NEUROLOGY 2004;63:17701771
Turning on the heat
The search for febrile seizure genes
Melodie Winawer, MD, MS; and Dale Hesdorffer, PhD
Febrile seizures (FS) occur in infancy or childhood
and are associated with fever without evidence of
intracranial infection or prior afebrile seizure. FS
are the most common seizure disorder in children,1
affecting 2 to 5% of children by age 6 in the United
States, and as many as 8.3% in Japan. After a first
FS, children have a 25% to 40% recurrence risk.
Genes clearly contribute to the risk of FS. FS are
more common in relatives of individuals with a his-
tory of FS,2 and risks are consistently higher in
monozygotic than dizygotic twins. A positive family
history of FS is also a strong risk factor for FS recur-
rence.3 These data suggest that the predisposition to
single FS and recurrence of FS are partially under
genetic control. Risk for epilepsy is also increased
after a first FS.4
Genetic heterogeneity is evident; recent genetic
linkage studies in large pedigrees and nuclear fami-
lies with FS have pointed to five chromosomal re-
gions likely to harbor FS susceptibility genes (FEB1
FEB5; table 1).5-10 Identification of the responsible
genes in these regions is lacking, but has been suc-
cessful in large families with heterogeneous pheno-
types that prominently include FS. Generalized
epilepsy with febrile seizures plus (GEFS) and se-
vere myoclonic epilepsy of infancy (SMEI) are two
such disorders. Mutations in the genes encoding
three sodium channel subunits (SCN1B, SCN1A,
and SCN2A) and the gamma 2 subunit of the GABAA
receptor have been found to cause GEFS,11-16 and
mutations in SCN1A have been found to cause SMEI
(table 2). Although these disorders include seizure
types other than FS, they may give insight into the
biology of age-limited temperature-dependent sei-
zure susceptibility. Even though these individual
genes may not be responsible for a large proportion
of FS in the population, each new gene discovery
gives insight into the biology of seizure susceptibil-
ity, and can point to novel therapeutic targets.
In this issue of Neurology, Nakayama et al.17 re-
See also page 1803
From Gertrude H. Sergievsky Center (Drs. Winawer and Hesdorffer) and Departments of Neurology (Dr. Winawer) and Epidemiology (Dr. Hesdorffer),
Mailman School of Public Health, Columbia University, New York, NY.
Supported by NIH grants K23 NS02211 and R01 HD36867, and CDC-MM0322.
Address correspondence and reprint requests to Dr. Melodie Winawer, Gertrude H. Sergievsky Center, Columbia University, 630 W. 168th Street, P&S Box
16, New York, NY 10032; e-mail: mw211@columbia.edu
1770 Copyright 2004 by AAN Enterprises, Inc.
Editorial
port linkage and association of FS to the IMPA2 gene
on human chromosome 18. This study combines
three powerful methods: linkage analysis to identify
a candidate region likely to house a susceptibility
gene, simulation studies to determine significance
levels for linkage, and association analysis to test a
candidate of interest within the linkage region. The
authors performed genome-wide linkage analysis in
48 families with two or more children with FS, iden-
tifying a susceptibility region on chromosome
18p11.2. They employed computer simulation to cal-
culate unbiased empirical significance values for in-
terpretation of the linkage analysis result; this is a
sound method for establishing appropriate cut-off
values for significant lod scores. They then examined
the linked chromosome 18 region for candidate
genes. Five known genes localize to the region, from
which they selected IMPA2, one with a biologic ratio-
nale for involvement in seizure susceptibility. IMPA2
encodes myo-inositol monophosphatase (IMPase) and
plays an important role in the phosphatidyli-nositol-
signaling pathway. The authors review the interest-
ing role that IMPA2 may play in psychiatric disease;
it is a candidate for bipolar disorder, and an associa-
tion between one variant of the gene and schizophre-
nia has been reported. IMPase may be a target of
lithium, an effective therapy for bipolar disorder
known to decrease seizure threshold in humans and
animal models, and the anticonvulsant carbamaz-
epine stimulates IMPase activity. The possibility
that a gene might raise risk for both psychiatric and
seizure disorders is intriguing, though evidence is
only suggestive thus far.
The authors conducted a genetic association anal-
ysis of IMPA2 variants with FS in their families.
Association studies assess correlations between DNA
variants and disease in unrelated individuals; the
associated variant may be causal or simply very
close to a causal variant. Single nucleotide polymor-
phisms (SNPs) biallelic genetic variantsand
Table 1 Genetic loci for febrile seizures
Locus Chromosomal region References
FEB1 8q13-21
FEB2 19p13.3
FEB3 2q23-24
FEB4 5q14-15
FEB5 6q22-24
strings of SNPs located together on a chromosome
(haplotypes) are examined for association with dis-
eases of interest. The authors tested six variants of
the IMPA2 gene in 24 randomly selected unrelated
individuals from their families, using unaffected
family members as controls, and found a significant
association of one SNP haplotype in the IMPA2 gene
with FS in the 59 nuclear families.
Association studies hold promise for the investiga-
tion of complex genetic diseases because they can
have greater statistical power than linkage studies
to detect genes of small effect.18 They are ideally
suited to discover relatively common polymorphisms
that raise risk for common diseases like FS. Studies
of candidate genes chosen because of a hypothesis
about their role in disease are more likely than
genome-wide studies to be successful. The combina-
tion of linkage to select a region with biologic ratio-
nale to select the candidate IMPA2 is promising.
Like any association result, this requires replication;
false positive results are a danger in association
studies. In addition, it is possible that FS risk is
influenced by a nearby variant in the genome rather
than by IMPA2 itself, though, as the authors point
out, the distance of the nearest gene to IMPA2 is so
great that an entirely different gene is unlikely to be
responsible for this effect.
Most genes implicated in human idiopathic sei-
zure disorders have been ion channel and receptor
genes; LGI1, the gene responsible for autosomal
dominant lateral temporal lobe epilepsy, and
EFHC1, mutated in some families with juvenile myo-
Table 2 Gene identification in syndromes with heterogeneous
phenotypes that include febrile seizures
Syndrome Gene Chromosomal region References
GEFS SCN1B 19q13
SCN1A 2q24 12, 13
SCN2A 2q24
GABRG2 5q31
SMEI SCN1A 23q24 2124
GEFS generalized epilepsy with febrile seizures plus;
SMEI severe myoclonic epilepsy of infancy.
clonic epilepsy, are notable exceptions.19,20 The
IMPA2 candidate suggests another novel mechanism
for seizure susceptibility. Identification of genes re-
5 sponsible for this pathologic response to fever could
6,7 dramatically improve understanding, treatment, and
8
perhaps prevention of this common seizure type that
results from a common insult.
9
10 References
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November (2 of 2) 2004 NEUROLOGY 63 1771
 Turning on the heat: The search for febrile seizure genes
Melodie Winawer and Dale Hesdorffer
Neurology 2004;63;1770-1771
DOI 10.1212/01.WNL.0000144285.17019.35

This information is current as of November 22, 2004

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