Epilepsy Research (2012) 101, 197201

j our nal homepage: www. el sevi er . com/ l ocat e/ epi l epsyr es

REVIEW
Emerging genetic inuences in benign epilepsy with
centro-temporal spikes BECTS
Anastasia Gkampeta

, Evangelos Pavlou
2nd Department of Pediatrics, Aristotle University of Thessaloniki, AHEPA General Hospital, Thessaloniki, Greece
Received 4 March 2012; received in revised form 6 June 2012; accepted 30 June 2012
Available online 19 July 2012
KEYWORDS
BECTS;
Genetics;
ELP4;
BDNF
Summary BECTS is considered to be the most common childhood epileptic syndrome. Multi-
factorial inheritance is the most important model accounting for the genetic behavior of the
common epilepsies. In recent years, different mutations in genes that control the excitabil-
ity of neurons have been described. Recent reports on the involvement of the BDNF and ELP4
genes with possible roles in cell motility, migration, and adhesion have provided rst insights
into the complex molecular bases of childhood focal epilepsies. However, in the most common
idiopathic benign childhood epilepsies (BECTS and occipital epilepsies), major breakthroughs
are still awaited.
2012 Elsevier B.V. All rights reserved.
Contents
Introduction.............................................................................................................. 197
Benign epilepsy with centro-temporal spikes BECTS.................................................................... 198
Molecular biology of epilepsy genes ...................................................................................... 198
Inheritance of centrotemporal sharp (CTS) waves in BECTS families...................................................... 198
Elongator Protein Complex 4 ELP4 ..................................................................................... 199
Brain-derived neurotrophic factor-BDNF.................................................................................. 199
Conclusions .............................................................................................................. 200
References ............................................................................................................... 200

Corresponding author at: St. Kyriakidi 1, Thessaloniki, zip code:

54636, Greece. Tel.: +30 2310994815; fax: +30 2310993514.
E-mail address: anastagab@yahoo.gr (A. Gkampeta).
Introduction
Epilepsy is one of the most common brain disorders. One
in 10 individuals will have at least one seizure during
his/her life, and about 3% of the population will develop
epilepsy. Epilepsy, dened as having two or more unpro-
voked seizures, is characterized by a category of symptom
0920-1211/$ see front matter 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.eplepsyres.2012.06.011
198 A. Gkampeta, E. Pavlou
complexes due to a number of disordered brain functions,
secondary to a variety of pathologic processes (World Health
Organization, 2005; Hauser et al., 1996). The onset of
seizures in more than 50% of cases occurs in childhood,
with prevalence from 0.7% to 1% (Cowan, 2002). There are
many epileptic syndromes which have been subdivided into
groups, based on clinical presentation, neuropsychomotor
development, neurological examination, electroencephalo-
gram (EEG) and magnetic resonance imaging (MRI) ndings
(Cameld and Cameld, 2002; Pazzaglia et al., 1982). Dif-
ferent mutations in genes that control the excitability of
neurons have been described in idiopathic childhood epilep-
sies and multifactorial inheritance is the most important
model accounting for the genetic behavior of the common
epilepsies. The strongest evidence for a genetic etiology
stems from families with BECTS. However, the genetics of
BECTS is not well understood and is often confused with the
genetics of the CTS trait.
Benign epilepsy with centro-temporal spikes
BECTS
BECTS is considered to be the most common childhood
epileptic syndrome, accounting for 820% of pediatric
patients with epilepsy (Holmes, 1993; Wirrell, 1998). It is
placed among the idiopathic localization-related epilep-
sies. It has a characteristic age of onset, seizure pattern,
neurodevelopmental prole, imaging and electroencephalo-
graphic pattern. The age of onset ranges from 1 to 14 years
with 75% starting between 7 and 10 years. Classically,
BECTS occurs in neurodevelopmentally normal children.
Ictal manifestations occur more frequently (75%) during
NREM (non-rapid eye movement) sleep, mainly at sleep
onset or just before awakening. The seizures are usually
brief lasting for 13 min. Seizures are somatosensory and
motor focal, mainly affecting the face and oropharynx,
with speech arrest and hypersalivation and in some cases
involving the upper limb. The characteristic EEG shows high-
voltage spikes or spike and waves in the centrotemporal
region that may shift from side to side with a normal back-
ground. Neuro-imaging is normal. The term benign refers
to the excellent prognosis of the disorder, regarding seizure
control and developmental outcome (Kellaway, 2000; Datta
and Sinclair, 2007; Berroya et al., 2005). Children become
seizure free by the age of 14, with normalization of the
EEG and without neurological decits. The diagnosis of
BECTS is based on characteristic seizure manifestations,
which are focal but may be secondarily generalized, and
typical EEG with sharp waves located in the centrotempo-
ral (centro-parietal, fronto-central, centro-occipital) leads
(Commission on Classication and Terminology of the ILAE,
1989). Carbamazepine or Oxcarbazepine is considered to
be the rst line drug of choice, although some children
with BECTS do not need antiepileptic therapy (infrequent
seizures, mild or nocturnal, onset close to the natural age
of remission) (Hauser et al., 1996; Kwan and Brodie, 2001).
Molecular biology of epilepsy genes
Benign partial epilepsies of childhood are dened as age
dependent, with no pathologic substrate, and spontaneous
recovery without intellectual decit. In 1985, Dalla Bernar-
dina et al. reviewed 260 patients that were divided into four
groups: BECTS (62%), benign psychomotor epilepsy (10%),
benign occipital epilepsy (7%), and others (20%). All of them
are believed to be idiopathic; however, the strongest evi-
dence for a genetic etiology stems from families with BECTS.
No gene has been identied, but an autosomal dominant
inheritance has been postulated (Bali et al., 2007).
In recent years, different mutations in genes that control
the excitability of neurons have been described in idiopathic
childhood epilepsies. Most commonly, sodium/potassium
channelopathies and GABA-receptor mutations are involved
and may result in abnormal neuronal hyperexcitability man-
ifesting with seizures. However non-ion channel proteins
may also be affected. Mutations in these voltage and ligand-
gated channels are increasingly recognized in familial, but
also in sporadic cases (Heron et al., 2007).
Broadly, epilepsies can be divided into those with sin-
gle gene inheritance and those with complex (polygenic or
multifactorial) inheritance. Multifactorial inheritance is the
most important model accounting for the genetic behavior
of the common epilepsies. Determination of genetic linkage
and subsequent identication of abnormal genes is relatively
easy in single gene disorders, but is much more difcult in
disorders with complex inheritance. Idiopathic single gene
epilepsies include benign familial neonatal convulsions and
benign familial infantile convulsions. Recently, four auto-
somal dominant partial epilepsies have been described:
autosomal dominant nocturnal frontal lobe epilepsy, autoso-
mal dominant partial epilepsy with variable foci, autosomal
dominant rolandic epilepsy with speech dyspraxia, and
familial temporal lobe epilepsy.
New molecular tools are now available for understand-
ing how multiple genes contribute to epileptogenesis. These
tools include genome wide association studies (GWASs)
which evaluate single nucleotide polymorphisms (SNPs)
located within and around genes. This methodology detects
subtle gene variations or polymorphisms that may associate
with the disease under study. So far, 20 genes have been
associated with risk for epilepsy, including BDNF, CHRNA7,
GABRG2 and GABRA1 (Jia et al., 2011). Recent reports on
the involvement of the SRPX2 and ELP4 genes with possible
roles in cell motility, migration, and adhesion have provided
rst insights into the complex molecular bases of childhood
focal epilepsies.
Inheritance of centrotemporal sharp (CTS)
waves in BECTS families
The EEG hallmark of BECTS are blunt, high-voltage, char-
acteristically shaped centrotemporal spikes (CTSs) often
followed by slow waves. The spikes are activated by sleep
and tend to spread from side to side (Bray and Wiser, 1964;
Commission on Classication and Terminology of the ILAE,
1989; Gutierrez et al., 1990). Although CTS can be found
in asymptomatic children, they are particularly associated
with idiopathic focal epilepsy syndromes. The inheritance
of CTS is presumed autosomal dominant but this is contro-
versial. Many authors have noted the presence of CTS in
siblings of children with BECTS, suggesting a genetic cause,
but the precise mode of inheritance of CTS is debated, as
Emerging genetic inuences in benign epilepsy 199
is the genetic basis of BECTS. Vadlamudi et al. trying to
analyze the etiology of BECTS, conducting a multicenter
twin collaboration with a large sample of twins, suggested
that noninherited factors are of major importance in BECTS
(Vadlamudi et al., 2004, 2006).
In 1964, Bray and Wiser reported that CTS follow an auto-
somal dominant mode of inheritance (Bray and Wiser, 1964).
Heijbel et al. (1975), applying stricter criteria for pheno-
type denition, tested this hypothesis in the families of 19
children. In the siblings of these children, who were inves-
tigated by waking and sleep EEG, they found that 11 (34%)
of 32 showed CTS. Basing on these ndings, they came to
the identical conclusion as that of Bray and Wiser. More
recently, Doose et al. (1997) studied 188 siblings of children
with epilepsy with CTS and observed CTS in 14% of siblings.
Most of the siblings were investigated with a single waking
electroencephalogram (EEG).
Several linkage studies exploring candidate loci gave
negative results. The rst positive evidence for linkage in
families with centrotemporal spikes was found on chromo-
some 15q14 with genetic heterogeneity by Neubauer et al.
(1998) who studied 22 families with BECTS. From this study
it was concluded that either the a
7
AChR subunit gene
(which is located there) or another closely linked gene is
implicated in pedigrees with BECTS and that the trait is
genetically heterogeneous. Since then, it has been shown
by Bali et al. (2007) that the segregation ratio of CTS in
BECTS families is consistent with a highly penetrant auto-
somal dominant inheritance, with equal sex ratio. Studies
conducted by Vadlamudi et al. (2004, 2006) showed no co-
twin concordance and suggested that conventional genetic
inuences in BECTS may be considerably less than for idio-
pathic generalized epilepsies, and that other mechanisms
such as environmental or epigenetic factors may well play
important role.
Very recently, a genome-wide study in 38 US families by
Strug et al. (2009) demonstrated linkage of the centrotem-
poral sharp wave EEG trait to 11p13 and several polymorphic
markers in the Elongator Protein Complex 4 (ELP4) gene
showed association with the phenotype. This study not only
argued in favor of genetic contribution, but also was the rst
report of a gene implicated in a common focal epilepsy and
the rst human disease association of ELP4. The results sug-
gest that ELP4 is associated with the pathogenesis of BECTS
and has a strong effect on risk for CTS in BECTS families.
Further deconstruction of the BECTS phenotype showed
that the component trait of speech sound disorder (SSD),
dened as developmentally inappropriate errors in speech
production that reduce intelligibility, is often comorbid in
BECTS patients and clusters in their seizure-free relatives,
which raises the hypothesis that SSD and CTS may share
underlying genetic risk (Shriberg et al., 1997; Clarke et al.,
2007). A recent linkage analysis by Pal et al. (2010) tested
the hypothesis of shared genetic risk of SSD with CTS at the
11p13 locus and suggested pleiotropic effects of the 11p13
locus for both SSD and the CTS electroencephalographic pat-
tern seen in BECTS families. According to a more recent
clinical genetic study conducted by Vears et al. (2012) BECTS
has a genetic component consistent with complex inheri-
tance. This study included 53 patients with a diagnosis of
BECTS and pedigree data were obtained for up to three
degrees of relatedness. The authors found that 9.8% of all
rst degree relatives had seizures, falling to 3% and 1.5%
in second- and third-degree relatives respectively. These
frequencies in relatives are typical of a complex trait.
The inheritance of CTS is clearly not identical to the
inheritance of BECTS, although an autosomal dominant CTS
locus would necessarily comprise a part of the etiology of
BECTS. CTS as a subclinical marker not only seems to be
under strong genetic inuence but may also be inherited
as a monogenic trait (Bali et al., 2007; Doose et al., 1997;
Neubauer, 2000). Indeed, up to half of the children with
CTS will not show any clinical manifestations, suggesting
that additional genetic and environmental factors sustain
the emergence of actual clinical symptoms.
Elongator Protein Complex 4 ELP4
The Elongator Protein Complex (ELP) regulates the growth of
cortical projection neurons. This means that it helps cortical
neurons to exhibit dendrite branching and radial migration
of neurons. If ELP is not working properly or is underex-
pressed then the neural network of the cerebral cortex
would not work properly. Elongator controls the migration
and differentiation of cortical neurons through acetylation
of alpha-tubulin (Creppe et al., 2009).
Elongator Protein Complex 4 (ELP4) is one of the six sub-
units of Elongator Protein Complex that has both nuclear and
cytoplasmic localization and two distinct roles in eukary-
otic cells: in transcription and in tRNA modication. Elp4 is
needed for histone acetyltransferase (HAT) activity which
makes DNA more accessible for transcription. The impor-
tance of HAT activity is the initiation of transcription as
well as its assistance of RNA polymerase II in transcription
elongation through chromatin and acetyl-CoA dependent
pathways. Elongator plays a key role in transcription of sev-
eral genes that regulate the actin cytoskeleton, cell motility
and migration. These functions are crucial in the nervous
system for nerve cell growth cone motility, axon outgrowth
and guidance, neuritogenesis and neuronal migration during
development (Creppe et al., 2009).
So, a non-coding mutation in ELP4 gene impairs brain
development, resulting in susceptibility to seizures and
neurodevelopmental disorders (Creppe et al., 2009). Sub-
stantiating ELP4 as a risk locus for CTS is the rst step
in assembling the complex genetic model of BECTS. Addi-
tional genetic factors though, need to be invoked to explain
the occurrence of seizures and reading disability in BECTS.
For example, although CTS is common in children, only an
estimated 10% of children with the trait manifest clinical
seizures (Heijbel et al., 1975).
Brain-derived neurotrophic factor-BDNF
Recently, much attention has been directed to the neu-
rotrophin BDNF because it is highly expressed in many areas
of the CNS and is critically involved in synaptic plasticity
and neurotransmission by mechanisms that are still poorly
understood.
Brain-derived neurotrophic factor (BDNF) is a member of
the neutrophin family of growth factors. It is involved in
numerous aspects of development, degeneration and dif-
ferentiation in the central nervous system and appears to
200 A. Gkampeta, E. Pavlou
play an important role in epileptogenesis in the hippocampus
(Koyama et al., 2004). BDNF has an important role in neuro-
genesis, cell survival, synaptogenesis and neural plasticity
throughout the brain (Chen et al., 2004). BDNF can regulate
synaptic transmission by increasing N-methyl-D-aspartic acid
(NMDA) receptor activity, reduce inhibition on GABAergic
postsynaptic cells at GABAergic synapses in hippocampal cul-
tures, evoke rapid excitation on neurons in rat hippocampi
rats, and promote epileptogenesis by TrkB signaling in a
mouse model of mesial temporal lobe epilepsy (Levine et al.,
1998; Wardle and Poo, 2003; Katz et al., 1999; Heinrich
et al., 2011). NMDA is an amino acid derivative that acts as a
specic agonist at the NMDA receptor, mimicking the action
of glutamate, which normally binds to that receptor. Acti-
vation of the NMDA receptor results in the opening of an ion
channel that is non-selective to cations and plays an impor-
tant role in cell death during status epilepticus (Deshpande
et al., 2008).
In humans the BDNF gene is located on chromosome
11p13, in close proximity to the ELP4 gene. Kanemoto et al.
(2003) were the rst to document an association between
BDNF allele variants and partial epilepsies. They observed
that the BDNF polymorphism at position 240 in the noncod-
ing region, but not at position 480 of the proBDNF sequence,
predisposes patients to partial epilepsy. The emerging role
of BDNF single-point mutations in frequent human neu-
rological pathologies (Alzheimers disease and impaired
memory, bipolar affective disorders, Parkinsons disease,
partial epilepsy) opens new questions related to the patho-
logical mechanisms underlying these disorders. Two distinct
human BDNF polymorphisms have been identied which sup-
port the idea that BDNF may be causally related to human
epilepsy, particularly to temporal lobe epilepsy (TLE). The
rst polymorphism, a valine to methionine substitution at
position 66 in the BDNF prodomain (val66met), has been
associated with a loss of function, decreased intracellular
trafcking from the cell body to the processes (dendrites and
axon), and decreased regulated, activity-dependent secre-
tion of BDNF. This polymorphism does not associate with TLE
or febrile seizures. Conversely, another human BDNF poly-
morphism (cys270thr, or C270T) has been associated with
idiopathic TLE (Chen et al., 2004; Kanemoto et al., 2003;
Egan et al., 2003; Chou et al., 2004). More recently, Nec-
toux et al. studied the inuence of Val66Met on the severity
of Rett syndrome. Their results showed that girls with the
Val66Val genotype tend to present earlier seizures as com-
pared to girls presenting the Met66 allele. The authors
concluded that the Met66 BDNF allele might protect at least
girls against seizures (Nectoux et al., 2008). On the other
hand, Louhivuori et al. (2009) showed that Val66Met poly-
morphism is associated with the development of epilepsy in
Fragile X syndrome.
The impact of BDNF single-point mutations in BECTS has
not been studied yet. The fact that BDNF gene is located
on chromosome 11p13, as ELP4 gene does, enhances the
possibility of a coaction of these two genes and the effect
of BDNF on BECTS.
Conclusions
The process of epileptogenesis, has been associated with
gene mutations. CTS waves, the EEG hallmark of BECTS,
are found in approximately 4% of the childhood population.
The inheritance of CTS is presumed autosomal dominant
but this is controversial. Multifactorial inheritance is the
most important model accounting for the genetic behavior
of the common epilepsies. It is hoped that future genetic
and neurobiological studies will provide better insight into
how multiple genes contribute to the common epilepsies. It
is hoped that understanding of the hyperexcitability asso-
ciated with BDNF and ELP4 in epilepsy may lead to novel
anticonvulsant or antiepileptogenic therapies.
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