indicate that Kcnq2 is
not as important for M-channel function in the mouse
brain as it is in humans.
Recent studies have shown that dominantly inherited
idiopathic early life seizures can also be caused by mutations in a gene that does not code for the M-channel. Two
families with seizures starting within the first 3.5 months
of life were found to have mutations in the voltage-gated
sodium channel subunit SCN2A, which has also been
implicated in GEFS+ (REF. 12). These findings once more
highlight the complex genotype–phenotype relationships
in idiopathic epilepsies.
Generalized epilepsy with febrile seizures plus. A wide
spectrum of epilepsy phenotypes can be present in families with GEFS+. Some of the more common phenotypes
are febrile seizures, febrile seizures plus (FS+ — attacks
with fever that continue beyond 6 years of age, sometimes
interspersed with afebrile seizures), FS+ and absence
seizures, FS+ and myoclonic seizures, and FS+ and atonic
seizures or myoclonic-astatic epilepsy18.
The mode of inheritance that underlies GEFS+ is still a
matter for debate. In some families, the trait seems to be
autosomal dominant, but in others it is probably better
described as oligogenic or as a major gene effect.A genetic
concept involving more than one gene would also
be more consistent with the clinical variability that is
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a
b
Cortex
Cortex
Cholinergic
fibres
Excitatory
projections
Non-ion channel genes in idiopathic epilepsy
Thalamus
GABA releasing
neurons
Efference/afference
Efference/afference
Figure 3 | Model of interactions between the thalamus and cortical pyramidal cells.
a | The thalamus and the layers of pyramidal cells in the cortex are interconnected by excitatory
(predominantly glutamatergic) projections (thalamocortical and corticothalamic axons). The
repetitive firing in the thalamocortical loop is inhibited by GABA (γ-aminobutyric acid)-releasing
neurons, which are densely spaced within the thalamic reticular nucleus (RN). The thalamocortical
and corticothalamic axons are connected to these GABA-releasing cells by collaterals and vice
versa. The collaterals from the thalomocortical loop excite the GABA-releasing cells, which
subsequently increase their inhibitory input in other parts of the thalamus but also prevent
excessive inhibitory stimulus by connecting to other GABA-releasing neurons within the RN.
Another regulating mechanism is provided by cholinergic fibres that release acetylcholine in the
vicinity of the main dendrite of pyramidal cells, controlling input from external cell layers. b | A gainof-function mutation in the nicotinic acetylcholine receptor would probably decrease the input
from external cortical layers. The reduced feedback from the external layers could reinforce the
backpropagation from the thalamus and deeper cortical layers. Such an imbalance could lead to
seizures by enhancing oscillation in the thalamocortical loop.
observed within and between GEFS+ families. Nevertheless, only one mutation has so far been identified in
each GEFS+ family. Mutations have been identified in
genes for three voltage-gated sodium channel subunits
(SCN1A, SCN2A, SCN1B)6–8,35, as well as in the γ2 subunit
gene (GABRG2) of the GABAA receptor9,10,36–38. SCN1A,
the most frequently involved gene, codes for a large receptor protein comprised of four domains, each of which
contains six transmembrane domains. Heterologous
expression of SCN1A with the accessory subunits SCN1B
and SCN2B in mammalian cells showed that certain
GEFS+ mutations cause a subtle gating defect. At depolarized potentials, the fast inactivation was less complete
than normal, leading to a persistent inward sodium current39. This gain-of-function effect probably enhances
neuronal excitability by prolonged membrane depolarization. Other GEFS+ mutations showed a reduction in
current density and accelerated recovery from slow inactivation and did not cause a persistent sodium current.
These findings indicate that either an increase or a decrease in sodium channel activity can result in seizures40,41.
404
Mutations in the SCN1A gene have also been found
in severe myoclonic epilepsy of infancy (SMEI or
Dravet’s syndrome), an intractable epilepsy of early
childhood that sometimes co-occurs in GEFS+
families42. So far, the genetic relationship between
GEFS+ and SMEI remains unclear. The most likely
explanation is that SMEI has a complex mode of inheritance, and that some of the genes that are involved in
this disorder are also responsible for the predisposition
to seizure phenotypes from the GEFS+ spectrum.
Mutations within the γ2-subunit of the GABAA
receptor were described as another cause of GEFS+
(REFS 9,10,36–38). However, the most common afebrile
seizure type in families with GABRG2 mutations is
absence seizures. Therefore, it remains a matter for
debate whether GABRG2 mutations indeed cause a
subtype of GEFS+, or whether they predispose for
childhood absence epilepsy.
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Although ion channels undoubtedly have an important
role in idiopathic epilepsies, we should not overlook the
fact that other pathways can lead to neuronal hyperexcitability. Mutant forms of any gene that is involved in
neuronal plasticity, development of neuronal networks
or neuronal metabolism are potential candidates for
causing epileptogenesis. Furthermore, even genes that
encode molecules that control more upstream events,
such as transcription factors or vesicle proteins, have to
be regarded as having a potential involvement in
epilepsy.
Familial lateral temporal lobe epilepsy. Autosomal dominant lateral temporal lobe epilepsy (ADLTE, also known
as autosomal dominant partial epilepsy with auditory
features) is an idiopathic syndrome that is characterized
by simple partial seizures with mainly acoustic and sometimes even visual hallucinations43. In some families, the
seizures can start with a brief sensory aphasia without
reduced consciousness44. The identification of LGI1
(leucine-rich glioma inactivated gene 1, located on chromosome 10q24) as the gene that is responsible for
ADLTE came as a surprise, because all the genes that were
previously implicated in idiopathic epilepsy coded for ion
channel subunits. The LGI1 mutations that have been
found in ADLTE families so far are mostly truncating
mutations, but several missense mutations have also been
described11,45–48.
The function of the LGI1 protein is still unknown,
but sequence analysis showed that it is not an ion channel subunit, and probably not even a membrane-bound
protein. The main sequence characteristics of LGI1, and
its three homologous genes LGI2, LGI3 and LGI4
(REF. 49), are a conserved leucine-rich repeat (LRR)
domain, followed by seven copies of an epitempin
repeat50,51. The LRR consists of repeated β-strands and
α-helices that are connected by loops. The LRR domain
usually acts as a framework for protein–protein interactions, and it is present in numerous proteins with diverse
functions. The nature of possible binding partners for
LGI proteins remains elusive.
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Common forms of idiopathic epilepsy
LGI1–LG14
LRR
Epitempin repeat
100 aa
MASS1/VLGR1
Calx-β domain
Epitempin repeat
TM
1000 aa
Figure 4 | 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 repeat13,49. 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 guidance47. 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.
β-PROPELLER
A protein domain that consists
of an array of β-sheet motifs,
which are configured in a ring to
resemble the blades of a
propeller.
G PROTEIN
A heterotrimeric GTP-binding
and -hydrolysing protein that
interacts with cell-surface
receptors, often stimulating or
inhibiting the activity of a
downstream enzyme. G proteins
consist of three subunits: the
α-subunit, which contains the
guanine-nucleotide-binding site;
and the β- and γ-subunits, which
function as a heterodimer.
FRINGS MOUSE MODEL
An inbred mouse strain with a
seizure phenotype that is
characterized by wild running,
loss of righting reflex, tonic
flexion and tonic extension in
response to high-intensity sound
stimulation.
AUDIOGENIC EPILEPSY
A form of epilepsy in which the
seizures are provoked by
auditory stimuli.
The second hallmark of LGI1 — the epitempin
repeat — is located in the C-terminus and consists of a
tandem repeat with a core of about 50 residues, which
probably fold into a β-PROPELLER structure51. The function
of the epitempin repeat is unknown, but it was also
found in another gene that has been associated with
epilepsy — the MASS1/VLGR1 gene (FIG. 4). MASS1/
VLGR1 codes for the very large G-PROTEIN coupled receptor, and mutations in this gene are responsible for the
52
FRINGS MOUSE MODEL of AUDIOGENIC EPILEPSY . Mutations in
the MASS1/VLGR1 gene also seem to be a rare cause of
febrile seizures in humans13. In the MASS1/VLGR1 protein, the epitempin repeat is part of the ligand-binding
ectodomain, so, like the LRR domain, this repeat might
be involved in protein–protein interactions. This raises
the question of whether this formerly unknown
sequence signature might be involved in a new mechanism of epileptogenesis. One possibility is that the
epitempin repeat might be important for mechanisms
like synaptogenesis or axon guidance that depend on a
communication between cells, or between cells and
extracellular matrix proteins. In such a model, the
epilepsy that is caused by mutations in the LGI1 gene
could be the result of abnormalities in synapse formation
or neuronal migration.
LGI1 was first cloned from the translocation breakpoint of a glioma cell line, and was subsequently shown
to be downregulated in many, but not all, glioblastoma
cell lines that were tested53,54. As no mutations or deletions of LGI1 were found in these cell lines, it remains
unclear whether the loss of LGI1 expression is indeed a
causative event in tumorigenesis. However, re-expression
of LGI1 in cell lines that lack LGI1 mRNA significantly
reduced cell proliferation, supporting the hypothesis that
LGI1 is a tumour suppressor gene54. No evidence has
been found that the LGI1 mutations in families with
ADLTE increase the rate of brain tumours or other
malignancies, excluding a role for LGI1 as a first-step or
high-penetrance tumour suppressor gene55.
NATURE REVIEWS | NEUROSCIENCE
In childhood and adolescence, about 30–40% of all
epilepsies belong to the group of idiopathic generalized
epilepsies (IGE). These include age-related subtypes like
juvenile myoclonic epilepsy, childhood absence epilepsy,
juvenile absence epilepsy and grand mal epilepsy on
awakening. Depending on the age of onset, individuals
with IGE might present with different subtypes,
and they often have a family history for epilepsy. The
concordance rate in monozygotic twins is up to 95%,
supporting an almost complete genetic aetiology of
IGE56. First-degree relatives of patients with IGE have
a risk of about 8–12% to be affected by IGE, whereas
the recurrence risk for second-degree relatives is only
about 1–2% (equal to the epilepsy risk in the general
population). These empirical risk numbers are more
compatible with an oligogenic than a monogenic mode
of inheritance in IGE. Several genes are probably
involved in each patient, and the rapid decrease of the
recurrence risk implies that the interaction of these gene
loci is multiplicative rather than additive. One attractive
theory is that some IGE genes determine the seizure
threshold by influencing neuronal excitability, whereas
other genes are responsible for the age of onset, and
therefore the seizure subtype57. However, this theory has
not yet been supported by experimental data.
So far, little is known about the genes that underlie
epileptogenesis in IGE. Linkage studies and association
approaches have highlighted numerous candidate
regions within the genome, but replication studies
usually failed to confirm the initial observations. One
example is the association with IGE that was found
for the α1A-calcium channel subunit gene (CACNA1A)
on chromosome 19 in one study58, but could not be
replicated using an independent approach59. Missense
mutations in another calcium channel gene —
CACNA1H on chromosome 16p13.3 — were found in
several patients with childhood absence epilepsy60.
These results indicate that CACNA1H might be a
susceptibility gene that is involved in the pathogenesis of
IGE. Of interest is the chromosomal region 3q26, which
was marked as a susceptibility region for common IGE
subtypes in a genome-wide search61. Follow-up studies
in this region identified mutations within the voltagegated chloride channel gene CLCN2 in 3 of 46 unrelated
IGE families, indicating a role for CLCN2 as a minor
locus for IGE. The µ-opioid receptor subunit gene
(OPRM1) was found to be associated with IGE in
two independent studies, but no mutations have been
identified so far62,63. In the future, even larger samples
of patients with IGE will be needed to overcome the
obstacles that come with the task of identifying genes in
disorders with complex inheritance.
Syndromes with epilepsy as a key feature
More than 200 inherited syndromes are known in
which epileptic seizures are an important, but not the
only, clinically prominent feature. In these syndromes,
the epilepsy is often accompanied by other neurological
symptoms, such as mental retardation, dementia or
ataxia. The genes that underlie these syndromes are
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©2004 Nature Publishing Group
REVIEWS
INTENTION TREMOR
A tremor that is exacerbated by
voluntary goal-directed
movements; for example, trying
to put a key in a lock.
DYSARTHRIA
A speech impairment that is
caused by damage to the nerves
or muscles that control speech
articulation. Although the
speech is difficult to understand,
it is usually linguistically normal,
thereby distinguishing this
condition from language
disorders.
RNA INTERFERENCE
(RNAi). A method by which
double-stranded RNA that is
encoded on an exogenous vector
can be used to interfere with
normal RNA processing, causing
rapid degradation of the
endogenous RNA and thereby
precluding translation. This
provides a simple way of
studying the effects of the
absence of a gene product in
simple organisms and in cells.
involved in tasks as different as glycogen metabolism,
respiratory chain activity and brain development. In
contrast to the idiopathic epilepsies, the course of these
disorders is often not benign — they are not a result
of an episodic and reversible disturbance of brain
function, but rather a developmental abnormality
or irreversible and progressive neuronal cell loss in the
brain. Some of the mechanisms by which certain genes
can cause syndromes with epilepsy are discussed in the
context of two disorders from the group of progressive
myoclonus epilepsies and a typical example of a neuronal
migration disorder.
Unverricht–Lundborg disease. Progressive myoclonus
epilepsy type 1 (EPM1), or Unverricht–Lundborg disease (also known as Baltic or Mediterranean myoclonus
epilepsy), is an autosomal recessive neurodegenerative
disorder that is characterized by progressive, stimulisensitive myoclonic jerks and generalized tonic-clonic
seizures. The age of onset is between 6 and 18 years of
age, and the course of the disorder is usually about 10 to
20 years in duration. Mental deterioration, INTENTION
TREMOR, DYSARTHRIA and mild ataxia can develop in later
stages of the disorder64. Pathological findings demonstrate a marked loss of Purkinje cells in the cerebellum,
neuronal loss in the spinal cord and the medial thalamus, and a proliferation of Bergmann glia65.
In most patients, Unverricht–Lundborg disease is
caused by a dodecamer repeat that is located upstream
of the initiation codon of the CSTB (cystatin B, also
stefin B) gene66. Expansion of the unstable dodecamer
repeat probably prevents transcription of CSTB by
increasing the distance between the transcription factor
binding sites and the transcription initiation site. CSTB
is a member of the family of type 1 cystatins, which are
intracellular inhibitors of cysteine proteases, and are
likely to protect the organism from proteolysis by controlling the activities of endogenous proteases. CSTBdeficient mice develop progressive ataxia and myoclonic
seizures owing to extensive apoptotic cell death in the
cerebellum, and they provide a good animal model for
Unverricht–Lundborg disease67,68. CSTB is known to
inhibit several different proteases in vitro, including
cathepsins B, H, L and S. In vivo studies in knockout
mice demonstrated that cathepsin S levels increase in
the absence of CSTB, indicating a feedback mechanism
between the two proteins. The imbalance between the
protease inhibitor CSTB and proteases such as cathepsin S
probably initiates the cascade of cellular events that lead
to progressive cell death and finally to clinical symptoms
in Unverricht–Lundborg disease68.
Table 2 | Lissencephaly genes
Gene
Chromosome
Phenotype
RELN
7q22
Lissencephaly and cerebellar hypoplasia
LIS1 (PAFAH1B1)
17p13.3
Lissencephaly type 1/Miller–Dieker Syndrome
YWHAE (14-3-3ε)
17p13.3
Miller–Dieker Syndrome
DCX (XLIS)
Xq22.3-q23
Lissencephaly type 1/double cortex syndrome
ARX
Xp22.13
Lissencephaly and genital abnormalities
406
| MAY 2004 | VOLUME 5
Lafora disease. Another autosomal recessive neurodegenerative disorder in which seizures are an important
part of the phenotype is Lafora progressive myoclonus
epilepsy. Lafora disease is the most common form
of adolescent-onset progressive epilepsy, and it leads
to cognitive decline, dementia and finally death within
10 years of onset. The presence of intracellular polyglycosan inclusion bodies — so-called Lafora bodies —
is pathognomonic for Lafora disease. In about 70–80%
of the patients, homozygous mutations of the EPM2A
gene on chromosome 6q24 are found69. A second gene
that is associated with Lafora disease (EPM2B/NHLRC1)
was recently identified on chromosome 6p22.3 (REF. 70).
EPM2A and EPM2B encode the proteins laforin and
malin, respectively. Laforin contains a dual-specifity
phosphatase catalytic domain and a carbohydratebinding domain. Experiments with transgenic mice
demonstrated that laforin interacts with itself and with
the glycogen-targeting regulatory subunit R5 of protein
phosphatase 1. Most EPM2A mutations that are found
in patients with Lafora interfere with the phosphatase
activity of laforin and disrupt its binding capacity to
glycogen and polyglycosans, as well as the interaction
with R5 (REF. 71). Malin is characterized by a zinc finger
of the RING type and six NHL-repeat protein–protein
interaction domains. The presence of a RING finger
implies that malin is involved in the ubiquitin pathway,
specifying substrates that have to be removed by the
proteasome system. It has been suggested that mutations in either laforin or malin might lead to improper
clearance and subsequent accumulation of polyglycosans in dendrites, and that the resulting disturbance of neuronal function is responsible for the clinical
features of Lafora disease70.
X-linked lissencephaly/double cortex syndrome. Several
lissencephaly syndromes are known in which mutated
genes cause a failure of neuronal migration during
embryonic development, resulting in cross-neocortical
disorganization (TABLE 2). The most common type of
lissencephaly is classical lissencephaly, or LIS1, which is
characterized by a smooth cerebral surface, a thick cortex
and no other brain malformations. The X-linked
lissencephaly/double cortex syndrome (XLIS) is an
X-chromosomal, dominantly inherited neuronal migration disorder, which manifests in males as classical
lissencephaly and in females as subcortical band heterotopia (double cortex) (FIG. 5). The affected individuals
have epilepsy and mental retardation of variable severity,
and the clinical phenotype is usually more pronounced
in hemizygous males than in heterozygous females.
The doublecortin (DCX) gene, which is located on
chromosome Xq22.3-q23, was identified as the causative
gene in XLIS. It encodes a microtubule-associated
protein that is expressed in migrating neuroblasts72.
Dcx-knockout mice did not show any neocortical malformations, so they did not provide a good model for
studying the mechanisms that underlie DCX pathology73.
However, using the RNA INTERFERENCE (RNAi) method, a
technology that allows acute targeting and disruption of
a specific RNA, Bai et al.74 showed that knocking down
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REVIEWS
a Normal
b DCX female
c DCX male
Figure 5 | Magnetic resonance imaging (MRI) scans of patients with X-linked
lissencephaly/double cortex syndrome. a | MRI brain scan of an unaffected individual.
b | Female individual with a DCX mutation. The white matter shows a heterotopic band of neurons
(‘subcortical band heterotopia’, marked by an arrow), which underlies the normal cortex. c | Male
individual with a DCX mutation. The cortex is abnormally thick and shows poor formation of gyri and
sulci (‘smooth brain’). Reproduced, with permission, from REF. 77  (2001) Macmillan Magazines Ltd.
DCX in utero impairs radial migration of neurons and
causes some neurons to occupy inappropriate laminar
positions. The phenotypic differences in males and
females are explained by the random X-inactivation that
causes a mosaic status for the remaining normal DCX
allele in neuronal cells of hemizygous females, leading to
a mixed pattern of normally migrated and migrationarrested cells. The abnormal microarchitecture of the
cortex is likely to create aberrant neuronal networks,
which can generate focal or secondarily generalized
cortical hyperexcitability.
Mitochondrial inheritance and MERRF
Mitochondrial encephalomyopathies are a genetically and
phenotypically heterogeneous group of disorders that are
caused by either mutations in the maternally inherited
mitochondrial genome or by mutations in the nuclear
DNA. So far, more than 200 disease-causing mutations of
mitochondrial DNA (mtDNA) are known. The variability of the clinical phenotypes in mitochondrial disorders
is mostly due to heteroplasmy of mtDNA; that is, nonuniform distribution of mitochondria in different tissues
and the coexistence of mutated and wild-type mtDNA
within the same cell organelle.
One of the best-known mitochondrial syndromes is
MERRF (myoclonic epilepsy with ragged red fibres),
which is characterized by myoclonus, epilepsy, ataxia,
muscle weakness, hearing loss, and elevated serum
lactate and pyruvate levels. Muscle biopsy typically shows
‘ragged red’-fibres and paracrystalline inclusions in
1.
2.
3.
4.
Steinlein, O. et al. A missense mutation in the neuronal
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with autosomal dominant nocturnal frontal lobe epilepsy.
Nature Genet. 11, 201–203 (1995).
This paper described the identification of the first
gene that was found to be responsible for idiopathic
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Fusco, M. D. et al. The nicotinic receptor β2 subunit is
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subsarcolemmal mitochondria. The MERRF syndrome
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mitochondrial genes, MTTK and, less often, MTTL1
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RNAs for lysine and leucine, respectively. Mutations in
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mitochondrial genes, causing multiple deficiencies in
the cell’s respiratory chain. In MERRF, the impairment
of mitochondrial protein synthesis mainly affects
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the wide range of cellular pathways and functions
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excitatory and inhibitory mechanisms within neuronal
networks that is caused by functionally impaired neurons.
The future of epilepsy genetics
It is difficult to predict how many epilepsy-associated
genes are still waiting to be discovered in the human
genome. We have already learned that ion channel
defects are one of the main causes of idiopathic epilepsies, and that syndromes in which epilepsy is an important feature can be caused by genes that are involved in
functions as diverse as neuronal migration, glycogen
metabolism and respiratory chain activity. There are
many possibilities if one wants to speculate about the
nature of genes that might cause epilepsy when mutated.
Such genes might code for cell adhesion proteins and
neurotrophic factors that are involved in establishing
brain architecture during embryogenesis, synaptic signalling proteins that govern synapse formation and
synaptic connectivity, or proteins that are involved in
extracellular matrix composition. Learning about the
different gene families that can cause epilepsy will not
only help us to understand the multitude of complex
pathways that underlie neuronal hyperexcitability, but
should also lead to the development of new, more powerful and precise treatment strategies. The latter task
would be much easier if at least some of the main pathways in epileptogenesis turn out to converge at some
point, using the same ‘end run’ that can serve as a target
for the development of new anti-epileptic drugs.
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Competing interests statement
The author declares that she has no competing financial interests.
Online links
DATABASES
The following terms in this article are linked online to:
Entrez Gene:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene
CACNA1A | CACNA1H | CHRNA4 | CHRNB2 | CLCN2 | CSTB |
DCX | EPM2A | EPM2B/NHLRC1 | GABRG2 | KCNQ2 | KCNQ3 |
LGI1 | LGI2 | LGI3 | LGI4 | MASS1/VLGR1 | MTTK | MTTL1 |
OPRM1 | SCN1A | SCN1B |SCN2A
OMIM: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
ADNFLE | BFNC | childhood absence epilepsy | EPM1 | GEFS+ |
grand mal epilepsy on awakening | IGE | juvenile absence epilepsy
| juvenile myoclonic epilepsy | Lafora progressive myoclonus
epilepsy | LIS1 | MERRF | SMEI | XLIS
FURTHER INFORMATION
Encyclopedia of Life Sciences: http://www.els.net/
epilepsy
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©2004 Nature Publishing Group