Neuroscience Research 44 (2002) 11 /30

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Review article

Genetics of epilepsy: current status and perspectives

Sunao Kaneko a,1,*, Motohiro Okada1 a, Hiroto Iwasa a, Kazuhiro Yamakawa1 b,
Shinichi Hirose1 c
a
Department of Neuropsychiatry, Hirosaki University, Hirosaki 036-8562, Japan
b
Laboratory for Neurogenetics, RIKEN Brain Science Institute, Wako-shi, Saitama 351-0198, Japan
c
Department of Pediatrics, Fukuoka University, Fukuoka 814-0180, Japan

Received 28 February 2002; accepted 28 April 2002

Abstract

Epilepsy affects more than 0.5% of the world’s population and has a large genetic component. The most common human genetic
epilepsies display a complex pattern of inheritance and the susceptibility genes are largely unknown. However, major advances have
recently been made in our understanding of the genetic basis of monogenic inherited epilepsies. Progress has been particularly
evident in familial idiopathic epilepsies and in many inherited symptomatic epilepsies, with the discovery that mutations in ion
channel subunits are implicated, and direct molecular diagnosis of some phenotypes of epilepsy is now possible. This article reviews
recent progress made in molecular genetics of epilepsy, focusing mostly on idiopathic epilepsy, and some types of myoclonus
epilepsies. Mutations in the neuronal nicotinic acetylcholine receptor a4 and b2 subunit genes have been detected in families with
autosomal dominant nocturnal frontal lobe epilepsy, and those of two K
channel genes were identified to be responsible for
underlying genetic abnormalities of benign familial neonatal convulsions. The voltage-gated Na
-channel (a1,2 and b1 subunit),
and GABA receptor (g2 subunit) may be involved in the pathogenesis of generalized epilepsy with febrile seizure plus and severe
myoclonic epilepsy in infancy. Mutations of Ca2
-channel can cause some forms of juvenile myoclonic epilepsy and idiopathic
generalized epilepsy. Based upon these findings, pathogenesis of epilepsy as a channelopathy and perspectives of molecular study of
epilepsy are discussed. # 2002 Elsevier Science Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Keywords: Epilepsy; Epilepsy genes; Channelopathy; Autosomal dominant nocturnal frontal lobe epilepsy; Benign familial neonatal convulsions;
Benign adult familial myoclonic epilepsy; Generalized epilepsy with febrile seizure plus; Progressive myoclonus epilepsy

1. Introduction Lennox, 1960; Sillampaa et al., 1991). Environmental

Epilepsy affects more than 0.5% of the world’s
population and has a large genetic component (Barais-
ter, 1990). The idea that epilepsy is not one general
disorder but can be differentiated into a number of
clinical subtypes provides a basis for studies investigat-
ing the genetics of idiopathic epilepsies. Strong support
for a genetic role in some epilepsies comes from twin
studies (Table 1) that report concordance rates consis-
tently higher in monozygotic (MZ) than in dizygotic
(DZ) twins, (Berkovic et al., 1998; Corey et al., 1991;
Harveld and Hauge, 1965; Inouye, 1960; Lennox and
* Corresponding author. Tel.:
/81-172-39-5065; fax:
/81-172-39-
5067
E-mail address: nosanai@cc.hirosaki-u.ac.jp (S. Kaneko).
1
The Epilepsy Genetic Study Group, Japan.
0168-0102/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
PII: S 0 1 6 8 - 0 1 0 2 ( 0 2 ) 0 0 0 6 5 - 2
influences are held to a minimum; MZ twins have
identical genotypes, whereas DZ twins are no more
genetically similar than any two siblings. Concordance
rates ranged from 10.8% in MZ pairs with acquired
brain injuries to 70% in those without these defects. In
DZ twins, concordance ranged from 3 to 10%, regard-
less of a brain injury in the proband (Treiman and
Treiman, 2001). Lennox and Lennox (1960) details of
seizure type (Table 1). Here the MZ/DZ difference in
concordance is striking, and recent genetic studies of
epilepsy have revealed responsible genes of some phe-
notypes of idiopathic epilepsy and progressive myoclo-
nus epilepsy.
The focus of research on the genetics of the epilepsies
is the identification of mutations causing epilepsies, and
the abnormal properties of the neuron glia system
through which the mutations are expressed and result
12 S. Kaneko et al. / Neuroscience Research 44 (2002) 11 /30

Table 1
Concordance for epilepsy among monozygotic and dizygotic twin pairs

Authors and year Type of epilepsy/proband Concordance

Monozygotic Dizygotic

N Percentage N Percentage

Berkovic et al., 1998 Major epilepsy syndromes 108 62.0 145 18.0
Corey et al., 1991 Febrile seizures 95 19.0 157 6.0
Sillampaa et al., 1991 Epilepsy 79 12.0 201 3.0
Harveld and Hauge, 1965 Epileptic seizures 89 3.4 221 1.4
Inouye, 1960 Undefined epilepsy 27 37.1 100 10.0
Lennox and Lennox, 1960 Seizures 14 54.0 14 7.1
Epilepsy and brain lesion 37 10.8 67 7.5
Epilepsy but no lesion 47 70.2 54 5.6
Seizure type a
Grand mal (GM) 51 82.0 52 15.0
Petit mal (PM) 20 75.0 14 0.0
GM and PM 13 77.0 8 0.0
Psychomotor 13 39.0 19 5.0
GM and psychomotor 11 27.0 10 0.0
a
Twins with multiple seizures types are counted more than once.

in clinical epilepsy. Once the mutated code scripts are
identified in the epilepsies, it will lead to an under-
standing of how neurons are regulated in the face of
such abnormal code scripts, and how development is
affected during embryogenesis and the immediate post-
natal period (Delgado-Escueta et al., 1994). Improving
the classification of epilepsy genotypes will undoubtedly
improve calculations of sibling risk for epilepsy, and
this, in turn, improves the accuracy of risk assessments
and facilitates genetic counseling. However, most idio-
pathic epilepsies are complex genetic diseases; they occur
with a greater frequency in relatives of affected indivi-
duals (Kaneko and Wada, 1998) yet do not exhibit a
simple Mendelian inheritance pattern, for it seems that
multiple genes are simultaneously involved and that a
diversity of ‘susceptible’ genes collaborate in determin-
ing risk (Delgado-Escueta et al., 1994). This article
reviews recent progress made in molecular genetics of
epilepsy and perspectives of molecular study of epilepsy.
2. Chromosomal localization of epilepsy genes and
identified genes of epilepsy
Chromosomally localized epilepsies and identified
mutations in the genes of some phenotypes of epilepsy
have been listed in Tables 2/5.
2.1. Localization related epilepsies (Table 2)
2.1.1. Benign rolandic epilepsy
Rolandic epilepsy is an idiopathic partial epilepsy
syndrome that begins between age 3 and 13 years and
remits before 16 (Lerman, 1977). The brief, simple,
partial hemifacial motor seizures frequently have asso-
ciated somatosensory symptoms and tend to evolve into
generalized tonic-clonic seizures. The EEG shows high-
voltage centrotemporal spikes, that are activated by
sleep. Neubauer et al. (1998) found evidence for linkage
of rolandic epilepsy to a region of chromosome 15q14
encompassing the 7-cM by analysis of 22 nuclear
families. The a7 subunit of neuronal acetylcholine
receptor (CHRNA7) is located in this region. On the
other hand, Vaughn et al. (1996) have reported two
children with centrotemporal spike discharges and with
seminological similarities to benign rolandic epilepsy.
Although the two children also expressed many mani-
festations that are not detected in benign rolandic
epilepsy, which might reflect extensive deletion of
chromosome 1, they suggested that the distal portion
of the long arm of chromosome 1 is a potential site for a
candidate gene for benign rolandic epilepsy.
2.1.2. Familial partial epilepsy
The responsible gene for familial partial epilepsy
(temporal lobe) has been mapped to 10q (Ottman et
al., 1995), but this locus has been excluded in Australian
families (Berkovic, 1997). A single nucleotide poly-
morphism (SNP) that results in a C
T transition at
511-base-pairs upstream of the transcription start site of
the interleukin 1 b (IL-1b ) gene (g .-511C
T) was
hypothesized to play a role in the etiology of temporal
lobe epilepsy (TLE) with hippocampal sclerosis (HS)
(Kanemoto et al., 2000). To confirm this finding, Buono
et al. (2001) determined the frequency of this poly-
morphism in a group of 61 TLE
/HS patients of
European ancestry and compared it with that found in
119 ethnically matched control subjects. However, they
 S. Kaneko et al. / Neuroscience Research 44 (2002) 11 /30 13

Table 2
Genes associated with localization related epilepsies

Epilepsy Chromosomal region Gene or protein Main reference

Autosomal dominant nocturnal frontal 20q13.2 /q13.3 a4 subunit of nicotinic acetylcholine Steinlein et al. (1995, 1997b), Hirose et al.
receptor (CHRNA4) (1999), Phillips et al. (2000)
lobe epilepsy (ADNFLE) type1 15q24 nicotinic acetylcholine receptor sub- Phillips et al. (1998)
unit genes
ADNFLE type2 1 (pericentromeric b2 subunit of nicotinic acetylcholine Fusco et al. (2000), Phillips et al. (2001)
region) receptor (CHRNB2)
ADNFLE type3 10q24 Leucine-rich, glioma-inactivated 1 Kalachikov et al. (2002)
gene (LGI1)
Autosomal-dominant partial epilepsy 1q deletion Vaughn et al. (1996)
with auditory feature
Benign rolandic epilepsy 15q14 CHRNA7? Neubauer et al. (1998)
Benign familial infantile convulsions 19q ? Guipponi et al. (1977)
(BFIC)
Infantile convulsions and choreoathe- 16p12 /q12 ? Caraballo et al. (2001)
tosis including BFIC

failed to confirm an association between the g .-511C
T
SNP and TLE
/HS. Recently, Kalachikov et al. (2002)
identified a causative gene, leucine-rich, glioma-inacti-
vated 1 gene (LGI1 ), in-patients with autosomal domi-
nant partial epilepsy with auditory features (ADPEAF).
ADPEAF is characterized by partial seizures with
auditory disturbances. They showed that the expression
pattern of mouse, and Lgi1 was predominantly neuronal
and was consistent with anatomic regions involved in
TLE. The discovery of mutations in LGI1 as a cause of
ADPEAF suggests a new avenue for research on
pathogenic mechanisms of epilepsies (Kalachikov et
al., 2002).
2.1.3. Autosomal dominant nocturnal frontal lobe
epilepsy (ADNFLE)
ADNFLE is characterized by a brief seizure during
light sleep, and is often misdiagnosed as nightmare or
parasomnia. ADNFLE is a monogenic disorder inher-
ited as an autosomal dominant trait with high pene-
trance. A first locus for ADNFLE has been mapped to
chromosome 20q13.2 (Phillips et al., 1995), and a
missense mutation in the neuronal nicotinic acetylcho-
line receptor (nAChR) a4 subunit (CHRNA4 ) gene has
been reported in an Australian family with ADNFLE
(Steinlein et al., 1995) followed by another report of an
insertional mutation of the CHRNA4 gene (Steinlein et
al., 1997b). In a Japanese family with ADNFLE, a ‘C’ to
‘T’ exchange (c.851C
T) was found in exon 5 of the
CHRNA4 gene on one allele of affected individuals.
c.851C
T replaced Ser284 in the second membrane
spanning domain (M2) of CHRNA4 with a leucine.
Ser284 is conserved characteristically in CHRNA4 (Hir-
ose et al., 1999). Recently, a de novo mutation c.851C
T
was identified: Ser284Leu was found to be a mutation in
the CHRNA4 gene in a women initially diagnosed as
sporadic nocturnal frontal lobe epilepsy (Phillips et al.,
2000). This discovery implies that some idiopathic

Table 3
Genes associated with generalized epilepsies

Epilepsy Chromosomal re- Gene or protein Main reference

gion

Juvenile myoclonic epilepsy (EJM1) 6p11 /p12 c6orf33 (LMPB1)a Greenberg et al. (1988), Suzuki et al. (2001)
(EJM2) 15q a7 nicotinic acetylcholin receptor Elmslie et al. (1997)
(CHRNA7)?
Benign familial neonatal convulsions 20q13 KCNQ2 (K
channel) Singh et al. (1998), Biervert et al. (1998), Ushida
(EBN1) et al. (2001)
Benign familial neonatal convulsions 8q KCNQ3 (K
channel) Charlier et al. (1998), Hirose et al. (2000a,b)
(EBN2)
Childhood absence epilepsy (CAE) 20q CHRNA4? Steinlein et al. (1997a,b)
CAE with generalized tonic-clonic 8q24.3 ? Fong et al. (1998)
seizure
CAE evolving to juvenile myoclonic 1p ? Delgado-Escueta et al. (1999)
epilepsy
Juvenile absence epilepsy 21q22.1 GluR (kainate receptor) Sander et al. (1997)

c6orf33: chromosome 6 open reading frame 33. LMPB1: lyrosomal membrane protein in brain-1.
a
A newly discovered gene mutated in patient with juvenile myoclonic epilepsy has been found, and it will be reported shortly.
14 S. Kaneko et al. / Neuroscience Research 44 (2002) 11 /30

Table 4
Genes associated with specific syndrome

Epilepsy Chromosomal re- Gene or protein Main reference

gion

Progressive myoclonus epilepsies Unverricht- 21q23 mutation of gene encoding cystatin B Pennacchio et al. (1996), Lalioti et al.
Lundborg type (EPM1) (1997a,b), Virtaneva et al. (1997)
Lafora’s disease (EPM2) 6q24 laforin Minassian et al. (1998), Serratosa et
al. (1995)
Northern epilepsy 8p ? Tahvanainen et al. (1994), Ranta et al.
(1997)
Infantile type of neuronal ceroid lipofuscinosis 1p mutation in the palmitoyl-protein Vesa et al. (1995)
(CLN1) thioesterase (PPT)
Late-infantile type of neuronal ceroid Lipofus- 11p15 pepstatin-insensitive lysosomal pepti- Sleat et al. (1997)
cinosis (CLN2) dase
Juvenile type of neuronal ceroid lipofuscinosis 16p12.1 CLN3 protein Mitchison et al. (1995, 1997), Golabek
(CLN3) et al. (2000)
Finish-variant late-infantile type of Neuronal 13q21 /q32 ? Savukoski et al. (1994)
ceroid lipofuscinosis (CLN5)
Variant late-infantile ceroid lipofuscinosis 15q21 /q23 ? Sharp et al. (1997)
(CLN6)
Juvenile Gaucher’s disease 1q21 /q31 human b-glucocerebrosidase Koprivica et al. (2000)
‘Cherry-red-spot-myoclonus’ syndrome or sia- 10q,20q,6p21.3 a-neurominidase Mueller et al. (1986), Pshezhetsky et
lidosis type 1 al. (1997)
Sialidosis type 2 ch3,ch22 stabilizing protein of the a-neuromini- Sips et al. (1985)
dase-b-glactosidase complex
Myoclonus epilepsy and ragged-red fibers Mitocondrial TRNALys mutation Schoffner et al. (1990)
(MERRF) DNA
Mitocondrial myopathy, encepholopthy, lactic Mitocondrial TRNA (Leu(UUR)) Moraes et al. (1993)
acidosis and stroke-like episodes (MELAS)
DNA TRNA /Leu(UUR) Goto et al. (1990)
Dentatorubal pallidoluysian atrophy 12p CAG trinucleotide repeat Koide et al. (1994), Nagafuchi et al.
(1994)
Principal inherited disorders with epilepsy As a
part of phenotype
Benign adulthood familial myoclonic epilepsy 8q23.3 /q24.1 ? Mikami et al. (1999)
Chorea-acanthocytosis 9q21 Chorein Ueno et al. (2001)

Table 5
Genes associated with febrile seizures and SMEI

Epilepsy Chromosomol re- Gene or protein Main reference

gion

Febrile convulsions (FS)

FEB1 8q13 /q21 ? Wallace et al. (1996)
FEB2 19q13 ? Johnson et al. (1997)
FEB3 2q23 /q24 ? Peiffer et al. (1999)
FEB4 5q14 /q15 ? Nakayama et al. (2000)
GEFS plus
FEB
1 19q13.1 Na
channel b1 subunit gene (SCN1B) Wallace et al. (1998)
FEB
2 2q24 /q33 Na
channel a1 subunit gene (SCN1A) Wallace et al. (2001a), Escayg et al. (2000,
2000)
FEB
3 5q34 g2 subunit gene of GABA receptor Baulac et al. (2001)
(GABRG2)
FEB
4 2q24 /q33 SCN2A Sugawara et al. (2001b)
FS
childhood absence epilepsy 5q34 GABRG2 Wallace et al. (2001b)
Severe myoclonic epilepsy of infancy
(SMEI)
SMEI 2q24 SCN1A Claes et al. (2001)
FS plus including SMEI 5q34 GABRG2 Harkin et al. (2002)

In this article, GEFS plus associated with SCN2A mutation was named GEFS
4.
 S. Kaneko et al. / Neuroscience Research 44 (2002) 11 /30
epilepsy syndromes may be caused by a single genetic
abnormality rather than multifactorial, the accepted
etiology for idiopathic epilepsies.
Some families have been shown to be not linked to
chromosome 20q, and a second locus on 15q24 has been
suggested in which there is a cluster of other nicotinic
acetylcholine receptor subunit genes, but specific muta-
tions have not yet been found (Phillips et al., 1998). A
third locus resides on chromosome 1, where a G to C
transversion in exon 5 of CHRNB2 (whose gene product
is b2 subunit of nicotinic acetylcholine receptor), leading
to missense a missense Val287Leu has recently been
reported as a cause of ADNFLE (Fusco et al., 2000).
Phillips et al. (2001) also reported a mutation of
CHRNB2 , resulting in a Val287Met substitution within
the M2 domain in a Scottish family with ADNFLE.
Interestingly, both mutations affect the same valine
residue within the M2 domain although different amino
acid substitutions occur. ADNFLE with genetic locus
on chromosome 20q13.2, 15q24 and 1 are now referred
to as ADNFLE type 1, 2 and 3, respectively.
For ADNFLE type 1, a missense mutation
(c.839C
T; Ser280Phe) (Steinlein et al., 1995), an
insertional mutation (c.873/874insGCT; L301/302)
(Steinlein et al., 1997b), and another point mutation
(c.851C
T; Ser284Leu) in the CHRNA4 gene were
found (Hirose et al., 1999). Both Sel280Phe and
Ser284Leu showed similar electrophysiological charac-
teristics (Weiland et al., 1996; Kuryatov et al., 1997;
Matsushima et al., 2002). In contrast, AChR bearing
Leu301/302 exhibited normal receptor function but a
higher affinity for AChR than that of wild type.
Reduced Ca2
permeability of the mutant nAChR
was recorded indicating the Leu301/302 results in
loss-of-function (Steinlein, 1998), which is similar to
Ser280Phe and Ser284Leu (Weiland et al., 1996; Kur-
yatov et al., 1997; Matsushima et al., 2002). Mutations
of the CHRNA4 are thought to decrease the activity of
nicotinic acetylcholine receptor by reducing its affinity
for acetylcholine and permeability to calcium (Kuryatov
et al., 1997; Bertrand et al., 1998). nAChRs are thought
to be almost exclusively presynaptic, regulating the
release of neurotransmitters such as glutamate and
GABA. However, the mechanisms by which hypoactive
nAChRs cause ADNFLE are unknown.
For ADNFLE type 3, the major effect of the b2
Val287Leu mutation was caused by the retardation of
channel desensitization (Fusco et al., 2000). Functional
receptors with the Val287Met mutation are highly
expressed in Xenopus oocytes and characterized by
/
10 fold increase in Ach sensitivity (Phillips et al., 2001).
These mutations are considered to lead to gain-of-
function although the phenotypes of type 1 and 3 are
indistinguishable from each other. Mutations of
CHRNA4 seem to cause loss-of-function while muta-
tions of CHRNB2 show opposite channel function,
15
gain-of function, indicating the necessity of further
studies of molecular pathogenesis of ADNFLE. The
genetic locus of ADNFLE type 2 (15q24), is of interest
since the cluster of a3,a5, andb4 subunits of nAChR
resides in this region (Phillips et al., 1998), given that
any constituents of nAChR could be involved in the
pathogenesis of ADNFLE phenotype. However, since
most ADNFLE families are not linked to CHRNA4 or
CHRNB2 , more genes responsible for ADNFLE await
discovery.
Note that the nomenclature for mutations is based on
the recommendations by Antonarakis, 1998 where the
first Met of gene products is amino acid 1 and A of
ATG encoding the first Met is nucleotide 1. Numbering
for nucleotides and amino acids of the mutations of
CHRNA are accordingly different from those given in
the original articles, which were mainly based on
Torpedo sequence and the nomenclature system by
Beaudet and Tsui (1993), where the first amino acid of
mature protein molecules is counted as amino acid
number 1 and the first nucleotide encoding the first
amino acid is counted as nucleotide number 1.
2.1.4. Benign familial infantile convulsions (BFIC) and
infantile convulsions and choreoathetosis (ICCA)
syndrome
The syndrome of benign familial infantile convulsions
(BFIC) is an autosomal-dominant epileptic disorder that
is characterized by convulsions, with onset at age 3/12
months and a favorable outcome (Caraballo et al.,
1997). BFIC had been linked to chromosome 19q in five
Italian families with a maximum two-point lod score of
6.36 at D19S114 (Guipponi et al., 1977), whereas the
infantile convulsions and choreoathetosis (ICCA) syn-
drome, in which BFIC is associated with paroxysmal
dyskinesias, have been linked to chromosome 16p12/
q12 (Szepetowski et al., 1997). ICCA is a new auto-
somal-dominant syndrome in which BFIC and parox-
ysmal choreoathetotic dyskinesia occur. Infantile
convulsions associated with various types of paroxysmal
dyskinesias have been linked to the chromosome 16
ICCA region in additional families (Lee et al., 1998;
Tomita et al., 1999; Swoboda et al., 2000). These data
suggest that families with pure BFIC can be linked to
chromosome 16 as well. Indeed, Caraballo et al. (2001)
obtained evidence for linkage in the ICCA region but
not in chromosome 19q, indicating that chromosome
16p12/12q is a major genetic locus underlying BFIC
and paroxysmal dyskinesias.
2.2. Generalized epilepsies (Table 3)
Childhood absence epilepsy (CAE), juvenile absence
epilepsy, and juvenile myoclonic epilepsy (JME) repre-
sent the most common idiopathic epilepsy (IGE) sub-
types. Regarding genes predisposing to IGE subtypes,
16 S. Kaneko et al. / Neuroscience Research 44 (2002) 11 /30
possible association of a silent polymorphism in
CHRNA4 with IGE has been suggested by Steinlein et
al. (1997a,b), but the gene encoding the a1A-voltage-
dependent calcium channel (CACN1A4) has been re-
lated neither to IGE, CAE, juvenile absence epilepsy nor
JME (Sander et al., 1998a).
2.2.1. Juvenile myoclonic epilepsy (JME)
Among IGE, juvenile myoclonic epilepsy (JME) is a
commonly occurring form of IGE, and is characterized
by awakening myoclonus, absence seizures associated
with fast spike-wave discharges on the EEG, and
generalized tonic /clonic or clonic /tonic /clinic seizures.
JME is widely accepted to be genetically determined,
although its mode of inheritance remains controversial.
Studies so far reported have provided evidence both for
and against the existence of locus on chromosome 6p
(Greenberg et al., 1988) (EJM1) or 15q (Elmslie et al.,
1997) (EJM2). Le-Hellard et al. (1999) found no
evidence that susceptibility to JME was associated
with HLA-DR13 (6p) in a French population, but
Morita et al. (2000) reduced the EJM1 region to 3.7
cM flanked by D6S436 and D6S1662. With nonpara-
metric methods, Zara et al. (1995) reported linkage to a
locus on 8q24 but not 6p. Sander et al. (1998a,b) failed
to confirm linkage to the 8q24 locus in affected families.
Therefore, the responsible gene for JME is not uncov-
ered yet to date. However, as a candidate gene for
EJM1, C6orf33 (Chromosome 6 Open Reading Frame
33: LMPB1 ), an integral membrane protein that targets
to lysosomal structures has been reported (Suzuki et al.,
2001). The expression of C6orf33 in postnatal but not in
prenatal is inconsistent with juvenile onset of JME. The
genes that encode lysosomal proteins have been reported
to be responsible for Batten disease (CLN3 gene),
classical late-infantile neuronal ceroid lipofuscinosis
(CLN2 gene), and sialidosis type 1 (lysosomal neurami-
nidase gene) (Mitchison et al., 1997; Sleat et al., 1997;
Pshezhetsky et al., 1997). The defective gene product of
Unverricht-Lundborg type epilepsy, cystatin B is also
thought to act as a protector against the proteinases
leaking from lysosomes (Lalioti et al., 1997a,b; Virta-
neva et al., 1997). However, all these phenotypes are
progressive myoclonus epilepsies, and they sharply
differ from symptoms of JME. It is, thus unclear how
defects in a lysosomal membrane protein such as
LMPB1 could underlie the etiology of JME, one of
the idiopathic epilepsies. Further analysis of EJM1 is
underway, and other candidate gene(s) will also be
reported shortly.
2.2.2. Benign familial neonatal convulsions (BFNC)
Benign familial neonatal convulsions (BFNC) is an
autosomal dominantly inherited disorder of newborns
with high penetrance and is characterized by clusters of
generalized and partial seizures, and remits sponta-
neously within 8 months. However, the incidence of
subsequent epilepsy later in life is about 11% in patients
with BFNC (Plouin, 1997).
BFNC has been linked to mutations in two
K
channel genes, KCNQ2 on chromosome 20
(BFNC1) and KCNQ3 (BFNC2) on chromosome 8
(Leppert et al., 1989; Ryan et al., 2002; Malafosse et al.,
1992; Lewis et al., 1993; Biervert et al., 1998; Charlier et
al., 1998; Singh et al., 1998; Hirose et al., 2000a,b;
Ushida et al., 2001). Abnormalities of both KCNQ2 and
KCNQ3 lead to dysfunction of the M-current, a slowly
activating and deactivating potassium conductance
critical to determining the subthreshold electrical excit-
ability of neurons (Wang et al., 1998). KCNQ2 and
KCNQ3 synergistically contribute to formation of the
native M current (Wang et al., 1998). In situ hybridiza-
tion studies have shown that the KCNQ2 and KCNQ3
messenger RNAs are co-localize in the brain (Schroeder
et al., 1998; Yang et al., 1998), and K
currents of
KCNQ K
-channels reconstituted in oocytes are fully
formed only when both KCNQ2 and KCNQ3 are co-
expressed (Wang et al., 1998; Selyanko et al., 1999).
Thus, both KCNQ2 and KCNQ3 are considered to
assemble into a heterometric tetramer to function as an
active K
-channels. Deficient KCNQ2 or KCNQ3 does
not necessarily abolish M-current but reduces it by 30%.
Nominal reduction of M-current, therefore, can under-
mine the inhibitory system of the CNS in the newborn.
Schwake et al. (2000) studied the single channel
properties of homo- and heterometric KCNQ2 and
KCNQ3 channels and reported that the increased
currents of heterometric channels were due to an
increased expression of active channels on the plasma
membrane. The C-terminus of KCNQ2 was found to
play an important role in such efficient surface expres-
sion. Most mutations of KCNQ2 so far found in
BFNC1 are located in the C-terminus, some of which
have been demonstrated to hamper the surface expres-
sion of heterometric channels with KCNQ3 and thereby
reduce K
current. The C-terminal of KCNQ molecules
bearing conserved amino acid sequence may serve as a
key element in assembly with homologous pore forming
subunits, which may be essential to traffic K
channels
to the plasma membrane. Alternatively, they per se may
convey export signals from endoplasmic reticulum to
Golgi apparatus to control surface K
channel num-
bers, such as demonstrated in inward rectifying K

channels, another K
channel family (Ma et al., 2001).
Some mutations located in transmembrane domains
including the pore region do not interfere with the
surface expression of channels but reduce K
current
(Schwake et al., 2000). Reduced K
current resulting
from mutations in either KCNQ2 or KCNQ3 can lead
to relative hyperexcitability of neurons. Thus, dysfunc-
 S. Kaneko et al. / Neuroscience Research 44 (2002) 11 /30
tion of either KCNQ2 or KCNQ3 results in indistin-
guishable convulsions in BFNC1 and 2. In fact, hetero-
zygous knockout mice of KCNQ2 show neuronal
hyperexcitability (Watanabe et al., 2000).
We have demonstrated that KCNQ K
channels
serve as a predominant inhibitory system in the CNS of
neonates and GABAergic-transmission serves as the
inhibitory system afterwards, indicating that deficient
KCNQ K
channels cause convulsions during the
neonatal period. In the same study, we also showed
that in mature CNS, dysfunction of KCNQ K

channels per se cannot affect seizure threshold during
the resting stage, but can lead to seizure activities under
the condition of neuronal hyperexcitability. These find-
ings indicate that deficient KCNQ K
channels are
involved in the age-dependent features of time of onset
and early spontaneous remission, and propensity for
future epilepsies in BFNC afterwards (Okada et al.,
2002).
The fact that mutations of KCNQ2 and KCNQ3 only
explain the genetic mechanisms involved in a small
number of the patients with BFNC indicates the
probable presence of a third, as yet unidentified, gene.
2.2.3. Childhood absence epilepsy (CAE)
Childhood absence epilepsy (CAE) is one of the most
common epilepsies. Age of onset is between 4 and 8
years, peaking at 6 /7 years. The characteristic seizure is
an abrupt impairment of consciousness accompanied by
a diffuse, bilaterally symmetric, 3-HZ spike-wave com-
plex lasting not more than 10 s. CAE has been mapped
to chromosome 20q (Steinlein et al., 1997a,b) and
8q24.3 (Fong et al., 1998). In the former, CHRNA4 is
speculated as a responsible gene. In the study of the
latter locus, haplotype and recombination analyses of
family members reduced the CAE region to 1.5 Mb
flanked by D8S554 and D8S502, and lod score of 4.10
(u /0) was obtained at D8S534 (Sugimoto et al. (2000)).
However, Sander et al. (1998b) did not replicate the
latter findings, and Delgado-Escueta et al., 1994 re-
ported linkage to chromosome 1p in families whose
probands had CAE evolving into juvenile myoclonic
epilepsy. Juvenile absence epilepsy occurs between 9 and
12 years of age, and the absence seizures are similar to
those in CAE but occur less frequently. The EEG shows
faster spike and polyspike wave patterns, and frequently
generalized tonic /clonic seizures occur at the onset or
later (Doose and Baier, 1989). Using a candidate gene
approach, Sander et al. (1997) reported an allelic
association with a GluR5 kainate receptor gene
(GRIK1 ) polymorphism in an affected family. To date,
no convincing gene is reported for absence, including
CAE and juvenile absence epilepsy.
17
3. Specific syndromes (Table 4)
3.1. Progressive myoclonus epilepsy
The progressive myoclonus epilepsies (PMEs) are a
collection of rare disorders presenting with the triad of
myoclonic seizures, tonic-clonic seizures, and progres-
sive neurologic dysfunction that often manifests as
dementia and ataxia. PMEs generally begin in late
childhood to adolescence.
There is ethnic and geographic variation in the
frequency of these disease syndromes, and most of
PMEs are autosomal recessive in inheritance (Kaneko
and Wada, 1998). Significant progress has recently been
made in the mapping and isolation of genes for
symptomatic Mendelian epilepsies such as Unverricht /
Lundborg disease, the neuronal ceroid lipofuscinoses,
Lafora body disease, sialidosis, dentatorubral /pallido-
luysian atrophy and myoclonic epilepsy with ragged red
fibers.
3.1.1. Unverricht /Lundborg disease
Unverricht /Lundborg disease (EPM1), described in
1891 (Unverricht, 1891) by Unverricht in Estonia and by
Lundborg (1903) in Sweden, is sometimes known as
Baltic myoclonic epilepsy because of its high prevalence
in that region. With onset between 6 and 15 years of age,
the EPM1 is manifested by stimulus-sensitive myoclo-
nus, tonic /clonic seizures, progressive slow intellectual
decline, emotional lability, and eventually ataxia, inten-
tional tremor, and dysarthria. The disorder has an
autosomal recessive transmission (Norio and Koski-
niemi, 1979), and has been mapped to 21.q22.3 in 12
Finnish families (Lehesjoki et al., 1991). A previously
described but unmapped protein, cystatin B, encoded by
an intracellular protease inhibitor gene, is found in this
region. Cystatin B DNA mutations have been found in
affected patients but not in unaffected individuals
(Pennacchio et al., 1996). The most common EPM1
mutation results from an unstable expansion of a
normally polymorphic dodecamer repeat unit in the
noncoding region upstream from the transcription start
site of the cystatin B gene (Lalioti et al., 1997a,b;
Virtaneva et al., 1997). This expansion represents the
first case of instability of a repeat unit other than
trinucleotides associated with human diseases (Lafre-
niere, et al., 1997). Cystatin B is a cystein/protease
inhibitor that is thought to protect against apoptosis,
but the mechanisms leading to Unverricht /Lundborg
disease remain to be elucidated.
3.1.2. Lafora body disease
Lafora body disease described in 1911 (Lafora and
Glueck, 1911) is a polyglucosan storage disorder, and is
inherited through an autosomal recessive trait. Linkage
of Lafora body disease to the chromosome 21 locus
18 S. Kaneko et al. / Neuroscience Research 44 (2002) 11 /30
(EPM1) associated with PME was excluded by Lehes-
joki et al. (1992). Serratosa et al. (1995) reported linkage
to a 17-cM interval of chromosome 6p23 /25 in nine
families with a maximum multi-point lod score of 10.58
and no evidence of heterogeneity. The gene (EPM2A )
encoding a novel protein tyrosine phosphatase (a
tyrosine kinase inhibitor) called laforin has been re-
ported to be mutated in the Lafora type PME (EPM2 )
(Minassian et al., 1998; Serratosa et al., 1999). Subse-
quently, a number of presumably loss-of-function muta-
tions in EPM2A have been identified in families with
Lafora body disease (Minassian et al., 2000a,b; Gomez-
Parre et al., 2000). Laforin may play regulatory roles in
glycogen metabolism (Serratosa et al., 1999; Minassian
et al., 2000b; Ganesh et al., 2000). A recent study
suggests that laforin is involved in translational regula-
tion and that protein misfolding may be one of the
molecular bases of the Lafora disease phenotype caused
by missense mutations in EPM2A (Ganesh et al., 2000).
Laforin is functionally conserved in mammals and is
involved in growth and maturation of neural networks
(Ganesh et al., 2001). The identification of other
proteins/substrate(s) that interact with laforin , in parti-
cular the enzymes involved in glycogen synthesis are
now essential.
3.1.3. Northern epilepsy
Northern epilepsy, also known as progressive epilepsy
with mental retardation (EPMR), is a recessive inherited
childhood epilepsy found in northern Finland (Hirvas-
niemi et al., 1994, 1995).
With onset between 5 and 10 years of age, the disease
is manifested by generalized tonic /clonic seizures. The
seizures increase in frequency until puberty, but subse-
quently seizure frequency declines, and by 35 years
many patients become seizure free. Mental development
deteriorates after the seizures begin, and becomes
progressively severe. Tahvanainen et al. (1994) assigned
EPMR to the distal region of chromosome 8p by linkage
analysis of 11 families. Haplotype analysis demonstrated
that, with one exception, both parents of all sibships but
one descended from one or two founding couples
(Ranta et al., 1997), suggesting that there is a different
mutation or a more widespread distribution of the
EPMR gene than occurs in the isolated Finnish popula-
tion in which the disorder was identified.
3.1.4. Neuronal ceroid lipofuscinoses
The neuronal ceroid lipofuscinoses (NCLs) are a
group of diseases that result in storage of lipopigments
in the brain and other tissues, and most are transmitted
as autosomal recessive traits. Diagnosis is frequently
based on visual problems, behavioral changes, and
seizures. Progression is reflected by a decline in mental
abilities, increasingly severe and untreatable seizures,
blindness, and loss of skills. Several forms of NCL are
differentiated according to age of onset, pathology, and
genetic linkage. These are infantile NCL (CLN1),
classical late-infantile NCL (CLN2), juvenile NCL
(CLN3), adult NCL (CLN4), two variant forms of
classical late-infantile NCL (CLN5 and CLN6), and
possibly other atypical forms (Boustany, 1996; Sharp et
al., 1997).
3.1.5. Infantile type of neuronal ceroid lipofuscinosis
(CLN1)
CLN1 typically presents at 12 /18 months with
developmental regression, myoclonus, ataxia, visual
failure, and some other features such as incoordination
of limb movement, acquired microcephaly, and optic
atrophy. Seizures include myoclonic jerks, and astatic,
atonic, or generalized seizures. EEG recordings show
progressive loss of electrocortical activity and attenua-
tion of the background (Santavouri, 1988). The defec-
tive gene in CLN1 has been identified by positional
candidate methods, and defects in the palmitoyl /protein
thioesterase gene have been reported to be responsible
for the diseases (Vesa et al., 1995).
3.1.6. Classical late-infantile neuronal ceroid
lipofuscinosis (CLN2)
CLN2 shares many clinical features with the CLN1.
By age 2/4 years, insomnia and intractable seizures
develop. As the disease progresses, irregular myoclonic
jerks evoked by proprioceptive stimuli, voluntary move-
ments, or emotional fluctuations become prominent.
Cognitive decline, ataxia, and visual failure with optic
atrophy and an abnormal EEG are typical (Harden et
al., 1973). Giant visual evoked responses and somato-
sensory potentials are observed. A characteristic EEG
pattern of occipital spikes on low-frequency photic
stimulation is observed (Pampiglione and Harden,
1973). The gene responsible for most cases has been
mapped to 11p15 (Sharp et al., 1997), and the identified
protein, a pepstatin-insensitive lysosomal peptidase was
deficient in CLN2. Mutations in the gene encoding this
protein were identified in CLN2 patients but not in
normal control (Sleat et al., 1997).
3.1.7. Juvenile type of neuronal ceroid lipofuscinosis
(CLN3)
CLN3 also known as Spielmeyer /Vogt disease or
late-onset Batten disease is the most common neurode-
generative disorder of childhood. Clinical onset begins
with visual failure between the age of 5 and 10 years,
slow intellectual deterioration and seizures. Diagnostic
criteria include the presence of inclusions in many cell
types that appear as so-called fingerprint profiles on
electron microscopy (Wissniewski et al., 1988). The
CLN3 maps to 16p12.1 (Eiberg et al., 1989; Mitchison
et al., 1995), and Lerner et al. (1995) have reported that
the disease gene encodes a novel 438 amino acid protein,
 S. Kaneko et al. / Neuroscience Research 44 (2002) 11 /30
and subsequently a cDNA was cloned by Mitchison et
al. (1997), Golabek et al. (2000) showed that CLN3
protein increased lysosomal pH in cultured human
kidney cells, whereas inhibition of CLN3 protein synth-
esis by antisense approach acidified lysosomal compart-
ments, and suggesting that the pathogenesis of CLN3
was associated with altered acidification of lysosomal
compartments. An interesting point of this report is that
CLN3 protein affects the metabolism of proteins
essential for cell functions, such as the amyloid-beta
protein precursor implicated in the pathogenesis of
Alzheimer’s disease.
3.1.8. Adult neuronal ceroid lipofuscinosis (CLN4)
CLN4 is the rarest, most heterogeneous and poorly
defined of the Batten subtypes. Berkovic et al. (1988) has
subdivided the entity into two main types: Type A,
characterized by generalized seizures and myoclonic
jerks and the absence of any visual symptom, and
Type B defined by the presence of facial dyskinesias
and an evolving picture of pyramidal and extrapyrami-
dal dysfunction. There are many reports on differential
diagnosis, neuropathology, ultrastructure, biochemistry,
and cell biology; however, at present, it is impossible to
yoke all of them into one plausible unifying theory. This
may not become feasible until the defective genes and
their products are identified (Boustany, 1996).
3.1.9. Finnish-variant late-infantile type of neuronal
ceroid lipofuscinosis (CLN5)
CLN5 is a variant subtype of the late-infantile form of
CLN which is a rare recessive disease enriched in the
limited region of Finland. Several atypical forms of
NCLs differ clinically and neurophysiologically from
CLN2 and CLN3 patients. The age at onset falls within
that of CLN3, but the clinical manifestations, the course
of the disease, and the neurophysiological findings are
very similar to those of classical CLN2 (Neubauer et al.,
1979). Savukoski et al. (1994) have reported the assign-
ment of the locus for CLN5 to a defined chromosomal
region 13q21.1 /q32 and demonstrate that, despite the
similarity of these clinical phenotypes, the classical form
of late-infantile form of NCL represents a nonallelic,
still-unidentified locus. The genealogical studies and the
observed linkage disequilibrium provide evidence that
the mutation causing the variant late-infantile form of
NCL is the result of a relatively recent founder effect in
the genetically isolated population of Finland.
3.1.10. Variant late-infantile neuronal ceroid
lipofuscinosis (CLN6)
CLN 6 is sometimes called ‘early juvenile’. A new
strategy based upon homozygosity mapping was
adopted in which a subset of five classical late infantile
NCL and two variant late infantile CLN consangui-
neous families were used in a genome search. A common
19
region of homozygosity was observed on chromosome
15q21/23 in the two variant families. (Sharp et al.,
1997).
The tissue findings of all types of CLNs are almost the
same at the light-microscopy level, with an accumula-
tion of storage particles consisting of ceroid- and
lipofuscin-like lipopigments in a majority of tissues.
The final outcome of the disease is also similar,
suggesting that more than four independent genetic
loci are involved in the pathogenesis of CLNs. The
defect could be the result of a dysfunction of a multimer-
molecule whose functional components are controlled
by independent loci spread in different autosomes, or
the defective genes in subtypes of CLN could code
different proteins, which function in successive steps of a
thus-far-uncharacterized metabolic pathway, essential
for the normal function and maturation of cortical
neurons (Savukoski et al., 1994).
3.1.11. Sialidosis
In mammals, three types of sialidoses, lysosomal,
plasma membrane and cytosolic, have been described
(Verheijin et al., 1983; Miyagi et al., 1990; Schneider-
Jakob and Cantz, 1991). For lysosomal sialidosis in
humans, the primary genetic deficiency results in an
autosomal recessive disease, sialidosis, associated with
tissue accumulation and urinary excretion of sialylated
oligosaccharides and glycolipids. The human lysosomal
enzyme occurs in complex with beta-galactosidase and
protective protein/cathepsin A (PPCA), and is deficient
in two genetic disorders: sialsidosis, caused by a
structural defect in the neuraminidase (sialidosis) gene,
and galactosialidosis, in which the loss of neuraminidase
activity is secondary to a deficiency of PPCA.
Sialidosis includes two main clinical variants: late-
onset, sialidosis Type 1 (Cherry-Red Spot/Myoclonus),
characterized by bilateral cherry-red spots and myoclo-
nus (Durand et al., 1977; O’Brien, 1979), and infantile-
onset, sialidosis Type 2 (Galactosialidosis), character-
ized by skeletal dysplasia, mental retardation and
hepatosplenomegaly (Till et al., 1987; Oohira et al.,
1985; Beck et al., 1984).
Regarding sialidosis Type 1, Mueller et al. (1986) have
shown that the sialidosis disorder results from a muta-
tion on chromosome 10, presumably encoding the
neuraminidase structural gene. Galactosialidosis is
caused by a mutation in a second gene required for
neuraminidase expression on chromosome 20. Pshez-
hetsky et al. (1997) mapped the lysosomal sialidosis gene
to chromosome 6p21.3, which was consistent with the
previous chromosomal assignment of this gene in
proximity to the HLA locus (Bonten et al., 1996).
However, enzyme assays for deficiency of a-neuroami-
nidase, the structural components of which are encoded
on chromosome 10, offer definitive diagnosis (Mueller et
al., 1985).
20 S. Kaneko et al. / Neuroscience Research 44 (2002) 11 /30
Sips et al. (1985) reported that the structural locus for
the beta-galactosidase polypeptide was located on
chromosome 3, and the protective protein on chromo-
some 22 was essential for the in vivo stability of beta-
galactosidase by aggregating beta-galactosidase mono-
mers into high molecular weight multimers. Zhou et al.
(1991) suggested that the dimerization process might be
a condition for the proper targeting and stable con-
formation of the protective protein. In the majority of
sialidosis Type 2, a partial deficiency of b-galactosidase
can be seen in addition to neuraminidase deficiency, and
this may be due to a defect in protective protein; the
gene locus for this protein is 20q13.1 (Wiegant et al.,
1991).
3.1.12. Juvenile Gaucher’s disease
Gaucher’s disease, the inherited deficiency of the
enzyme glucocerebrosidase, is the most common inher-
ited lysosomal hydrolase deficiency. Three types of
Gaucher’s disease are known: type 1, a chronic form
with adult onset which has no associated neurologic
manifestations; type 2, a rare form associated with
infantile demise; and type 3, a chronic form with
neurological impairment that develops in childhood or
early adulthood.
The gene for glucocerebrosidase is located on chro-
mosome 1q21. Over 100 different glucocerebrosidase
mutations have been identified in DNA from patients
with Gaucher disease (Koprivica et al., 2000). The
molecular diagnosis of this disease is complicated by
the presence of a pseudogene sharing 96% homology in
the coding region, which is located 16 kb downstream of
the functional gene on chromosome 1q21 (Winfield et
al., 1997). Metaxin , a convergently transcribed gene
adjacent to the 3? end of the glucocerebrosidase pseu-
dogene, also has a highly homologous pseudogene
located between the glucocerebrosidase gene and pseu-
dogene (Long et al., 1996). The metaxin gene encodes
for a 317 amino acid protein which is part of a
preprotein import in the outer membrane of mammalian
mitochondria (Armstrong et al., 1997).
There is significant phenotypic variation, not only
among patients with the same disease type but also
among patients with identical genotypes (Grabowski,
1997). Even among patients from a geographic isolate */
such as the Norrbottnian region of Sweden, where type
3 Gaucher’s disease is seen with increased frequency */a
wide spectrum of presentations are encountered,
although all of the patients are homozygous for the
point mutation Leu444Pro (Dahl et al., 1990).
The frequency of specific mutated alleles varies in
different populations. Founder effects may account for
such population differences. Mutations Asn370Ser,
Leu444Pro, c.84 /85insGly, and IVS2
/1Gly 0/Ala ac-
count for /96% of the mutated alleles in Ashkenazi
Jewish patients, although they constitute B/75% of the
mutated alleles in non-Jews (Beutler and Gelbert, 1993).
Among the Japanese population with this disease,
neither mutation Asn370Ser nor c.84 /85insGly are
seen, but Leu444Pro and Phe213Ile are relatively
common (Eto and Ida, 1999). These reports support
the founder-effect theory. Tayebi et al. (2000) recently
reported a novel recombinant allele consisting of a
duplication of the glucocerebrosidase pseudogene and
a fusion between the metaxin gene and its pseudogene,
resulting from a crossover between metaxin and pseu-
dometaxin in the region downstream of the glucocer-
ebrosidase gene. This type of study can contribute to
genotype-phenotype analysis, and some genotype-phe-
notype correlation’s do exist. However, Koprivica et al.
(2000) caution against relying solely upon genotype for
prognostic or therapeutic judgements because other
genetic and environmental factors also contribute to
the phenotypes.
3.1.13. Dentatorubural-pallidoluysian atrophy
(DRPLA)
DRPLA is a rare autosomal dominant disease seen
predominantly in the Japanese population. The disorder
is related to a trinucleotide (CAG) expansion on
chromosome 12p (Koide et al., 1994; Nagafuchi et al.,
1994). Symptoms begin in infancy to early childhood
with myoclonus, ataxia, dementia or seizures (general-
ized tonic /clonic, atypical absence, or atonic), and these
clinical manifestations are dependent on the length of
the unstable trinucleotide repeats and vary from a
juvenile-onset PME to an adult-onset syndrome with
ataxia, dementia, and choreoathetosis (Hattori et al.,
1997).
3.2. Principal inherited disorders with epilepsy as a part
of phenotype
3.2.1. Benign adult familial myoclonic epilepsy
(BAFME)
BAFME is an autosomal dominant-inherited idio-
pathic epileptic syndrome characterized by adult-onset
tremulous finger movement, myoclonus, epileptic sei-
zure, and a non-progressive course. The gene for
BAFME was recently assigned to chromosome
8q23.3 /q24.1 in a Japanese family (Mikami et al.,
1999). This data clearly revealed that BAFME and
some other epilepsy phenotypes such as familial adult
myoclonic epilepsy (FAME) were the same disease
(Plaster et al., 1999). Lewis et al. (1993) have reported
linkage of benign familial neonatal convulsions
(BFNC2) with markers D8S284 and D8S256 localized
at 8q24.13-qter, and familial febrile convulsions have
been mapped to 8q13 /21 (Wallace et al., 1996). How-
ever, the locus of BAFME is distinct from these loci.
 S. Kaneko et al. / Neuroscience Research 44 (2002) 11 /30
3.2.2. Chorea-acanthocytosis
Chorea-acanthocytosis (CHAC) is a neurodegenera-
tive disorder with peripheral red cell acanthocytosis, and
is a rare hereditary disease with autosomal recessive
transmission that produces adult-onset choreic involun-
tary movement. Other clinical symptoms include psy-
chiatric features, epilepsy, peripheral neuropathy,
myopathy, and oral self-mutilation (Brin, 1993). Link-
age of CHAC to 9q21 has been found (Rubio et al.,
1997), and Ueno et al identified a gene, named chorein
(2001). They found a deletion in the coding region of the
cDNA leading to a frame shift resulting in the produc-
tion of a truncated protein in both alleles of patients and
in single alleles of obligate carriers.
3.3. Diseases of the mitochondrial DNA
Mitochondria contain a circular genome (16.569 bp)
that codes for a number of proteins required for
mitochondrial function. Mutations in mitochondrial
DNA will lead to defects in oxidative phosphorylation
and a reduction in energy production by the mutated
mitochondria. The heterogeneity in mitochondrial DNA
composition within a cell, termed heteroplasmy, is an
important cause of variable expression in mitochondrial
disorders. All mitochondrial genomes are inherited from
the mother and this means that only females can
transmit mitochondrial diseases to their male and female
offspring with equal incidence. Although a number of
deleterious tRNA mutations have been described, the
two most common are nucleotide substitution in the
tRNALeu gene at 3243 and in the tRNALys gene at 8344
(Sternberg et al., 2001).
3.3.1. Myoclonus epilepsy and ragged-red fibers
(MERRF)
Onset of MERRF occurs before 20 years of age, with
ataxia and seizures that are predominantly myoclonic.
Like many of the PMEs, giant somatosensory evoked
potentials are observed. Lactic acidosis and the presence
of ragged-red fibers on muscle biopsy are essential for
the diagnosis. The inheritance pattern is compatible with
maternal transmission. In the majority of cases, an A to
G mutation at nucleotide pair 8344 in human mitochon-
drial DNA (mt DNA) has been identified as the cause of
MERRF. The mutation alters T psi C loop of the tRNA
(Lys ) gene, resulting in a point mutation (tRNALys), and
creates a CviJI restriction site, providing a simple
molecular diagnostic test for the disease (Schoffner et
al., 1990). Another mutation in tRNALeu found by
Moraes et al. (1993) caused a neurological syndrome
resembling MERRF plus optic neuropathy, retinopa-
thy, and diabetes. This mutation was heteroplasmic,
with higher percentage of mutant mt DNA pool in
affected tissues, and undetectable levels in maternal
relatives. The morphological and biochemical altera-
21
tions appear only when the proportion of mutant
mtDNA exceeds 90% of the total cellular mtDNA
pool (Moraes et al., 1993).
3.3.2. Mitochondrial myopathy, encephalopathy, lactic
acidosis, and stroke-like episodes (MELAS)
MELAS is one of the clinically defined mitochondrial
diseases, characterized by early onset and stroke-like
symptoms. A point mutation at nucleotide pair 3243
within the tRNA /Leu (UUR ) gene was found (Goto et
al., 1990) in 80% of patients with MELAS and another
mutation at 3271 was found in 10% (Goto et al., 1991).
4. Febrile seizures (Table 5)
4.1. Febrile seizures (FS)
FS affect approximately 3% of all children under 6
years of age and are by far the most common seizure
disorders. No specific gene responsible for simple FS has
yet been identified but, four putative loci of FS have
been mapped (FEB1 : 8q; FEB2 : 19p, FEB3 : 2q, FEB4:
5q) (Wallace et al., 1996; Johnson et al., 1997; Peiffer et
al., 1999; Nakayama et al., 2000).
4.2. Generalized epilepsy with febrile seizures plus
(GEFS
/)
A clinical subset, termed generalized epilepsy with
febrile seizures plus (GEFS
/type 1), in which many
family members have seizures with fever that may persist
beyond 6 years of age or be associated with afebrile
generalized seizures has been mapped to chromosome
19q13.1. And Wallace et al. (1998) identified a mutation
in the b1 subunit gene (SCN1B ) controlling voltage-
gated sodium (Na
)-channel. Co-expression of the
mutant b1 subunit with a brain Na
-channela subunit
in Xenopus laevis oocyte demonstrates that the mutation
interferes with the ability of the subunit to modulate
channel-gating kinetics consistent with a loss-of-func-
tion allele (Wallace et al., 1998).G
GEFS
/type 2 has been associated with mutations in
SCN1A , and Arg1648His is a mutation in SCN1A that
may reduce the rate of inactivation of SCN1A , resulting
in increased Na
influx, and increased excitability in the
CNS (Escayg et al., 2000). Wallace et al. (2001a)
performed single-stranded conformation analysis of
SCN1A in 53 unrelated index cases to estimate the
frequency of mutations in patients with GEFS
/, and
found that the combined frequency of SCN1A and
SCN1B mutations in familial cases with GEFS
/ was
17%.
Recently, Baulac et al. (2001) reported that a Lys289-
Met mutation (Lys289Met) in the GABA-A receptor g2
subunit (GABRG2 ) was identified in a family with a
22 S. Kaneko et al. / Neuroscience Research 44 (2002) 11 /30
phenotype closely related to GEFS
/, and this pheno-
type was named as GEFS
/type 3. The Lys289Met
mutation affects a highly conserved residue located in
the extracellular loop between transmembrane segment
M2 and M3. A to T transversion in exon 8 resulted in
the substitution of a positively charged lysine residue for
a neutral amino acid, methionine. Analysis of mutated
and wild-type receptors in xenopus laevis oocytes con-
firmed that there was a decrease in the amplitude of
GABA-A activated currents due to the mutation. Thus,
functional deficit resulted from the incorporation of the
g2 Lys289Met-subunit into pentameric receptors.
However, GEFS
/ is not a proper nomenclature,
because seizures in individuals who are thought to have
GEFS
/ apparently encompass partial seizure pheno-
type (Sugawara et al., 2001a,b; Ito et al., 2002). There-
fore, we proposed that this phenotype should be called
‘autosomal dominant epilepsy with febrile seizure plus’
(Ito et al., 2002). In addition, it is noteworthy that
Val1418Ala is the first instance of a mutation in the pore
region of a Na channel causing a human disorder.
Recently, Wallace et al. (2001b) found that a muta-
tion in GABRG2 in a large family with various forms of
epilepsy, such as childhood absence (CAE) and febrile
seizures (FS). The 245 Gly to Ala nucleotide substitu-
tion in exon 2 changes a highly conserved arginine to a
glutamate at residue 43 of the mature GABRG2 protein.
Arg 43 is located within the first two high-affinity
benzodiazepine-binding domains. This mutation abol-
ished the actions of benzodiazepine on the GABA
receptor; however, there was no difference in the
GABA-A receptor activated currents. The mutated
GABRG2 may cause incorrect assembly of the GABRG2
subunit with the receptor complex, which would abolish
sensitivity to benzodiazepine. Wallace et al. (2001b)
speculate that the GABRG2 mutation contributes to the
pathogenesis of both FS and CAE, and that this
mutation is one of the genes that contributes to, but
alone is insufficient to cause, the CAE phenotype in this
family.
They studied another family that has GEFS
/,
including severe myoclonic epilepsy in infancy (SMEI)
and found a novel GABRG2 mutation (Harkin et al.,
2002), lies in the intracellular loop between the third and
fourth transmembrane domains of the receptor and
introduces a premature stop codon at Q351 in the
mature protein (Q351X). GABA sensitivity in Xenopus
laevis oocytes expressing the mutant g2Q351X subunit is
completely abolished, and fluorescent-microscopy stu-
dies have shown that receptors containing GFP-labeled
g2Q351X protein are retained in the lumen of the
endoplasmic reticulum. Based upon these data, they
speculated that for individuals heterozygous for the
Gly351X mutation, the truncated receptor subunit
reduces the density of functional GABA-A receptor
complexes on the cell surface, leading to a decreased
inhibitory response to GABA and, consequently, to
increased neuronal excitability and seizures.
4.3. Severe myoclonic epilepsy of infancy (SMEI)
SMEI is a rare disorder that occurs in isolated
patients. The disease is characterized by generalized
tonic, clonic, and tonic /clonic seizures that are initially
induced by fever and begin during the first year of life.
Later, patients also manifest other seizure types, includ-
ing absence, myoclonic, and simple and complex partial
seizures. Around the 2nd year of life, psychomotor
development also becomes delayed. Claes et al. (2001)
screened seven unrelated patients with SMEI for muta-
tions in SCN1A and identified a mutation in each
patient: four had frameshift mutations, one had a
nonsense mutation, one had a splice-donor mutation,
and one had a missense mutation. All mutations were de
novo mutations that were not observed control chromo-
somes. For these findings, they speculated that in the
majority of patients with SMEI, the mutation results in
early termination of translation, thereby producing a C-
truncated SCN1A protein from one of the SCN1A
alleles. Rapid degradation of these truncated transcripts
or proteins could lead to a loss of function comparable
with haploinsufficiency. Alternatively, some of the
transcripts could lead to abnormal proteins with a toxic
increase in function. Fig. 1 illustrates schematic repre-
sentation of the sodium channel protein with the
position of mutations associated with GEFS
/ and
SMEI.
Thus, autosomal dominant epilepsy with febrile
seizure plus (GEFS
/) and SMEI are now associated
with mutations of genes encoding both Na
channel
subunit and the g2-subunit of the GABA-A receptor.
These mutations may contribute to lowering the epilep-
togenic threshold in a nonspecific manner. However, as
Na
channel blockers and GABAergic neurotransmis-
sion enhancers are the two major categories of AEDs
used clinically, the nature of the mutant channel may
modulate the response to a given treatment.
5. Characterization of epilepsy as channelopathies
CHRNA4 has been identified as the first gene under-
lying an idiopathic partial epilepsy syndrome in humans,
ADNFLE (Steinlein et al., 1995, 1997b; Hirose et al.,
1999; Phillips et al., 2000). The mutant receptor
exhibited faster desensitization upon activation by
acetylcholine and recovery from the desensitized state
was much slower than in the wild type receptor
suggesting that the reported mutations caused seizures
via a diminution of the activity of the a4b2 neuronal
nicotinic acetylcholine receptor (Weiland et al., 1996).
The gene for the electroencephalographic variant pat-
 S. Kaneko et al. / Neuroscience Research 44 (2002) 11 /30 23

Fig. 1. Organization of Na
channel and localization of mutations with GEFS
/ or SMEI The neuronal voltage-gated sodium-channel a-subunit
(SCN1A , SCN2A ) is a monomer and consists of four homologous domains, in which each domain has six transmembrane segments. The fourth
transmembrane segment of each domain has several positively charged amino acids and represents the voltage sensor. Both b1 and b2 subunits bear
one transmembrane domain shown left and right in the figure, respectively. Green circles: SCN1A mutations identified in patients with SMEI. Blue
circles: SCN1A mutations identified in patients with GEFS
/. Red circle: A SCN2A mutation identified in a family with GEFS
/. White circle: A
SCN1B mutation identified in a family with GEFS
/.

tern 1 (EEGV1 ) also maps to the same region, suggest-
ing that CHRNA4 may possibly be involved in several
epileptic disorders, such as CAE and juvenile absence
epilepsy.
BFNC (EBN1 and EBN2) is caused by mutations in
the KCNQ2 or the KCNQ3 potassium channel genes.
KCNQ2/KCNQ3 mutations identified in BFNC pedi-
grees compromise the function of the respective sub-
units, but exert no dominant-negative effect on KCNQ2 /
KCNQ3 heteromeric channels. Schroeder et al. (1998)
predicted that a 25% loss of heteromeric KCNQ2 /
KCNQ3 channel function is sufficient to cause the
electrical hyperexcitability in BFNC, indicating that
BFNC is due to a loss of KCNQ2 /KCNQ3 heteromeric
channels which may lead to impairment of repolariza-
tion. Amino acid sequence comparison revealed that
both genes shared strong homology to KCNQ1 , which is
responsible over 50% of inherited long QT syndrome.
Individually, expression of KCNQ2 or KCNQ3 in
Xenopus oocytes elicits voltage-gated, rapidly activating
K
-selective currents similar to KCNQ1 ; however,
unlike KCNQ1 , KCNQ2 and KCNQ3 currents are not
augmented by co-expression with the KCNQ1b subunit,
KCNE1 (min K, IsK). Co-expression of KCNE1 with
the two channels strongly suppressed current amplitude
and slowed kinetics of activation (Yang et al., 1998).
The functional interaction between KCNQ2 and
KCNQ3, and that between KCNQ-channel dysfunction
and dysfunction of the inhibitory neurotransmission
system provide a framework for understanding the
occurrence of BFNC and how mutations in channels
can cause a form of idiopathic generalized epilepsy
(Yang et al., 1998; Zhu et al., 2000).
SCN1B , SCNA1 , SCN2A and GABRG2 were identi-
fied as responsible genes underlying febrile convulsion
plus generalized epilepsy and SMEI. Animal studies also
suggest that genes encoding K
, Na
and Ca2

channels are at least partly responsible for convulsions,
24 S. Kaneko et al. / Neuroscience Research 44 (2002) 11 /30
and most AEDs bind to or affect various ion channels
(Kaneko and Okada, 1998). These reports support a
hypothesis that some types of idiopathic epilepsy are a
form of channelopathy. Understanding gained from
work in this area of epilepsy research not only enables
characterization of the molecular and physiologic basis
of these epilepsies but also ultimately sheds light on our
understanding of the pathophysiology of more common
epilepsies, and promises new vistas of AED treatment
that may benefit large numbers of affected individuals
(Hirose et al., 2000a,b).
6. Perspectives of molecular study of epilepsy
Responsible genes for idiopathic epilepsy phenotypes
so far reported all follow simple Menderian inheritance,
but common phenotypes such as absence and general-
ized tonic /clonic convulsions do not. Multiple genes
may be simultaneously involved and diversity of suscep-
tible genes may collaborate in determining the risk of
such common phenotypes of epilepsies. Although more
epilepsy genes await discovery, the mode of inheritance
of these phenotypes of epilepsy are not known. There-
fore, the new tools such as x-ray crystallography, mass-
spectrometry, and new methods such as nonparametric
allele-sharing analytic techniques, including sibling-pair,
affected sibling-pair, or affected pedigree-member meth-
ods, can be used. Association studies also do not depend
on analysis of familial inheritance patterns but compare
the frequency of alleles at a marker locus in patients and
a control population. If the distribution of alleles is
different in the two populations, an association is said to
exist. Thus, association studies are also useful in
identifying genes responsible for common phenotypes
of epilepsy.
Recently, attention has focused on the use of whole-
cell linkage disequilibrium methods to map common
disease genes. Such studies would employ a dense map
of single nucleotide polymorphisms (SNPs) to detect
association between a marker and disease (Kruglyak,
1999). Construction of SNP maps is currently under-
way. When a dense map of SNP becomes available, the
whole-cell linkage disequilibrium will be a good tool for
identifying the genetic basis of common phenotypes of
epilepsy. Microarray technology permits the measure-
ment of the expression of thousands of genes simulta-
neously. Lockhart et al. (1996) described a method for
the simultaneous monitoring of the expression levels of
many genes in parallel. Sequence information alone is
insufficient for a full understanding of gene function,
expression, regulation, and splice-site variation. As
cellular processes are governed by the repertoire of
expressed genes, and their levels and timing of expres-
sion, it is important to directly monitor large numbers of
mRNAs in parallel. The array developed by Lockhart et
al. (1996) is designed based on sequence information
alone and is synthesized in situ using a combination of
photolithography and oligonucleotide chemistry. This
approach provides a way to directly use the growing
body of sequence information for highly parallel experi-
mental investigations.
7. Conclusions
The discovery of dysfunction of ion channels in
idiopathic epilepsies has led to the concept of channe-
lopathies. At the same time, the genetic heterogeneity of
epilepsies has also become apparent. Different genes and
different mutations may cause the same epilepsy phe-
notype. Intrafamilial phenotypic heterogeneity is also
clear. The expression of the mutated genes may differ
among family members, causing clinical heterogeneity,
or the gene may intervene in epileptogenesis at a very
general level, affecting the epileptogenic threshold, and
other genetic or environmental factors may influence the
electroclinical profile of the epilepsy in each affected
subject (Gourfinkel-An et al., 2001). The progress in
epilepsy genetics facilitates genetic counseling, elucidat-
ing pathogenesis, clarifying the definition of syndromes,
and generates new treatment methods. Genes respon-
sible for common phenotypes of epilepsy have been
uncovered yet;, however, research in this area is moving
rapidly, and genes that relate to major phenotypes of
epilepsy will undoubtedly be discovered soon.
Acknowledgements
Our research was conducted as part of a comprehen-
sive project organized by The Epilepsy Genetic Study
Group, Japan (Chairperson, S.K.) and supported in part
by Grants in Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science and
Technology of Japan (09470206, 13035049, 12470174,
12559010, 14658263), The Epilepsy Research Founda-
tion, Uehara Memorial Foundation, Heiwa Nakajima
Foundation, Kobayashi Magobei Memorial Medical
Foundation, Brain Science Foundation, International
Fund of Kyushu University School of Medicine Alumi-
ni, The Clinical Research Foundation, and grants from
Fukuoka and Hirosaki Universities.
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