LGI1 Mutations in Autosomal Dominant and Sporadic
Lateral Temporal Epilepsy
Carlo Nobile,1?Roberto Michelucci,2Simonetta Andreazza,3Elena Pasini,2Silvio C.E. Tosatto,3and Pasquale Striano4
1CNR–Institute of Neurosciences, Section of Padua, Padova, Italy
2Department of Neurosciences, Bellaria Hospital, Bologna, Italy
3Department of Biology, University of Padua, Padova, Italy
4Muscular and Neurodegenerative Diseases Unit, Institute ‘‘G. Gaslini,’’ University of Genoa, Genova, Italy
Communicated by Prof. Christine Van Broeckhoven
Received 19 June 2008; accepted revised manuscript 10 September 2008.
Published online 3 February 2009 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/humu.20925
epilepsy (ADLTE) or autosomal dominant partial epi-
lepsy with auditory features (ADPEAF) is an inherited
epileptic syndrome with onset in childhood/adolescence
and benign evolution. The hallmark of the syndrome
consists of typical auditory auras or ictal aphasia in most
affected family members. ADTLE/ADPEAF is associated
in about half of the families with mutations of the
leucine-rich, glioma-inactivated 1 (LGI1) gene. In addi-
tion, de novo LGI1 mutations are found in about 2% of
sporadic cases with idiopathic partial epilepsy with
auditory features, who are clinically similar to the
majority of patients with ADLTE/ADPEAF but have no
family history. Twenty-five LGI1 mutations have been
described in familial and sporadic lateral temporal
epilepsy patients. The mutations are distributed through-
out the gene and are mostly missense mutations
occurring in both the N-terminal leucine rich repeat
(LRR) and C-terminal EPTP (beta propeller) protein
domains. We show a tridimensional model of the LRR
protein region that allows missense mutations of this
region to be divided into two distinct groups: structural
and functional mutations. Frameshift, nonsense and
splice site point mutations have also been reported that
result in protein truncation or internal deletion. The
various types of mutations are associated with a rather
homogeneous phenotype, and no obvious genotype–
phenotype correlation can be identified. Both truncating
and missense mutations appear to prevent secretion
of mutant proteins, suggesting a loss of function effect of
mutations. The function of LGI1 is unclear. Several
molecular mechanisms possibly leading to lateral tempor-
al epilepsy are illustrated and briefly discussed.
Hum Mutat 30, 530–536, 2009.
& 2009 Wiley-Liss,
KEY WORDS: lateral temporal epilepsy; ADTLE; AD-
PEAF; LGI1; epitempin; LRR domain; in silico analysis
Autosomal Dominant Lateral Temporal Epilepsy (ADLTE;
MIM] 600512) is an inherited epilepsy syndrome characterized
by partial seizures with predominant auditory symptoms
originating from the lateral temporal lobe cortex. This syndrome
was first described by Ottman and colleagues  as Autosomal
Dominant Partial Epilepsy with Auditory Features (ADPEAF).
Subsequently, several families with similar clinical features were
reported by different groups [Brodtkorb et al., 2002; Michelucci
et al., 2000; Poza et al., 1999; Winawer et al., 2002]. Because other
ictal sensory manifestations of lateral temporal origin (e.g., visual,
aphasic) occurred in some families, either accompanying auditory
symptoms or isolated, the term ADLTE seemed to be more
appropriate [Poza et al., 1999]. In 2002, mutations responsible for
ADLTE/ADPEAF were identified in the leucine-rich, glioma
inactivated 1 gene (LGI1; GeneID 9211; MIM] 604619) by
positional cloning [Kalachikov et al., 2002; Morante-Redolat et al.,
2002]. A number of ADLTE/ADPEAF families mutated in LGI1
have been described subsequently [Berkovic et al., 2004; Chabrol
et al., 2007; Fertig et al., 2003; Gu et al., 2002; Hedera et al., 2004;
Kobayashi et al., 2003; Michelucci et al., 2003; Ottman et al., 2004;
Pisano et al., 2005; Pizzuti et al., 2003; Striano et al., 2008].
Overall, LGI1 mutations are found in about 50% of the
ADLTE/ADPEAF families [Berkovic et al., 2004; Michelucci
et al., 2003; Ottman et al., 2004], indicating that the syndrome
is genetically heterogeneous. De novo LGI1 mutations have
also been identified in sporadic (nonfamilial) cases with idiopathic
partial epilepsy with auditory features (IPEAF) [Bisulli et al.,
2004a; Michelucci et al., 2007]. Overall, de novo LGI1
mutations account for about 2% of sporadic IPEAF cases,
who are clinically similar to the ADLTE patients with auditory
The LGI1 gene was cloned in 1998 due to its rearrangements in
the T98G glioblastoma multiforme cell line, and was found to be
downregulated in many malignant gliomas, suggesting a possible
tumor suppressor function [Chernova et al., 1998]. However,
neither point mutations affecting the LGI1 coding sequence nor
differential methylation of its core promoter region could be
demonstrated in these tumors, arguing against a role of LGI1 as a
tumor suppressor gene [Krex et al., 2002; Piepoli et al., 2006;
Somerville et al., 2000]. Recent studies have implicated LGI1 in the
control of proliferation and invasiveness of glioma cell lines
[Kunapuli et al., 2003]. Particularly, control of glioma cell
invasiveness is achieved by regulating expression of the matrix
metalloproteinases MMP1 and MMP3 through the ERK 1/2
& 2009 WILEY-LISS, INC.
?Correspondence to: Carlo Nobile, Istituto di Neuroscienze del CNR, Sezione di
Padova, Dipartimento di Scienze Biomediche Sperimentali, Universita ` di Padova,
viale G. Colombo 3, 35121 Padova, Italy. E-mail: email@example.com
pathway, suggesting that LGI1 may serve as a tumor metastasis
suppressor gene [Kunapuli et al., 2004].
The LGI1 gene is located on the long arm of chromosome 10
within the band 10q23.33. It consists of eight exons and seven
introns that span 39.6kb, has an open reading frame of 1671bp,
and is transcribed from centromere towards telomere. LGI1 is
expressed mainly in the brain and to a lesser degree in skeletal
muscle [Chernova et al., 1998]. In both tissues, two mRNA
isoforms resulting from alternative splicing are present: a full-
length 2254-bp transcript, which is more abundantly expressed in
the brain, and a shorter splice isoform of 1456bp, encompassing
the 50half of the full-length coding region, which is expressed at
lower levels [Chernova et al., 1998; Morante-Redolat et al., 2002].
LGI1 expression in the brain is predominantly neuronal, with little
or no expression found in glial cells [Kalachikov et al., 2002;
Piepoli et al., 2006; Senechal et al., 2005]. In situ hybridization
experiments have shown that expression of the murine Lgi1 gene
is higher in some areas, particularly in the neocortex and limbic
regions [Kalachikov et al., 2002; Senechal et al., 2005]. Variable
LGI1 protein expression has been demonstrated in human brain
tissue samples by immunoblot analysis [Furlan et al., 2006]. The
main transcription product encodes a protein of 557 amino acids
with a predicted molecular weight of 63.8kDa. Analysis of the
amino acid sequence of this polypeptide predicts an N-terminal
signal peptide and two distinct structural domains, each spanning
about half of the protein: the N-terminal region contains four
leucine-rich repeats (LRR) flanked by conserved cysteine clusters
[Kobe and Kajava, 2001], whereas the C-terminal region consists
of seven copies of a repeat of 40–43 residues named EPTP [Staub
et al., 2002] or EAR [Scheel et al., 2002], likely forming a beta-
propeller structural domain [Paoli, 2001]. LRR and beta-propeller
motifs are known to mediate protein–protein interactions in many
other proteins [Buchanan and Gay, 1996; Paoli, 2001].
The same structural disposition of LRR and EPTP/EAR
domains has been identified in three putative paralogues, named
LGI2, LGI3, and LGI4, which map to 4p15.2, 8p21.3, and
19q13.12, respectively [Staub et al., 2002]. Expression levels of
these genes are generally low throughout the brain except in some
distinctive areas: LGI2 is highly expressed in the pyriform cortex
and the thalamic reticular nucleus; LGI3 in the facial nerve
nucleus; and LGI4 in the purkinje cell layer of the cerebellar cortex
and in the olfactory cortex [Senechal et al., 2005] and throughout
the periferal nervous system (PNS) [Bermingham et al., 2006].
These specific areas of expression suggest that mutations in each
of these paralogues could result in distinctly different neurological
phenotypes. Recently, the murine Lgi4 gene, which is expressed
primarily by Schwann cells in the developing and mature PNS, has
been found to carry a mutation in claw paw mutant mice,
resulting in peripheral hypomyelination [Bermingham et al.,
Although a single transmembrane domain was initially
predicted in its central part [Chernova et al., 1998], the Lgi1
protein does not contain any transmembrane domain and is
therefore thought to be secreted [Morante-Redolat et al., 2002;
Staub et al., 2002]. This view is supported by in vitro experiments
that have shown that the Lgi1 protein produced by transfected
cells is secreted into the cell medium [Furlan et al., 2006; Senechal
et al., 2005]. Similarly, the Lgi2-4 proteins produced in vitro by
transfected cells also are secreted [Senechal et al., 2005].
LGI1 was the first nonion channel gene identified in human
idiopathic epilepsy. Its role in seizure generation likely differs from
the so far known mechanisms of epileptogenesis. However, the
function of LGI1 is largely unclear.
In this paper, we summarize the mutational reports published
in the last 6 years since the first two publications [Kalachikov
et al., 2002; Morante-Redolat et al., 2002]. A total of 25 mutations
have been described so far, all found in the heterozygous state. We
also describe the predicted effects of the missense mutations
occurring in the LRR region on the tridimensional conformation
of this domain and outline the current views about the possible
functions of LGI1.
Mutations and polymorphisms in the lgi1 gene
To date, a total of 25 LGI1 mutations have been described,
either segregating in ADLTE/ADPEAF families or occurring
de novo in sporadic IPEAF patients (Fig. 1 and Table 1; nucleotide
numbering uses the A of the ATG translation initiation start site as
nucleotide11). Twenty-four mutations segregate in 25 affected
families, whereas two, c.406C4T and c.1420C4T, are de novo
mutations identified in nonfamilial cases, the latter occurring in
both a family and a sporadic case [Bisulli et al., 2004b; Morante-
Redolat et al., 2002]. Of these mutations, 16 allow single amino
acid substitutions, whereas eight result in protein truncation due
to frameshift deletions (c.329delC, c.611delC, c.758delC, and
c.1050_1051delCA) or insertion (c.1639_1640insA), and to
nonsense (c.1420C4T) or splice site (c.359-3C4A, c.839-
2A4G) mutations. The only internal deletion, of exons 3 and 4,
as yet identified results from altered splicing (c.43111G4A).
Thus, even though it cannot be excluded that some point
mutations allowing amino acid replacement might actually be
hidden splice-site mutations giving rise to protein truncation,
the majority of the mutations as yet identified are missense
nucleotide changes. The mutation distribution along the gene is
rather uniform, with a slight preference of missense mutations
for the 50-half (exons 1–6) and of truncating mutations for the
30-half (exons 7–8) of the gene (Fig. 1). These two gene regions
correspond to the N-terminal LRR and C-terminal EPTP (beta
propeller) domains of the protein, respectively.
At the protein level, all the missense mutations affect amino
acids that are conserved in many species, including mouse,
rat, chicken, zebrafish, and Xenopus tropicalis (not shown). Ten
out of 16 nonsynonymous mutations occur in the LRR region, six
of which affect amino acid residues located in the LRR repeats 2,
3, and 4, whereas the other four modify conserved cysteine
residues flanking the LRR repeats. To explore if their consequences
could be rationalized in terms of structure and/or function,
we mapped these missense mutations onto a homology model
based on the predicted similarity of human Lgi1 to various LRR
proteins. Predicting the structure of such a repeat protein requires
a special approach [Kajava and Kobe, 2002]. A full report of
the prediction process will be described elsewhere (S. Andreazza,
C. Nobile, and S. Tosatto, in preparation). Briefly, the initial
structure search using MANIFOLD [Bindewald et al., 2003]
revealed the Nogo-66 receptor LRR domain [Barton et al., 2003]
to be remotely similar to that of Lgi1. Given the repetitive
nature of the LRR, the Nogo-66 receptor structure was used
as a template to manually identify and realign the single repeat
units. As shown in Figure 2a and b, the Lgi1 sequence conforms to
the typical distribution, with hydrophobic residues, especially
leucine, preferentially located on the protein interior. Only the
first repeat is somewhat more degenerate than the rest. The typical
N- and C-terminal LRR flanking motifs, with their disulfide
bridge-forming cysteine residues at defined positions, are also
HUMAN MUTATION, Vol. 30, No. 4, 530–536, 2009
clearly conserved in LGI1 and highlighted in Figure 2a. From this
analysis, it is possible to derive the approximate structural model
(Fig. 2b) colored by CONSURF residue conservation [Landau
et al., 2005].
The known LGI1 mutations mapping to the LRR domain are
highlighted in Figure 2b and c.
Given their distribution on the LRR structure, it is possible to
divide them into two groups. The first group is composed of
Exons are shown as gray boxes, introns as thin lines (not to scale). Different geometric symbols are assigned to the various protein domain
types indicated by the abbreviations: SP, signal peptide; LRR, leucine-rich repeat region; N-Cys, cysteine-rich region N-terminal to LRR; C-Cys,
cysteine-rich region C-terminal to LRR; EPTP, C-terminal repeats as defined by Staub et al. . Gene exons (GenBank reference sequence
NM_005097.2) are approximately aligned with the corresponding protein repeats. The positions of missense mutations in the various exons are
indicated. Vertical thick lines denote the endpoints of truncating mutations along the gene and protein, the horizontal line the extent of the
deletion mutation. Asterisks indicate de novo mutations.
Schematic representation of the LGI1 gene organization, protein repeat domains, and localization of the 25 reported mutations.
LGI1 Mutations Reported in the Literature
Nucleotide change Predicted effectGene/protein region Effect on protein secretionReference
Ottman et al. 
Berkovic et al. 
Gu et al. ; Pizzuti et al. 
Ottman et al. 
Hedera et al. 
Kalachikov et al. 
Striano et al. 
Di Bonaventura et al. [submitted]
Michelucci et al. 
Chabrol et al. 
Hedera et al. 
Pisano et al. 
Michelucci et al. 
Kalachikov et al. 
Chabrol et al. 
Morante-Redolat et al. 
Kobayashi et al. 
Ottman et al. 
Fertig et al. 
Kalachikov et al. 
Kalachikov et al. 
Michelucci et al. 
Berkovic et al. 
Morante-Redolat et al. ; Bisulli et al. 
Kalachikov et al. 
Secretion test performed by:
aSirerol-Piquer et al. ;
bNobile et al. [unpublished];
cStriano et al. ;
dSenechal et al. ;
eChabrol et al. .
NT, not tested. LGI1 GenBank reference sequence: NM_005097.2. Nucleotide numbering uses the A of the ATG translation initiation start site as nucleotide11.
HUMAN MUTATION, Vol. 30, No. 4, 530–536, 2009
structural mutations that have a clear impact on the overall
domain stability. It includes critical mutations of the conserved
cysteine residues (p.C42R, p.C42G, p.C46R, and p.C200R), which
disrupt disulfide bridges responsible for proper N- and C-terminal
closure of the domain, and mutations of hydrophobic core
residues to polar/charged residues (p.A110D, p.I122K, and
p.L154P), which are highly destabilizing of the protein domain
fold. The second group (p.E123K, p.R136W, and p.S145R) consists
of mutations probably related to the function of the LRR domain,
as they occur at residues located on the surface that exhibit higher
sequence variability between repeat units (see Fig. 2b and c). It can
be expected that the impact of these functional mutations would
probably not alter the protein fold, but rather influence the LRR
interaction properties. LRR domains usually function as pro-
tein–protein interaction scaffolds through the flat surface on the
concave side. As the majority of the functional mutations found in
other LRR proteins map to this part of the structure, this precept
appears to be valid for LGI1 as well.
The seven EPTP repeats spanning the C-terminal half of
the Lgi1 protein are predicted to fold up to generate a seven-blade
beta-propeller structure, which is the most preferred conforma-
tion of this class of proteins [Paoli, 2001]. The six point mutations
regions and the four central repeats. Conserved positions in the four LRR repeats are highlighted and the consensus sequence is shown in the
last row. Disulfide bridges are shown as brackets underneath the sequence in the flanking regions. For the central repeats, the positions above
the sequences are numbered relative to the repeat unit and the absolute sequence position shown for the first and last residue before and after
the sequence itself. b: The trace of a single repeat unit is shown with an arrow representing the short beta strand on the concave side and the
irregular structure on the convex side. The connecting loops are shown as black lines and circles represent each amino acid position along the
repeat unit. The positions are numbered in accordance with (a). Residues where a single amino acid type is predominant throughout subsequent
repeat units are shown with single letters. Hydrophobic core positions are highlighted in pink, fully exposed surface positions in blue and
partially exposed positions in white. Position 9, although part of the hydrophobic core, is occupied by residues able to stabilize the protein
interior with hydrogen bonds to nearby backbone atoms. Specific LGI1 mutations falling into the regular repeat units are superimposed. c:
Approximate model of the Lgi1 LRR repeat domain. The manually reconstructed model of the Lgi1 LRR domain based on the Nogo-66 structure is
shown in cartoon representation, with the concave side on the bottom. The coloring scheme represents the degree of conservation in a
representative sequence alignment, ranging from cyan (unconserved) to magenta (strictly conserved). Known LGI1 mutations are shown in
sphere representation and highlighted with arrows. Picture drawn with PyMol (DeLano Scientific LLC, Dorset, UK).
a: Sequence alignment of the LRR domain. Residues 34 to 223 of the full protein are broken down into the N- and C-terminal flanking
HUMAN MUTATION, Vol. 30, No. 4, 530–536, 2009
so far identified in this region modify evolutionarily conserved
amino acids, each in a distinct repeat from EPTP 1–6 (Fig. 1).
Finally, in proteins truncated by mutations, the length of amino
acid sequence removed varies from as little as 11 to 448 residues,
with apparently no significant phenotypic differences.
The effects of several epilepsy-causing mutations on protein
secretion have been tested by cell-transfection assay using HEK293
or 293T cell lines. As summarized in Table 1, all of the
nonsynonymous and truncating LGI1 mutations so far tested
abolish or considerably reduce secretion of the corresponding
mutant proteins [Chabrol et al., 2007; Senechal et al., 2005;
Sirerol-Piquer et al., 2006; Striano et al., 2008]. Interestingly, point
mutations occurring in the LRR or EPTP domain have the same
negative effect on protein secretion, suggesting that both domains
are necessary for secretion.
Very few polymorphisms have been identified in the LGI1
promoter region and coding exons. The minimal promoter
sequence necessary for gene transcription in vitro has been shown
to lie in the 531bp immediately upstream of exon 1 [Sommerville
et al., 2000]. Analysis of this region has revealed two polymorph-
isms, ?500G4A and ?507G4A [Bovo et al., 2008]. These single
nucleotide polymorphisms (SNPs) are localized at the border of a
stretch of sequence conserved in the mouse Lgi1 promoter, within
or near a predicted AP-2 transcription factor binding site. Because
AP-2 is a critical neural transcription factor [Mitchell et al., 1991],
these SNPs may affect LGI1 transcription levels with potential
functional implications. We analyzed these polymorphisms in a
cohort of 104 Italian sporadic IPEAF patients but their frequencies
did not differ from those found in a control population of similar
age, gender, and geographic origin [Bovo et al., 2008].
Only one SNP, the synonymous polymorphism c.657C4T
(rs1111820) in exon 6, has been identified in the LGI1 coding
region to date. It was found only once in our population of Italian
IPEAF cases, in agreement with its low frequency reported in
databases (heterozygosity: 0.043).
The ADLTE/ADPEAF syndrome, first reported in an American
kindred [Ottman et al., 1995; Winawer et al., 2000], was initially
considered a very rare epileptic syndrome. Subsequently, pedigrees
from several European countries (Italy, Spain, Germany, France,
Norway) and from Australia and Nepal have been described
[Berkovic et al., 2004; Brodtkorb et al., 2002, Chabrol et al., 2007;
Fertig et al., 2003, Mautner et al., 2000; Michelucci et al., 2003;
Pisano et al., 2005; Poza et al., 1999; Striano et al., 2008], suggesting
that ADLTE/ADPEAF, although rare, is a worldwide condition.
It is not yet clear whether LGI1 is involved in transmission of
synaptic currents or neuronal development, or in both processes.
The structural features of its protein product, which do not
resemble those of known ion channel subunits, suggest that LGI1
may not be directly implicated in neuronal transmission
[Kunapuli et al., 2004; Staub et al., 2002]. This view has been
questioned by recent findings that show association of the Lgi1
protein with the rapidly inactivating Kv1 (shaker type) potassium
channel [Schulte et al., 2006]. This channel is located mainly in
presynapses and consists of two alpha subunits, Kv1.1 and Kv1.4,
and one beta subunit, Kvbeta1. It has been shown in transfected
Xenopus oocytes that Lgi1 selectively prevents inactivation of Kv1
channels mediated by the Kvbeta1 subunit [Schulte et al., 2006].
These results suggest that LGI1 mutations may cause changes in
inactivation gating of neuronal Kv1 channels, thereby giving rise
to epileptic activity. However, analysis of the genes encoding
Kv1.1, Kv1.4, and Kvbeta1 has revealed no mutations in 9 LGI1-
negative families with typical ADLTE/ADPEAF, throwing doubt
upon the involvement of this channel in lateral temporal epilepsy
[Diani et al., 2008].
In another recent work, the Lgi1 protein has been found
associated with a postsynaptic protein complex containing PSD-
95 and the receptor ADAM22 [Fukata et al., 2006]. Particularly,
ADAM22, a neuronal transmembrane protein, has been shown to
serve as a receptor for Lgi1. This receptor–ligand interaction
ultimately potentiates synaptic AMPA currents in hippocampal
slices, where the effects of Lgi1 on synaptic transmission appear to
be exclusively postsynaptic [Fukata et al., 2006]. These findings
suggest a role for Lgi1 in the control of synaptic strength at
excitatory synapses and point to ADAM22 as a strong candidate
for ADLTE. Yet, a mutational screening of this gene in two series
of ADLTE/ADPEAF families without LGI1 mutations failed to find
any disease-causing mutations, thus excluding a genetic contribu-
tion of the ADAM22 gene to this condition [Chabrol et al., 2007;
Diani et al., 2008].
An alternative functional hypothesis postulates a role for LGI1
in brain development, as suggested by its expression in the
developing mouse brain [Piepoli et al., 2006; Ribeiro et al., 2008]
and by the structural homology of the LRR region with that of
other LRR proteins essential for the development of the central
nervous system, such as slit, tartan, and toll [Cowell, 2002]. This
hypothesis has recently received support by in vitro experiments
showing that LGI1 is involved in the control of proliferation and
survival of neuroblastoma cell lines [Gabellini et al., 2006]. These
results suggest that the levels of LGI1 expression may be important
for neuronal cell survival during brain development and,
consequently, that LGI1 mutations could result in subtle structural
abnormalities of the temporal cortex underlying seizure discharge
in ADLTE/ADPEAF. In keeping with this, a subtle structural
anomaly not detectable by standard magnetic resonance imaging
(MRI) has been shown in the left lateral temporal cortex of
patients with LGI1 mutations by voxel-based diffusion tensor
imaging [Tessa et al. 2007]. That LGI1 may have a function in
brain development is indirectly supported also by the recent
identification of the claw paw mutation in the mouse Lgi4 gene,
demonstrating that the function of Lgi4 is required in peripheral
nerve development [Bermingham et al., 2006]. In addition to Lgi1
and Lgi4, the Lgi3 gene has also been found to be expressed in the
developing mouse nervous system [Lee et al., 2006]. Thus, their
expression patterns, structural similarity, and common evolu-
tionary origin from a single ancestral precursor gene [Gu et al.,
2005] suggest that the LGI family members may play important
roles during development.
Overall, the studies described above suggest that Lgi1 may be a
versatile protein involved in several different functions, each of
which has to be clarified independently to assess its relevance to
lateral temporal epilepsy.
Clinical and diagnostic relevance
ADLTE/ADPEAF refers to an epileptic syndrome inherited in
autosomal dominant fashion with reduced penetrance and
clinically characterized by focal seizures with prominent ictal
HUMAN MUTATION, Vol. 30, No. 4, 530–536, 2009
auditory phenomena (described as ringing, humming, whistling,
or singing), which suggest a lateral temporal lobe onset of
discharge. Additional sensory symptoms (i.e., visual, aphasic,
olfactory, vertiginous) may occur other than the distinctive
auditory manifestations. Seizures may be triggered by environ-
mental sounds or noises and secondarily generalized tonic–clonic
seizures are almost invariably present, although occurring
sporadically [Ottman et al., 1995, 2004; Michelucci et al., 2003].
In some families, affected individuals experience short-lasting
aphasia at seizure onset [Brodtkorb et al., 2002; Michelucci et al.,
2003; Ottman et al., 2004; Pizzuti et al., 2003]. Other seizure
phenotypes, such as febrile seizures and idiopathic generalized
epilepsy, have occasionally been described in family members
carrying mutations in LGI1 [Ottman et al., 2004; Pisano et al.,
2005]. However, it is still unclear whether their occurrence is
coincidental or rather reflects the impact of a second gene in these
The onset of the disease is quite variable even within families,
although it usually manifests in young individuals. The evolution
of the condition is relatively benign because seizures are usually
well controlled with standard antiepileptic drugs, although
recurrence after drug withdrawal is frequently reported [Miche-
lucci et al., 2003; Ottman et al., 1995; Poza et al., 1999]. In most
cases, conventional brain MRI is normal and electroencephalo-
grams frequently show mild temporal abnormalities. Because the
clinical diagnosis of ADLTE/ADPEAF is based mainly on the
presence of an auditory aura, which may be elusive in some
patients or families, testing for mutations in LGI1 is important to
confirm diagnosis of this syndrome, especially in families with
only a few patients available. Testing for mutations in LGI1 could
also contribute—together with the clinical data—to avoiding long
presurgical studies or preventing unnecessary surgery.
Available penetrance rates for ADLTE/ADPEAF widely ranges
between 50% and 85%, depending on the family ascertainment
strategies, and the penetrance of LGI1 mutations is estimated
around 67% [Rosanoff and Ottman, 2008]. Incomplete pene-
trance could potentially explain the involvement of only a single
generation in some families. However, it is much more likely that
the clinical symptoms remain undiagnosed in some generations
because of the mild nature of the seizures, as suggested by the fact
that many patients had a diagnosis delayed by months or years
[Michelucci et al., 2003; Ottman et al., 1995; Ottman et al., 2004].
Mutations in LGI1 are found in about 50% of ADLTE/ADPEAF
families, suggesting that this syndrome is genetically heteroge-
neous [Berkovic et al., 2004; Michelucci et al., 2003; Morante-
Redolat et al., 2002; Ottman et al., 2004]. Notably, families
without LGI1 mutations have no clinical features that distinguish
them from those with LGI1 mutations. Further detailed clinical
and molecular studies are needed to elucidate other loci
responsible for ADLTE/ADPEAF.
Sporadic cases with IPEAF have been widely reported [Bisulli
et al., 2004a]. Similar to the majority of familial cases, these
patients have auditory partial epilepsy, normal conventional MRI,
benign outcome, but no family history of epilepsy. De novo LGI1
mutations account for about 2% of sporadic IPEAF patients
[Bisulli et al., 2004b; Michelucci et al., 2007]. However,
identification and screening of additional patients is needed to
determine the precise proportion of cases caused by de novo LGI1
mutations and for genetic counselling purposes.
Overall, considering all the 25 mutations identified thus far, no
obvious genotype-phenotype correlations seem to emerge. In
particular, no striking differences can be identified between
patients with truncating and missense mutations in the LGI1 gene.
A larger number of kindreds with LGI1 mutations is needed in
order to correlate genotypes and phenotypes reliably.
The 25 known LGI1 mutations are heterozygous point
mutations (substitution, deletion, or insertion of a single base)
occurring in coding exons or splice sites. It is possible that a
proportion of patients have long-range deletions or duplications
involving multiple exons or the entire gene, which cannot be
detected by the PCR-based direct sequencing method commonly
used for mutation analysis. Only one study of several European
ADLTE/ADPEAF families included a semiquantitative PCR
analysis of LGI1 exons to identify gross mutations but no such
mutations were found [Michelucci et al., 2003]. Future mutation
testing of familial and sporadic patients with lateral temporal
epilepsy should include the search for LGI1 deletions, which can
now be performed using the very reproducible multiplex ligation-
dependent probe amplification (MLPA) method.
The ability of epilepsy-causing LGI1 mutations to abolish or
strongly reduce protein secretion in vitro is currently considered a
functional assay of the pathogenicity of these mutations. This
assay, however, is commonly carried out in nonneuronal cells that
overexpress the Lgi1 protein, that is, under conditions far from
physiological. Studies aimed to ascertain whether or not Lgi1 is
secreted in primary neuronal cell culture and animal models will
be important not only to evaluate the reliability of the secretion
test of mutations but also to define whether Lgi1 exerts its
function extra or intracellularly, a basic question still open.
The features of its domain structure strongly suggest the Lgi1
protein likely interacts with other proteins. The identification of
the interacting partners of Lgi1 will shed light on its function(s)
and provide valuable information as to the pathogenic mechanism
leading to ADLTE/ADPEAF as well as its localized effect. A better
understanding of the function of the LGI1 gene will hopefully
allow the development of new therapeutic strategies more specific
and effective than current treatments.
We thank the members of the Genetic Commission of the Italian League
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