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NEUROLOGY 2004;63:17701771 Editorial

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 port linkage and association of FS to the IMPA2 gene
and are associated with fever without evidence of on human chromosome 18. This study combines
intracranial infection or prior afebrile seizure. FS three powerful methods: linkage analysis to identify
are the most common seizure disorder in children,1 a candidate region likely to house a susceptibility
affecting 2 to 5% of children by age 6 in the United gene, simulation studies to determine significance
States, and as many as 8.3% in Japan. After a first levels for linkage, and association analysis to test a
FS, children have a 25% to 40% recurrence risk. candidate of interest within the linkage region. The
Genes clearly contribute to the risk of FS. FS are authors performed genome-wide linkage analysis in
more common in relatives of individuals with a his- 48 families with two or more children with FS, iden-
tory of FS,2 and risks are consistently higher in tifying a susceptibility region on chromosome
monozygotic than dizygotic twins. A positive family 18p11.2. They employed computer simulation to cal-
history of FS is also a strong risk factor for FS recur- culate unbiased empirical significance values for in-
rence.3 These data suggest that the predisposition to terpretation of the linkage analysis result; this is a
single FS and recurrence of FS are partially under sound method for establishing appropriate cut-off
genetic control. Risk for epilepsy is also increased values for significant lod scores. They then examined
after a first FS.4 the linked chromosome 18 region for candidate
Genetic heterogeneity is evident; recent genetic genes. Five known genes localize to the region, from
linkage studies in large pedigrees and nuclear fami- which they selected IMPA2, one with a biologic ratio-
lies with FS have pointed to five chromosomal re- nale for involvement in seizure susceptibility. IMPA2
gions likely to harbor FS susceptibility genes (FEB1 encodes myo-inositol monophosphatase (IMPase) and
FEB5; table 1).5-10 Identification of the responsible plays an important role in the phosphatidyli-nositol-
genes in these regions is lacking, but has been suc- signaling pathway. The authors review the interest-
cessful in large families with heterogeneous pheno- ing role that IMPA2 may play in psychiatric disease;
types that prominently include FS. Generalized it is a candidate for bipolar disorder, and an associa-
epilepsy with febrile seizures plus (GEFS) and se- tion between one variant of the gene and schizophre-
vere myoclonic epilepsy of infancy (SMEI) are two nia has been reported. IMPase may be a target of
such disorders. Mutations in the genes encoding lithium, an effective therapy for bipolar disorder
three sodium channel subunits (SCN1B, SCN1A, known to decrease seizure threshold in humans and
and SCN2A) and the gamma 2 subunit of the GABAA animal models, and the anticonvulsant carbamaz-
receptor have been found to cause GEFS,11-16 and epine stimulates IMPase activity. The possibility
mutations in SCN1A have been found to cause SMEI that a gene might raise risk for both psychiatric and
(table 2). Although these disorders include seizure seizure disorders is intriguing, though evidence is
types other than FS, they may give insight into the only suggestive thus far.
biology of age-limited temperature-dependent sei- The authors conducted a genetic association anal-
zure susceptibility. Even though these individual ysis of IMPA2 variants with FS in their families.
genes may not be responsible for a large proportion Association studies assess correlations between DNA
of FS in the population, each new gene discovery variants and disease in unrelated individuals; the
gives insight into the biology of seizure susceptibil- associated variant may be causal or simply very
ity, and can point to novel therapeutic targets. close to a causal variant. Single nucleotide polymor-
In this issue of Neurology, Nakayama et al.17 re- phisms (SNPs) biallelic genetic variantsand

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:

1770 Copyright 2004 by AAN Enterprises, Inc.

Table 1 Genetic loci for febrile seizures clonic epilepsy, are notable exceptions.19,20 The
Locus Chromosomal region References
IMPA2 candidate suggests another novel mechanism
for seizure susceptibility. Identification of genes re-
FEB1 8q13-21 5 sponsible for this pathologic response to fever could
FEB2 19p13.3 6,7 dramatically improve understanding, treatment, and
FEB3 2q23-24 8
perhaps prevention of this common seizure type that
results from a common insult.
FEB4 5q14-15 9
FEB5 6q22-24 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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Genetic linkage
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