Partial and generalized epilepsy with

febrile seizures plus and a novel

SCN1A mutation
B. Abou-Khalil, MD; Q. Ge, PhD; R. Desai, MS; R. Ryther, BS; A. Bazyk, MS; R. Bailey, PhD;
J.L. Haines, PhD; J.S. Sutcliffe, PhD; and A.L. George, Jr., MD

Article abstract—Background: Generalized epilepsy with febrile seizures plus (GEFS⫹) is an autosomal dominant
syndrome characterized by febrile seizures (FS) and a variety of afebrile generalized seizure types. GEFS⫹ has previously
been linked to mutations in two genes encoding the voltage-gated sodium channel ␣-subunit (SCN1A) and ␤1-subunit
(SCN1B). We studied a large family with FS and partial as well as generalized seizure types. Methods: All but two living
affected family members were interviewed and examined. Information on deceased affected family members was sought.
EEG for 11 affected family members and one unaffected family member were obtained. Genetic linkage analysis and
mutation screening of SCN1A were performed on blood samples from 16 affected individuals and their first-degree
relatives. Results: There were 27 affected family members; 18 were alive at the time of the study. All affected family
members had FS; seven had FS only, and 19 also had afebrile seizures. Eleven individuals continued to have FS beyond 6
years of age. FS were complex in 12 family members, usually with prolonged duration. The index patient had right
temporal lobe epilepsy and hippocampal sclerosis. Four other patients had strong historical evidence of temporal lobe
epilepsy, and three others had nonlocalizing evidence of partial epilepsy. Pedigree analysis indicated autosomal dominant
transmission. All affected individuals who were tested and one asymptomatic individual had a sodium channel mutation
of SCN1A, an A3 C transversion at nucleotide 3809 resulting in the substitution of lysine 1270 by threonine in the D3/S2
segment (designated as K1270T). Conclusions: Our findings indicate that partial epilepsy preceded by FS can be associ-
ated with sodium channel mutations and may represent a variant of GEFS⫹.
NEUROLOGY 2001;57:2265–2272

Febrile seizures (FS) are defined as seizures that
occur usually during the first 6 years of life in asso-
ciation with fever, without CNS infection or other
definable causes, and without antecedent by afebrile
seizures. FS occur in about 3% of all children.1 Indi-
viduals with FS during childhood have an increased
likelihood of developing afebrile seizures.2,3 About 7%
of affected children develop afebrile seizures by 25
years of age.3 Epidemiologic studies have shown that
the risk of epilepsy in these children is up to 10
times greater than that expected in the general
population.4
A variety of epilepsy syndromes are associated
with antecedent childhood FS.1 However, there
seems to be some specificity in the epilepsy types
associated with FS.1 Temporal lobe epilepsy (TLE)
has a stronger association with childhood FS than
does extratemporal partial epilepsy,5 and general-
ized epilepsy is also preceded by childhood FS more
often than expected. Simple FS are more likely to
precede generalized epilepsy, whereas complex FS,
especially those of prolonged duration, are more
likely to precede TLE.5
A syndrome of generalized epilepsy preceded by
FS was recently described and characterized geneti-
cally.6,7 The syndrome of generalized epilepsy with
febrile seizures plus (GEFS⫹) includes FS that may
persist beyond the usual limit of 6 years.6 Some pa-
tients with GEFS⫹ will also have afebrile general-
ized tonic– clonic seizures, while others may have
absence, myoclonic, or atonic seizures or even myo-
clonic–astatic epilepsy.6 Further study revealed the
association of GEFS⫹ with mutations in genes en-
coding the voltage-gated sodium channel ␤1-subunit
(SCN1B)7 located on chromosome 19 and ␣-subunit
(SCN1A)8-10 located on chromosome 2.
Studies that led to the concept of GEFS⫹ rarely
reported TLE; therefore, TLE was considered excep-
tional.11 We describe here a large family with multi-
ple members with FS⫹ and partial epilepsy as well
as generalized epilepsy; linkage to chromosome 2
was established, and an SCN1A mutation was found.

From the Departments of Neurology (Drs. Abou-Khalil and Ge), Medicine (Dr. George and B. Desai), and Molecular Physiology & Biophysics (R. Ryther,
A. Bazyk, and Drs. Bailey, Haines, and Sutcliffe), Vanderbilt University School of Medicine, Nashville, TN.
Supported by the Epilepsy Foundation through the Kathy Holden Genetic Research Fund. Also supported by a grant from the Roland and Ruby Holden
Foundation on behalf of Ronald and Arlene Holden, by NIH grants NS32387 (A.L.G.) and T32-GM07347 (R.R.), and by the Vanderbilt Program in Human
Genetics.
Received April 11, 2001. Accepted in final form August 27, 2001.
Address correspondence and reprint requests to Dr. Bassel Abou-Khalil, Department of Neurology, Vanderbilt University, MCS Room 336, 2100 Pierce
Avenue, Nashville, TN 37212; e-mail: Bassel.Abou-Khalil@mcmail.vanderbilt.edu

Copyright © 2001 by AAN Enterprises, Inc. 2265

Figure 1. Pedigree of a family with partial epilepsy as well as generalized epilepsy with febrile seizures plus. Squares
represent males, circles represent females, and diamonds represent multiple unaffected offspring whose sex was not other-
wise specified. Underlined pedigree numerals identify tested individuals, and boxed numerals denote those carrying the
mutation. Open symbols indicate clinically unaffected individuals. Vertical black bands identify individuals with febrile
seizures only. Completely filled symbols indicate individuals with febrile seizures and then generalized seizure(s) or epi-
lepsy. Half filled symbols represent patients with febrile seizures and then partial epilepsy. The circle with a black circu-
lar insert indicates an individual with febrile seizures and then epilepsy of uncertain classification. Asterisks indicate
febrile seizures followed by a single afebrile generalized tonic– clonic seizure. The plus sign identifies one individual who
had both partial and generalized seizures. Subject III-1 was considered to have had febrile seizures only, because it was
not known if afebrile seizures occurred. The black arrow indicates the proband (Patient V-4).

Methods. Family ascertainment. The proband (V-4; fig-
ure 1) of a multigenerational family from Kentucky was
referred for investigation of intractable partial seizures.
She also had antecedent FS. After noting the presence of
FS as well as afebrile seizures in the patient’s first- and
second-degree relatives, we contacted the family to investi-
gate additional affected members. We were made aware of
long-estranged distant family members with epilepsy. We
got in touch with these distant relatives and found two
additional family groups with three affected generations.
We contacted all the family groups to build a pedigree and
to obtain informed consent for participation in collection of
clinical and EEG data and DNA samples. The Institutional
Review Board of Vanderbilt University (Nashville, TN) ap-
proved the consent forms used in this study.
Clinical evaluation. Individuals with a putative sei-
zure history were first interviewed by telephone. Their
seizure histories were corroborated through interviewing
their close relatives, such as parents, spouses, or siblings.
Medical records, including results of previous investiga-
tions, were reviewed when available. Seizure history and
diagnosis of deceased individuals were obtained only from
close relatives, because medical records of these individu-
als could not be retrieved. We undertook two field trips to
interview and examine all available affected and some un-
affected family members, as well as to collect blood sam-
ples and cheek swabs from all available affected
individuals and their first-degree relatives. A board-
certified neurologist (B.A.-K.) performed neurologic exami-
2266 NEUROLOGY 57 December (2 of 2) 2001
nation with epilepsy history. One additional field trip was
made to obtain EEG for affected individuals. Additional
EEG were obtained later at Vanderbilt University
Hospital.
EEG were obtained with a digital electroencephalo-
graph (XLTEK, Toronto, Ontario, Canada); the 10 –20 elec-
trode system and 18-channel recordings were used. The
recording included hyperventilation and intermittent
photic stimulation. Patient V-4 underwent long-term vid-
eo–EEG monitoring. A board-certified clinical neuro-
physiologist (B.A.-K.) interpreted results of all clinical
neurophysiology studies. Available clinical and EEG data
were used to classify seizure types and epilepsy syndromes
according to international classifications.12,13
Genetic analysis. Individuals with a history of febrile
convulsions or afebrile seizures, regardless of type, were
designated as “affected.” All participating individuals and
parents or guardians of minors gave informed consent.
Based on available pedigree information, estimates of
power to detect linkage assuming dominant inheritance
and reduced penetrance were calculated by the SIMLINK
program.14 Microsatellite markers were selected at each of
the five known loci for GEFS⫹ or FS based on findings
from previously published reports.9,15-19 Genotype data
were analyzed by using FASTLINK20; two-point lod scores
were calculated under a model of dominant inheritance
with reduced (80%) penetrance and a disease allele fre-
quency of 0.01. Follow-up analysis of the GEFS2 locus
Table 1 Characteristics of FS

Ages at onset to offset

Subject Age at end of 2000, y of FS, y Complex feature Duration of longest FS Number of FS

V-4 38 1.2–12 P, R, F 9 h, “on” and “off” Multiple

periods
III-1 Died at 69 Unknown to 12 Unknown Multiple
IV-1 Died at 49 1–12 Unknown Multiple
IV-2 59 1–11 R Unknown Multiple
V-2 Died at 21* 0.75–12 P, R 15–20 min Multiple
V-3 Died at 24† 0.75–11 R 10 min Multiple
V-5 35 3 No 2.5 min 1
VI-2 9 0.6 to ongoing P, R 2.5 h 4
VI-3 7 0.9–6 No 10 min ⬃12
IV-3 40 0.5 to unk P 30 min Unknown
IV-4 37 ⬍1–10 R, F 4–5 min ⬃20
IV-5 Died at 53 Unknown to 16 Unknown Unknown Unknown
V-6 19 1.8–14 P, R, F 1.5 h ⬃40
V-7 18 0.9–5 P, R 45–60 min 8
IV-14 50 ⬍1–3 No 3–4 min 10–15
V-11 26 1.5–2 No 5 min 2
V-12 32 1–3 No 5 min 3
V-13 24 1.25–4 P 3h 3
V-15 30 1.5–2.5 No 2 min 2
V-17 26 0.75–10 P, R, F 8h Multiple
V-18 29 1–5 P, R 30 min 5

The table is organized by family groups, starting with the proband. Subjects III-3, IV-4, IV-6, IV-7, IV-8, IV-13, and IV-16 were not in-
cluded in the list because of limited information.

* Had been seizure free since 15 or 16 years of age; he had a seizure at age 22 and fell from his boat and drowned.
† Drowned.

FS ⫽ febrile seizures; P ⫽ prolonged; R ⫽ repeated in the same febrile illness; F ⫽ focal (ictally or postictally).

included markers D2S141, D2S156, D2S2230, D2S382,
D2S335, and D2S1391.
Mutation screening. Intronic oligonucleotide primers
flanking each exon were designed based on the genomic
organization of SCN1A that was deduced from a publicly
available human genomic sequence (accession no.
AC010127; GenBank, Bethesda, MD). For exons 1, 6, 9, 10,
11, 15, 16, 21, 25, and 26, multiple primer sets with over-
lapping products were designed to facilitate PCR amplifi-
cation of smaller exon segments. Complete data regarding
primers and reaction conditions are available upon
request.
PCR amplification of genomic DNA (25 ng) was per-
formed in a total volume of 25 ␮L containing 0.5 ␮M con-
centrations of each respective forward and reverse primer,
0.2 mM concentrations of each deoxyribonucleotide
triphosphate, and 0.4 ␮L of a 9:1 mixture of Taq and PwoI
DNA polymerases (Roche Biochemicals, Indianapolis, IN).
After thermal cycling, amplified products were electropho-
resed on 0.5 ⫻ Mutation Detection Enhancement gels (Bio-
Whittaker Molecular Applications, Rockland, ME) at 4
watts overnight and stained with silver nitrate. Abnormal
conformers were excised from dried gels, eluted in sterile
water overnight, reamplified with use of the same primer
pair, and directly sequenced by means of Big Dye Termina-
tor chemistry on an automated sequencer (model 3700; PE
Biosystems, Foster City, CA).
The presence of the SCN1A mutation K1270T was veri-
fied by using allele-specific oligonucleotide hybridization of
independently amplified samples. The allele-specific oligo-
nucleotide probe sequence was 5'-AATGCTTCTAACATGG-
3', and hybridization was performed at 42 °C.
Results. Pedigree. The pedigree of the family (see fig-
ure 1) showed that there were 27 affected individuals; 18
of the family members were alive at the time of the study.
All affected individuals had FS. Nineteen family members
also had epilepsy with afebrile seizures. Pedigree analysis
indicated autosomal dominant transmission. All affected
individuals had affected parents except in Generations I to
III, where parents were all deceased and medical histories
were not available.
FS. Age at onset of FS varied from 6 months to 3 years
but was unknown for some individuals (table 1). FS
stopped at or before 6 years of age in nine family members
and after 6 years of age in 11 (age range, 10 to 16 years).
These 11 family members were considered to have FS⫹.
December (2 of 2) 2001 NEUROLOGY 57 2267
Table 2 Characteristics of afebrile seizures, epilepsy, classification, and EEG findings

Age at onset to offset of Afebrile seizure type (total no. Epilepsy classification/ EEG finding (age at time of
Subject afebrile seizures, y or frequency) localization study)

V-4 12 to ongoing CPS (D), SPS (W), PGTC (M) Partial epilepsy/TLE Right inferomesial temporal
seizure onset (34 y)
IV-1 40–49 GTC (2) ?Generalized
IV-2 10 GTC (1) ?Generalized Normal (59 y)
V-2 21 GTC (1) ?Generalized
V-3 10–24* GTC (M) ?Generalized
VI-2 2 to ongoing Prolonged AABS with atonic Generalized Normal (9 y)
features (4)
VI-3 1.5–6 ABS (D in past), long AABS Generalized Generalized posteriorly
(11), ABS evolving to GTC (2) dominant 3- to 5-Hz SW
discharges, with PS and
spontaneously (7 y)
IV-3 Unknown to ongoing PGTC, SPS Partial
IV-4 ?10–12 GTC (5) Generalized Normal (36 y)
IV-5 50–53 PGTC (4–5) Partial
V-6 3 to ongoing CPS (M), PGTC (R), SPS (Y) Partial Normal (19 y)
V-7 6–8 GTC (2) Generalized Normal (18 y)
IV-13 6 to ongoing CPS (W), PGTC (Y), SPS (W) Partial Normal (51 y)
IV-14 12 to ongoing CPS (W–M), PGTC (⬍Y) Partial Normal (49 y)
V-11 22 to ongoing GTC (3), ABS (M), MYO (M) Generalized
V-13 14 to ongoing PGTC (5), SPS (W), CPS (W), Partial
?MYO (W)
V-15 3–3 GTC (2) Generalized
V-17 6 to ongoing GTC (W†), CPS (M†) Generalized plus Right postictal slowing (11 y);
partial; only partial generalized onset of 2 GTC
after CC seizures (14 y); generalized
slow activity (26 y)

The table is organized by family groups, starting with the proband. Subject III-3 was not included in the list because of absence of
data. Normal EEG not listed here were obtained for subjects V-5 and IV-10.

* Drowned.
† Frequency before CC.
Frequency: D ⫽ daily; W ⫽ weekly; M ⫽ monthly; Y ⫽ yearly; R ⫽ rarely. Seizure type: CPS ⫽ complex partial; SPS ⫽ simple partial;
PGTC ⫽ partial becoming generalized tonic– clonic; GTC ⫽ generalized tonic– clonic (generalized onset); AABS ⫽ generalized atypical
absence; ABS ⫽ generalized absence; MYO ⫽ generalized myoclonic; ? ⫽ probable; TLE ⫽ temporal lobe epilepsy; SW ⫽ spike-and-
wave; PS ⫽ photic stimulation; CC ⫽ corpus callosotomy.

For seven family members, the age at FS termination was
not known. One other family member (IV-8) died at 6
months of age. FS were simple in six individuals and had
complex features in 12 individuals (focal, 4; prolonged, 9;
and multiple, 10). One family member had 1 FS, six had 2
to 5 FS, and 12 had ⬎5 FS.
Epilepsy phenotypes. Nineteen patients had a clear
history of afebrile seizures following the onset of FS (table
2). It was not known if afebrile seizures ever occurred in
one deceased individual. The data allowed classification of
seizures or epilepsy in most patients. Five individuals had
evidence of TLE. They had seizure auras that included fear
(V-4), déjà vu experience (V-13, IV-13, and IV-14), epigas-
tric sensation—“butterflies in the stomach”—(V-6), and ol-
factory hallucination (IV-13). Two other family members
had evidence of partial epilepsy, based on the presence of a
clear aura, but the features were not specific for a tempo-
ral lobe origin. For example, one deceased individual (IV-5)
2268 NEUROLOGY 57 December (2 of 2) 2001
consistently had reported a “crazy” or “silly” feeling in the
head before her seizures, and one individual (IV-3) who
could not be interviewed directly had isolated seizure
warnings that suggested simple partial seizures.
One individual (V-17) with mild mental retardation had
left hemibody seizures, sometimes with a jacksonian
march, and generalized tonic– clonic seizures. When this
individual was 14 years of age, two generalized tonic–
clonic seizures were recorded at another institution, and
these seizures were found to be of generalized onset. She
also had staring spells lasting 30 seconds without clear
postictal drowsiness. She then underwent corpus calloso-
tomy at age 14. Postoperatively, she had focal motor sei-
zures on the right side with altered awareness, as well as
generalized tonic– clonic seizures that consistently in-
volved adversive head turning to the right. This patient
appeared to have had both generalized and partial seizure
types, but her epilepsy was modified by corpus calloso-
Figure 2. (A) T2*-weighted MRI scan for a patient (V-4) with febrile seizures; the image demonstrates the typical find-
ings of right hippocampal sclerosis, including atrophy and increased signal (arrow). (B) EEG for Patient V-4. The first
two EEG segments demonstrate interictal epileptiform activity in the right temporal region, predominating at the right
sphenoidal electrode (Sp2). Although the discharges were small and brief, they were considered epileptiform because of
their consistent localization. The third segment demonstrates a seizure onset. The first arrow indicates the point at which
the patient pushed the alarm button when she had an aura. The second arrow indicates the approximate onset of the
rhythmic ictal activity, which also predominated at the right sphenoidal electrode. This activity started at approximately
8 Hz and slowed down to 5 to 6 Hz in conjunction with a widening field. Vertical lines mark 1-second intervals.

tomy; at the time of this study, her condition was classified
as partial epilepsy.
Six individuals (VI-2, VI-3, IV-4, V-7, V-11, and V-15)
appeared to have generalized epilepsy. The historical de-
tails for two of them (VI-2 and VI-3) are provided below.
For four other patients (IV-1, IV-2, V-2, and V-3), informa-
tion was limited because the number of seizures was small
or the individuals were deceased and could not be closely
questioned about the occurrence of an aura and other sei-
zure manifestations. However, because there was no evi-
dence of focal features, epilepsy in these family members
was classified as probably generalized. One deceased indi-
vidual (III-3) had afebrile seizures, but the classification of
these seizures is totally unknown.
Individual case histories for the immediate family of the
index patient. The seizure classification was well docu-
mented for the index patient (V-4). She had prolonged
repetitive FS at 14 months of age, with postictal left hemi-
paresis. The episode lasted 5 hours. It was suspected to be
secondary to encephalitis, but she had a similar recurrence
at 19 months of age that lasted 9 hours. Individual FS
recurred thereafter, continuing even beyond 12 years of
age. Afebrile seizures started at 12 years of age. She had
an aura of fear, usually followed by staring and swallow-
ing, and sometimes secondary generalization. The seizures
were refractory to medical therapy. Presurgical evaluation
indicated right TLE with right hippocampal sclerosis (fig-
ure 2A). Interictal epileptiform discharges originated from
the right mesial– basal temporal region, and recorded sei-
zures had a right temporal origin, with mesial– basal pre-
dominance (see figure 2B). She eventually underwent right
temporal lobectomy. Hippocampal sclerosis was demon-
strated pathologically, with marked loss of pyramidal cells
and gliosis in CA1 and CA3. The lateral cortex was nor-
mal. She had complete seizure control for 2 years after
surgery, but occasional generalized tonic– clonic seizures
recurred thereafter. Seizures came under control with ad-
justments in medical therapy.
Her mother (IV-2) had many FS between 1 and 11 years
of age, usually occurring in clusters, but also had one afe-
brile generalized tonic– clonic seizure with no known aura
or focal features. She was never treated with antiepileptic
drugs. One of the index patient’s brothers (V-3) had fre-
quent short and symmetric FS, sometimes with two sei-
zures in the same day. These seizures continued until he
was 11 years of age. Afebrile generalized tonic– clonic sei-
zures started when he was 10 years old. At 24 years of age,
he had a seizure and drowned. Her other brother (V-5) had
a single simple FS at 3 years of age, but two of his three
children (VI-2 and VI-3) had FS followed by development
of afebrile seizures.
The older affected son (VI-2) started having FS at 7
months of age. His FS were generalized and prolonged,
lasting 2.5 hours the first time and 30 minutes the second
time. He would convulse for 1 minute, stop for 1 minute,
and then start again. The last FS, which occurred when he
was 9 years old, was short, lasting only 3 to 4 minutes.
Afebrile seizures started at 2 years of age. They were pro-
longed atypical absence seizures with decreased tone. He
would have a blank stare and at times lose tone and be-
come limp. Unresponsiveness lasted from 1 to 10 minutes.
Postictally, he was mildly hyperactive during the more
prolonged episodes but returned to normal immediately
after shorter ones. These seizures were controlled with
administration of ethosuximide (250 mg PO twice a day)
and recurred only when ethosuximide treatment was
stopped after prolonged seizure-free periods. The last sei-
zure occurred when he was 4 years of age (when ethosux-
imide therapy was stopped). Surprisingly, no EEG were
December (2 of 2) 2001 NEUROLOGY 57 2269

obtained until he was 9 years old; at that time, an EEG
was normal.
The younger affected son (VI-3) started having FS at 11
months of age. They were simple, with no focal features,
and lasted ⱕ10 minutes. The last FS occurred when he
was 6 years old. Afebrile seizures started at 1.5 years of
age. He stared blankly, stopped his activity, and was unre-
sponsive. Some of these seizures lasted seconds only and
had no postictal manifestations. These seizures were ex-
tremely frequent when he was treated with carbamaz-
epine. However, the more notable seizures involved staring
up and to the left; these seizures usually lasted for 5 to 10
minutes but could last up to 30 minutes. These seizures
left him with a little postictal sleepiness. A total of about
13 such prolonged episodes occurred. Rarely, these sei-
zures evolved into generalized tonic– clonic activity: at 3
years of age, he had a convulsive seizure that lasted 1.5
hours, and diazepam administration was required for the
seizure to stop; a shorter episode also occurred when he
was 6 years old, at which time his medication was
switched from valproate to ethosuximide. At the time of
this study, he was receiving valproate treatment and was
free of seizures. An EEG at 7 years of age revealed gener-
alized, posteriorly dominant, 3- to 5-Hz spike-and-wave
discharges during photic stimulation at 20 and 25 Hz and
to a lesser extent spontaneously (figure 3).
Genetic analysis. We initially screened the family with
use of microsatellite markers at five different loci repre-
2270 NEUROLOGY 57 December (2 of 2) 2001
Figure 3. EEG for the nephew (Patient
VI-3) of the proband (Patient V-4) in
the study of a family with partial epi-
lepsy as well as generalized epilepsy
with febrile seizures plus. Bilateral
spike-and-wave discharges are shown
with biposterior predominance during
photic stimulation at 20 Hz with the
patient’s eyes closed. An abbreviated
longitudinal bipolar montage was used
for display.
senting the known FS loci (FEB1, chromosome 8q13– q21;
FEB2, chromosome 19p13.3; and FEB4, chromosome
5q14 – q15) and the two GEFS⫹ loci (GEFS1, chromosome
19q13.1; and GEFS2/FEB3, chromosome 2q21– q33). Two
of these loci (FEB3 and GEFS2) map to overlapping chro-
mosomal intervals and may represent the same disorder.
We obtained a maximum lod score of 4.88 with marker
D2S2330 at the GEFS2/FEB3 locus on chromosome 2q22–
q24. Next we screened family members for SCN1A muta-
tions (GEFS2) by using single-strand conformation analysis.
We detected an abnormal single-strand conformer in
SCN1A exon 19 that cosegregated with FS and epilepsy.
Sequence analysis of the exon 19 conformer identified an
A3 C transversion at nucleotide 3809 (nucleotide 1 as-
signed to the first base of the ATG start codon) that pre-
dicted replacement of lysine 1270 with threonine in the
D3/S2 transmembrane segment (mutation was designated
as K1270T) (figure 4). Lysine at this position is highly
conserved in voltage-gated sodium channel ␣-subunits
from vertebrate and invertebrate species (see figure 4).
This allele was not detected in 267 unrelated controls and
was present in all affected individuals who were tested
(analysis of K1270T linkage to GEFS⫹ in this family gave
a lod score of 6.37). One 11-year-old unaffected boy (VI-4) also
carried the mutation, suggesting incomplete penetrance.
Discussion. We describe a family with multiple
members who had FS and FS⫹ and also frequently
Figure 4. Results of nucleotide sequence
analysis of a mutation of SCN1A (desig-
nated as K1270T) that was found in a
family with partial epilepsy as well as
generalized epilepsy with febrile seizures
plus (GEFS⫹). (A) Electrophoretograph
of a partial DNA sequence corresponding
to K1270T in exon 19. Sequencing of
PCR-amplified DNA from a heterozygous
individual was performed. The position
of the heterozygous nucleotide is indi-
cated by the arrow labeled C/A. (B)
Alignment of amino acid sequences of the
SCN1A region containing K1270T
(D3/S2 segment) with other known
voltage-gated sodium channels.
had subsequent afebrile seizures. All affected family
members who were tested had an SCN1A mutation,
while unaffected family members, with the exception
of one individual, did not. The epileptic syndrome in
this family resembles GEFS⫹ in several respects: it
has an autosomal dominant inheritance pattern; FS
were a uniform feature; FS frequently persisted be-
yond 6 years of age; and many affected individuals
had afebrile seizures coexistent with FS that contin-
ued thereafter. However, one distinct difference be-
tween this family and previously described families
with GEFS⫹ is the frequent occurrence of partial epi-
lepsy, specifically TLE in affected family members.
Scheffer and Berkovic6 initially described GEFS⫹
in a family from rural Victoria, Australia; the de-
scription included only generalized seizure types.
However, there were diverse epilepsy phenotypes in
the same family. These phenotypes included the fol-
lowing: pure febrile convulsion syndrome, with FS
confined to the early childhood period; FS⫹, which
included generalized tonic– clonic seizures both with
and without fever, continuing beyond 6 years of age;
FS⫹ and absences; FS⫹ and myoclonic seizures;
FS⫹ and atonic seizures; and myoclonic–astatic epi-
lepsy. The investigators thus introduced the concept
of “a genetic epilepsy syndrome where a single major
gene may be associated with diverse individual epi-
lepsy phenotypes.” In a subsequent report from the
same investigators,11 one additional large family
from Tasmania and eight other small families were
described. Two individuals from smaller families had
FS⫹ and TLE. One of these individuals had convul-
sive status epilepticus in childhood, and the investiga-
tors concluded that “TLE may be an occasional late
consequence of the GEFS⫹ syndrome,” presumably
based on hippocampal injury from prolonged FS.
In the family we describe here, TLE occurred
more than occasionally. Five individuals had evi-
dence of TLE, and two others had evidence of partial
epilepsy that may be temporal. Before all clinical
information was obtained, we hypothesized that TLE
in this family would be associated with complex and,
in particular, prolonged FS. This hypothesis was in
accordance with previous evidence that generalized
epilepsy is more likely to be preceded by simple FS
and TLE is more likely to be preceded by complex
FS.3,5,21 We initially thought that the genetic muta-
tion in this family led to generalized epilepsy and
that TLE was related to hippocampal injury during
febrile status epilepticus (prolonged FS), as was pre-
viously suggested.11 This mechanism is supported by
several lines of evidence, including direct demonstra-
tion of hippocampal injury after febrile status epilep-
ticus,22 observations in identical twins,23 observations
in kindreds with familial febrile convulsions,24 and
volumetric MRI data.25 However, characteristics of FS
in the family described here could not clearly predict
classification (TLE or generalized). Of the five patients
with TLE, three had complex FS (prolonged, 3; repeti-
tive, 2; and focal, 2), one had simple FS, and one had
unknown FS features. Of the six patients with clear
generalized epilepsy, three had complex FS (prolonged,
2; repetitive, 3; and focal, 1). Of the remaining four
patients with probable generalized epilepsy, all four
had FS seizures that were complex (duration: pro-
longed, 1; and unknown, 1; repetition: multiple, 3; and
unknown, 1; and focality: focal, 0; and unknown, 1).
Acquired factors may not be necessary for deter-
mining the form of epilepsy that eventually develops.
In support of this notion, a family with an SCN1B
mutation in which there was a member with TLE
and no antecedent FS was recently described.26 The
idea that both partial epilepsy and generalized epi-
lepsy may be associated with the same genotypes is
also supported by genetic epidemiology studies.27 The
possibility should also be considered that another
gene may interact with the currently described mu-
tation to determine whether the resultant epilepsy is
partial or generalized. Evidence for linkage to more
than one gene has recently been found in idiopathic
generalized epilepsy as well as in one family with
both febrile convulsions and TLE.28,29
In the family described here, the mutation most
likely linked with the condition is an SCN1A muta-
tion, reflecting a sodium channelopathy. Other mu-
tations in SCN1A have been described in association
with GEFS⫹.8-10 In one family, all affected individu-
als appeared to have generalized tonic– clonic sei-
zures, while two had hemiclonic seizures (one of
these two also had versive seizures).18 In another
family, affected individuals also appeared to have
generalized seizures, although one had hemicorpo-
real seizures.30 More recent reports have identified
other SCN1A mutations in the original family from
Victoria, Australia, as well as in three additional
families.9 Only one of 20 affected individuals in the
three additional families had evidence of partial sei-
zures, and a specific temporal localization was not
reported for this individual. The family we describe
is therefore clinically distinct with respect to the re-
sultant epilepsy, which may reflect a specific dys-
function in the sodium channel. The family is also
distinct with respect to FS features. Most affected
patients had complex features, in particular pro-
longed and multiple FS. The original description of
GEFS⫹ indicated that FS were usually brief and
indistinguishable from the febrile convulsion syn-
drome.6 Most other reports did not comment on FS
features, but one report indicated that FS duration
was often ⬎10 minutes.30 Penetrance appears to be
high in the current family, more than previously re-
ported.11 Another notable feature is that interictal
epileptiform abnormalities were infrequent; they
were rare even in the proband during prolonged
EEG monitoring.
The findings for this family suggest that a sodium
channelopathy, possibly influenced by other genes,
may underlie a much wider spectrum of epilepsy
than previously thought. It will be of importance to
determine how frequently a sodium channelopathy
underlies the syndrome of FS with subsequent TLE,
which represents one of the most common syndromes
December (2 of 2) 2001 NEUROLOGY 57 2271
encountered in epilepsy centers. This question would
be of interest in familial cases,31 as well as in the
more common sporadic ones.
Acknowledgment
The authors thank Cindy Notgrass and Tonise Jackson for assis-
tance with recording EEG and collecting DNA samples during
field trips, and Jennifer Moore for help with constructing the
pedigree figure.
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