Epilepsia, 46(Suppl.

10):41–47, 2005
Blackwell Publishing, Inc.


C International League Against Epilepsy

Neonatal Epilepsy Syndromes and Generalized Epilepsy with

Febrile Seizures Plus (GEFS+)

∗ †‡Ingrid E. Scheffer, §Louise A. Harkin, §Leanne M. Dibbens,

§John C. Mulley, and ∗ Samuel F. Berkovic
∗ Department of Medicine (Neurology), The University of Melbourne, Austin Health, Melbourne, Victoria; †Department of Neurology,
Royal Children’s Hospital, Melbourne, Victoria; ‡Department of Neurosciences, Monash Medical Centre, Melbourne, Victoria;
§Department of Genetic Medicine, Women’s and Children’s Hospital, Adelaide, South Australia and Department of Pediatrics, The
University of Adelaide, Adelaide, South Australia; and School of Molecular and Biomedical Sciences, The University of Adelaide,
Adelaide, South Australia, Australia

The molecular revolution during the past decade has
had a major impact on our understanding of the genet-
ics of the epilepsies. Molecular discoveries have been
particularly important for two groups of epilepsy syn-
dromes: the autosomal-dominant seizure syndromes of
the first year of life, and the “genetic epilepsy syndrome”,
generalized epilepsy with febrile seizures plus (GEFS+).
Indeed, the neonatal syndrome benign familial neonatal
seizures (BFNS) is the only autosomal-dominant epilepsy
syndrome where the molecular basis has essentially been
solved with the vast majority of families having muta-
tions of the potassium channel subunit genes KCNQ2 or
KCNQ3. GEFS+ is characterized by phenotypic hetero-
geneity and is associated with mutations in four genes,
although mutation-positive cases only account for a mi-
nority of GEFS+ patients overall. The most severe end
of the phenotypic GEFS+ spectrum is severe myoclonic
epilepsy of infancy (SMEI), or Dravet syndrome, and
closely related phenotypic variations. In SMEI, molecular
genetics has elucidated much of the etiology of this devas-
tating disorder with about 80% of SMEI patients carrying
mutations of the sodium channel alpha 1 subunit gene,
SCN1A. This has already impacted on clinical diagnosis
and management of patients with SMEI.
AUTOSOMAL-DOMINANT SEIZURE
SYNDROMES OF INFANCY
There are three seizure syndromes that begin in the
first year of life, follow autosomal-dominant inheritance,
and have very similar clinical characteristics. These syn-
dromes are largely distinguished by their average ages of
onset and associated gene defects. The earliest onset syn-
Address correspondence and reprint requests to Prof. I.E. Scheffer,
Epilepsy Research Centre, Repatriation Campus, Austin Health,
Locked Bag 1, West Heidelberg, Victoria, Australia 3081. E-mail:
scheffer@unimelb.edu.au
drome is BFNS, also known as benign familial neonatal
convulsions; the later onset syndrome is benign familial
infantile seizures (BFIS); and more recently, an interme-
diate subgroup benign familial neonatal-infantile seizures
(BFNIS) with intermediate age of onset and molecular
specificity have gained prominence.
These three syndromes arise in previously well and
developmentally normal neonates or infants who present
with clusters of convulsive seizures over a few days. Al-
though BFNS and BFIS were included in the 1989 Inter-
national League Against Epilepsy (ILAE) classification as
“generalized” syndromes (1), the seizures often have focal
clinical and electroencephalogram (EEG) features. These
disorders share a good outcome with affected babies hav-
ing normal development and only a minority having later
febrile seizures or epilepsy.
Benign familial neonatal seizures (BFNS)
Rett and Teubel first recognized BFNS in 1964 (2).
BFNS is an autosomal-dominant disorder where previ-
ously well newborn infants develop seizures on day 2 or
3 of life in 80% of cases (3). If the neonate is premature,
seizure onset may be delayed until the baby is chronologi-
cally at term (4). Seizures usually start in the first week; the
vast majority have onset within the first month with rare
cases reported with later onset (5). Seizures have a variety
of manifestations including tonic attacks, apnoea, clonic,
focal, and autonomic features. Attacks are often stereo-
typed with hypertonia that may be diffuse or show varying
lateralization and apnoea, followed by motor manifesta-
tions involving the oculofacial region and clonic activity,
which may involve the limbs symmetrically or asymmet-
rically (3,6). The babies remain relatively well between
seizures such that they can feed normally; transient hy-
potonia may occur (3). Interictal EEG is normal or may
have focal or multifocal abnormalities (3). Ictal studies
show diffuse flattening evolving to focal or generalized

41
42 I. E. SCHEFFER ET AL.

spikes (7). Seizures typically remit by 4 months but may somes 1 and 19 although both localizations require repli-
continue until 18 months (8). Later, febrile seizures occur cation (34). A mutation in ATP1A2 on chromosome 1q23
in 5% of individuals and epilepsy in 11% of individuals has been found in a single family with familial hemi-
(3). Focal epilepsy may develop later including rolandic plegic migraine and infantile convulsions (35). ATP1A2
epilepsy (5,9,10). Poor outcome with refractory epilepsy is a sodium-potassium, ATPase transporter and is likely to
and mental retardation is rare (11,12); one family had later be important in familial hemiplegic migraine although its
onset of myokymia (13). role in BFIS requires confirmation.
Mutations in potassium channel subunits KCNQ2 and
Benign familial neonatal-infantile seizures (BFNIS)
KCNQ3 were discovered in BFNS in 1998 (14–16). Most
BFNIS was reported in a large North American family
families with BFNS have mutations in KCNQ2 with only
in 1983 (36). No further families were recognized un-
three mutations reported in KCNQ3 (5,8,10,17–20). The
til 2002 when two families were described with a mean
penetrance of BFNS mutations is about 85%. De novo mu-
seizure onset of around 3 months, falling in between the
tations in KCNQ2 have been reported in sporadic neonatal
average onset of seizures for BFNS (day 2 or 3) and BFIS
seizures (21).
(6 months). Both families had mutations of SCN2A, the
KCNQ2 and KCNQ3 form a heteromeric potassium
gene encoding the alpha-2 subunit of the sodium chan-
channel responsible for the M-current, which has a key
nel (37). There are now a total of eight families reported
role in the stabilization of membrane potential and thus
with mutations of SCN2A including one recurrent muta-
neuronal excitability (22–24). In vitro studies of mutant
tion found in three unrelated Italian families (38). Included
potassium channel subunits show variable loss of func-
in these eight families is the “BFIS” family of Malacarne
tion. Effects include decreased potassium current, reduced
et al. (2001) that was mapped to 2q24 and prompted muta-
cell surface channel expression, altered channel gating
tion screening of the SCN1A-SCN2A-SCN3A gene cluster
kinetics, and altered voltage dependence of activation
in the same chromosomal region (39). SCN2A has been
(11,13,14,17,23,25). Some mutations exert a dominant
studied in over 100 cases of other early childhood epilep-
negative effect (5,12,26).
sies, including GEFS+, and no mutations were found (38).
The absolute specificity of SCN2A mutations for BFNIS
Benign familial infantile seizures (BFIS)
was questioned by a single small Japanese family with a
Fukuyama recognized benign infantile convulsions in
SCN2A mutation with phenotypes of febrile and afebrile
1963 and the autosomal-dominant inheritance pattern seen
seizures, where it was difficult to apply a clear syndro-
in some families was brought to the fore by Vigevano and
mal classification (40). Given the recent SCN2A data, it
colleagues in 1992 (27,28). Seizures typically begin be-
is possible that BFNIS is more important than previously
tween 4 and 7 months of age. The seizures typically com-
appreciated and accounts for some families formerly re-
prise slow head and eye deviation, which may alternate in
garded as having BFIS.
different seizures. They may have unilateral clonic or bi-
lateral features sometimes with hypertonia. The seizures
may occur singly, but often present as a cluster over a few GENERALIZED EPILEPSY WITH FEBRILE
days, raising concern about a more serious condition. In- SEIZURES PLUS (GEFS+)
terictal EEG studies are usually normal; ictal recordings The familial epilepsy syndrome GEFS+ is charac-
show a focal onset, often parieto-occipital, and there may terized by heterogeneous epilepsy phenotypes or sub-
be parietal spikes and slowing between seizures during a syndromes within families (41) (Fig. 1). Recognition of
cluster (29,30). GEFS+ as a syndrome came from careful clinical evalu-
There is a related and overlapping syndrome called ation of large autosomal-dominant kindreds where pene-
infantile convulsions and choreoathetosis (ICCA) (31). trance of seizure disorders was around 50–60% (42). After
These families have infantile convulsions indistinguish- validation of GEFS+ as a specific syndrome, confirmed
able from BFIS and a paroxysmal movement disorder that by segregation of a single pathogenic mutation in some
often begins later. Not all individuals in a family expe- families (43–46), it has been recognized that GEFS+ oc-
rience both types of attacks. The choreoathetosis begins curs more frequently in smaller families and even sporadic
at any time from infancy to adolescence and may have cases may have specific GEFS+ phenotypes. GEFS+ and
prominent dystonic and kinesigenic features; it is often
triggered by rest, exertion, or anxiety (30,31).
A molecular locus for ICCA, as well as for some fam-
ilies with BFIS alone, has been mapped to the pericen-
tromeric region of chromosome 16 (31–33). Despite con-
siderable effort, there has been no success in finding BFIS
genes in this region, which is complicated by chromo-
somal duplication. Two other BFIS loci map to chromo- FIG. 1. Spectrum of phenotypes within GEFS+.

Epilepsia, Vol. 46, Suppl. 10, 2005

 NEONATAL EPILEPSY SYNDROMES AND GEFS+
the classical idiopathic generalized epilepsies (IGEs) are
subgroups of the broad category of idiopathic generalized
epilepsy with GEFS+ tending to occur in families sepa-
rately from the classical IGEs such as childhood absence
epilepsy (CAE) and juvenile myoclonic epilepsy, although
overlap may occasionally be seen (47,48). The phenotypes
within GEFS+ usually have seizure onset within the first
decade of life and the vast majority begin with febrile
seizures, although this is not universal (42).
The most common phenotypes or subsyndromes within
GEFS+ are febrile seizures (FS) and febrile seizures plus
(FS+) (41,42,48). FS are convulsions (generalized tonic–
◦
clonic seizures [GTCS]) with fever over 38 C between 3
months and 6 years of age.
FS+ may have a number of different presentations.
The most straightforward presentation is where the febrile
seizures continue beyond the defined age range of FS of
3 months to 6 years. In this situation, the child may have
febrile seizures that continue into late childhood or ado-
lescence. A second type of presentation of FS+ is where
afebrile GTCS occur in addition to FS. These afebrile
GTCS may occur only within the typical time frame of
febrile seizures (3 months to 6 years), or alternatively,
they may occur after the febrile seizures remit. Some-
times, there may even be a relative break of several years
without seizures before the afebrile GTCS occur (41,42).
In rare instances, family members with afebrile GTCS
alone, for example, occurring in late childhood, carry the
same GEFS+ mutation as other family members with typ-
ical GEFS+ phenotypes (44). It is difficult to accept these
individuals as having FS+ as they have never had a febrile
seizure. Thus, Afebrile GTCS (AGTCS) is a GEFS+ phe-
notype in which FS do not occur.
Both FS and FS+ may be associated with other seizure
types. It is more common for generalized seizures to be
associated with GEFS+ although focal seizures may oc-
cur and have been associated with the same mutations.
In terms of generalized seizure types, absence seizures
can be seen although they often differ from classical CAE
as they are often relatively infrequent yet quite definite
attacks. Myoclonic or atonic seizures are also well recog-
nized (41,42).
Focal epilepsies in individuals with GEFS+ pheno-
types include temporal lobe epilepsy and frontal lobe
epilepsy. Temporal lobe epilepsy may occur following FS
or FS+ and can be associated with hippocampal sclero-
sis (42,49,50). Interestingly, temporal lobe epilepsy may
also occur without preceding FS suggesting that tempo-
ral lobe epilepsy alone may be a phenotype of GEFS+ in
its own right albeit rare (51). Frontal lobe epilepsy has
been described in French GEFS+ families with hemi-
clonic seizures and orofacial motor seizures (52).
The GEFS+ spectrum includes more severe phenotypes
such as the epileptic encephalopathies Myoclonic-astatic
43
epilepsy (MAE), and SMEI and related phenotypes. These
syndromes are discussed below.
Myoclonic-astatic epilepsy (MAE)
Doose first described MAE and recognized that it had
a genetic etiology (53). MAE begins with febrile seizures
in one-third of cases and afebrile GTCS in other cases.
The child then develops a number of generalized seizure
types including the key seizure type of myoclonic-astatic
seizures as well as a combination of myoclonic, atonic,
absence, and GTCS (54). Onset occurs between 1 and 5
years and boys are more commonly affected than girls.
MAE has a variable course with intellectual disability be-
ing common but by no means universal. Tonic seizures
and episodes of nonconvulsive status epilepticus are as-
sociated with a poorer prognosis. The EEG shows fast
generalized spike wave activity (55,56).
Affected family members of MAE probands studied
by Doose most commonly had febrile and afebrile GTCS
beginning before 5 years (57), akin to FS and FS+ in
GEFS+. Doose’s family study was consistent with com-
plex inheritance of MAE (54). To date, only a few pa-
tients with MAE have been found to carry mutations of
GEFS+ genes including mutations of sodium channel
subunit genes, SCN1A and SCN1B, and a GABAA recep-
tor subunit gene GABRG2 (see below) (43,44,47,58,59).
Even in these patients with a familial mutation, it is likely
that additional unidentified modifier genes contribute to
the more severe MAE phenotype.
Despite the description of many large families with
GEFS+ where there is clinical and molecular genetic ev-
idence of a major gene of dominant effect, the majority of
individuals have complex inheritance of GEFS+ pheno-
types and thus have no family history or only a small fam-
ily history of seizure disorders. Clues suggestive of poly-
genic inheritance include the finding of a bilineal family
history of seizure disorders (43). In disorders with com-
plex inheritance, such as the classical IGEs, the recurrence
risk to siblings is relatively low. Formal epidemiological
studies of GEFS+ are necessary to establish the true re-
currence risks in the general population.
GEFS+ genes
Genes encoding both voltage-gated and ligand-gated
ion channel subunits have been implicated in GEFS+,
specifically, sodium channels and GABAA receptors are
involved. These findings are not surprising given the key
role of ion channels in the pathophysiology of seizure
disorders.
The neuronal sodium channel is made up of an alpha
pore-forming subunit comprising four transmembrane do-
mains, flanked by two beta subunits that regulate channel-
gating kinetics. The beta subunit has an extracellular
immunoglobulin-like fold considered critical for its regu-
latory function. The alpha-1 subunit gene, SCN1A, is the
Epilepsia, Vol. 46, Suppl. 10, 2005
44 I. E. SCHEFFER ET AL.
most important GEFS+ gene to date and a number of
missense mutations scattered throughout the gene have
been reported in GEFS+ families (60). The beta-1 sub-
unit gene, SCN1B, has been associated with four differ-
ent mutations in GEFS+, all localized to the extra cel-
lular immunoglobulin-like fold (43,50,61). The recurrent
C121W mutation disrupts a putative disulphide bridge
within the extracellular immunoglobulin-like fold. A dele-
tion mutation has also been reported in a single family
(62).
The GABAA receptor is a heteropentamer with the most
common configuration in human brain comprising two al-
pha, two beta, and a gamma subunit. The GABAA receptor
is a ligand-gated chloride channel that has a major role in
inhibition in the brain. Four mutations have been described
in the gamma-2 subunit gene, GABRG2, three occurring
in families with GEFS+ phenotypes (46,58,63). GABRG2
is involved in both GEFS+ and IGE phenotypes as two
families with mutations have classical CAE as a central
phenotype; this differs considerably from most GEFS+
pedigrees (47,58,64). Importantly, one of the GEFS+-
associated GABRG2 mutations occurs in a family where
the proband has SMEI (63).
GABAA receptors are composed of different combina-
tions of subunits that confer specific functional charac-
teristics to the receptor. For example, a GABAA receptor
comprising two alpha, two beta, and a gamma subunit
is mostly subsynaptic in location, rapidly desensitizing,
and mediates basic inhibition. GABRD encodes the delta
subunit of the GABAA receptor, which usually takes the
place of the gamma subunit in combining with two al-
pha and two beta subunits. This configuration of GABAA
receptor lies either in the perisynaptic or extrasynaptic re-
gion and is a relatively nondesensitizing channel with a
role in tonic inhibition. We recently reported a mutation
in a small GEFS+ family in GABRD and suggested that
GABRD could represent a susceptibility gene for GEFS+
and IGE (65). The E177A GABRD mutation was found
in a family with siblings with FS+ and FS and in their
unaffected mother.
Electrophysiological in vitro studies of the E177A mu-
tation in recombinant GABAA receptors expressed in hu-
man embryonic kidney cells showed that the mutant re-
ceptors had markedly reduced currents compared with the
wild-type receptors when exposed to a saturating concen-
tration of GABA (65). This finding illustrates the func-
tional effect of the mutation and suggests that it may have
a significant role in the GEFS+ phenotype and be one of
several or many genes contributing to GEFS+ phenotypes
in this family.
Severe myoclonic epilepsy of infancy (SMEI)
Charlotte Dravet described SMEI in 1978 and it has
been suggested that the syndrome be renamed Dravet syn-
Epilepsia, Vol. 46, Suppl. 10, 2005
drome (66). SMEI is a distinctive epilepsy syndrome: a
previously well and developmentally normal infant de-
velops febrile seizures at around 6 months of age, often
presenting with hemiclonic or generalized febrile status
epilepticus. One or two months later, they present with a
hemiclonic seizure on the alternate side or further gener-
alized seizures and they may have frequent episodes of
febrile status epilepticus. Between 1 and 4 years, other
seizure types develop including myoclonic seizures in
most, but not all, children. Partial seizures are frequent
and atonic and atypical absence seizures may also occur.
These children are often prone to seizures with fever or in
warm water such as bathing.
Development is normal in the first year of life with
psychomotor slowing thereafter. Ataxia and pyramidal
signs may evolve. Intellectual outcome is usually poor
and seizures remain refractory.
SMEI is often associated with de novo mutations of
SCN1A, the gene encoding the alpha-1 subunit of the
sodium channel (67). Many groups have described SCN1A
mutations in SMEI cases, with the reported frequency
varying from 33% to 100% of cases; this variation may de-
pend on the screening procedure used and the mode of as-
certainment and diagnosis of cases (68–75). With current
optimal detection techniques, approximately 80% of clas-
sical SMEI cases have mutations. Over 100 mutations are
now described and most commonly comprise truncation
mutations, although splice site, deletion, and missense mu-
tations are also reported (60). SCN1A missense mutations
in SMEI have a predilection for the S5–6 transmembrane
segments of each domain and the linker between them,
which together form the ion channel pore. A high propor-
tion of mutations occur in the C-terminus, important in lo-
calizing the channel to the axonal membrane, as well as the
N-terminus. The majority of more than 100 SCN1A muta-
tions so far characterized are novel with current estimates
suggesting around 95% (76/80) arise de novo (60). Famil-
ial mutations in SMEI most commonly involve SCN1A
mutations; for example, 3 of 33 cases of SMEI had fa-
milial mutations in a large French-Italian study (73). To
date, there are only two familial GABRG2 mutations re-
ported in individuals with SMEI (63,71). Interestingly, in
the rare familial mutation families, usually only one indi-
vidual has SMEI, with milder phenotypes in other affected
family members.
Despite the fact that 95% of SCN1A mutations arise
de novo in SMEI, many probands have a family history
of seizures (76). Specific study of the family history has
determined that family members have seizure disorders
consistent with the GEFS+ spectrum (77,78). This led to
the concept that SMEI is the most severe phenotype within
the GEFS+ spectrum. The high proportion of SMEI indi-
viduals with de novo SCN1A mutations does not explain
the relatively high rate of a family history of seizures,
 NEONATAL EPILEPSY SYNDROMES AND GEFS+
which suggests the potential involvement of other genes
and remains an intriguing puzzle to unravel (79).
Severe myoclonic epilepsy of infancy border-
land/borderline (SMEB) is a phenotype where individuals
have many, but not all, of the key features of SMEI. For ex-
ample, they may not have myoclonus or generalized spike
wave on EEG. A subset of these patients have intractable
childhood epilepsy with tonic–clonic seizures (ICETCS).
SMEB cases have SCN1A mutational rates of around 30%,
usually arising de novo (74). ICEGTC has also been asso-
ciated with missense mutations in SCN1A (70). There has
been a single case of idiopathic infantile spasms associ-
ated with SCN1A mutation in the C-terminus (75). There
has also been a single SMEB-like case, with later onset,
associated with a mutation of SCN2A (80).
In terms of management implications, the diagnosis of
SMEI means the clinician should use lamotrigine with
caution as it may exacerbate seizures (81). There is a re-
port of the use of stiripentol, an unlicensed agent that in-
hibits cytochrome P450, showing that 70% of 20 patients
with SMEI had a 50% reduction of seizures with use of
this agent (82). It worked better in combination with val-
proate and clobazam. There is also experience suggesting
that topiramate is valuable in SMEI; in particular a com-
bination of valproate, topiramate, and clobazam should be
considered (83).
In conclusion, GEFS+ has only been associated with
known genes in less than 20% of families. Complex inher-
itance is usual and is the basis of the characteristic pheno-
typic heterogeneity. The phenotypic heterogeneity associ-
ated with single mutations segregating vertically in large
autosomal-dominant families suggests the involvement of
modifier genes affecting expressivity. Currently, molec-
ular findings do not have a direct impact on treatment
apart from awareness of potential lamotrigine exacerba-
tion in SMEI. Although there are a number of antiepileptic
drugs with known effects on sodium channels or GABA
receptors, they do not have specific effects with a known
molecular defect. Thus, their targeted use at present is not
indicated.
In terms of understanding the interrelationship of the
classical IGEs and GEFS+, both can be associated with
preceding febrile seizures, which occur in 3% of children.
The sodium channel subunit genes, SCN1A and SCN1B,
are associated with GEFS+, with SCN1A having a critical
role in SMEI. There is some overlap between GEFS+ and
the classical IGE, although this is not common, and both
may be associated with GABAA receptor subunit genes,
GABRG2 and GABRD. There is still considerable work to
be done to understand the many combinations and permu-
tations of genes likely to be relevant to FS, GEFS+, and
classical IGE and their interaction incorporating each indi-
vidual’s specific genetic background to produce a specific
epilepsy syndrome.
45
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