Epilepsy Research 120 (2016) 73–78

Contents lists available at www.sciencedirect.com

Epilepsy Research
journal homepage: www.elsevier.com/locate/epilepsyres

Short communication

Screening LGI1 in a cohort of 26 lateral temporal lobe epilepsy patients
with auditory aura from Turkey detects a novel de novo mutation
Yesim F. Kesim a , Gunes Altiokka Uzun b , Emrah Yucesan a , Feyza N. Tuncer a ,
Ozkan Ozdemir a , Nerses Bebek b , Ugur Ozbek a , Sibel A. Ugur Iseri a,∗ , Betul Baykan b
a
b

Istanbul University, Institute of Experimental Medicine, Department of Genetics, Istanbul, Turkey
Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Clinical Neurophysiology Unit, Istanbul, Turkey

a r t i c l e

i n f o

Article history:
Received 5 June 2015
Received in revised form 2 November 2015
Accepted 9 December 2015
Available online 12 December 2015
Keywords:
Lateral temporal lobe epilepsy (LTLE)
Autosomal Dominant Lateral Temporal
Epilepsy (ADLTE)
Idiopathic Partial Epilepsy with Auditory
Features (IPEAF)
LGI1
De novo Mutation
Auditory aura

s u m m a r y
Autosomal dominant lateral temporal lobe epilepsy (ADLTE) is an autosomal dominant epileptic syndrome characterized by focal seizures with auditory or aphasic symptoms. The same phenotype is also
observed in a sporadic form of lateral temporal lobe epilepsy (LTLE), namely idiopathic partial epilepsy
with auditory features (IPEAF). Heterozygous mutations in LGI1 account for up to 50% of ADLTE families
and only rarely observed in IPEAF cases. In this study, we analysed a cohort of 26 individuals with LTLE
diagnosed according to the following criteria: focal epilepsy with auditory aura and absence of cerebral lesions on brain MRI. All patients underwent clinical, neuroradiological and electroencephalography
examinations and afterwards they were screened for mutations in LGI1 gene. The single LGI1 mutation
identified in this study is a novel missense variant (NM 005097.2: c.1013T > C; p.Phe338Ser) observed de
novo in a sporadic patient. This is the first study involving clinical analysis of a LTLE cohort from Turkey
and genetic contribution of LGI1 to ADLTE phenotype. Identification of rare LGI1 gene mutations in sporadic cases supports diagnosis as ADTLE and draws attention to potential familial clustering of ADTLE in
suggestive generations, which is especially important for genetic counselling.
© 2015 Elsevier B.V. All rights reserved.

Introduction
Lateral temporal lobe epilepsy (LTLE) is a group of conditions
with specific seizure characteristics including auditory aura or
aphasic symptoms with a high tendency to generalize. Non-lesional
LTLE characterized by negative magnetic resonance imaging (MRI)
findings has been described for a number of familial and sporadic
cases. Familial non-lesional LTLE, namely Autosomal Dominant Lateral Temporal Lobe Epilepsy (ADLTE; OMIM 600512) is inherited
in an autosomal dominant fashion presenting reduced penetrance
with an overall estimate of 66% (Ho et al., 2012). Sporadic nonlesional LTLE, on the other hand, is known as idiopathic partial
epilepsy with auditory features (IPEAF). Both ADTLE and IPEAF are

Abbreviations: ADTLE, Autosomal Dominant Lateral Temporal Lobe Epilepsy;
AED, Antiepileptic drugs; EEG, Electroencephalography; EPTP, Epitempin; IPEAF,
Idiopathic Partial Epilepsy with Auditory Features; LGI1, Leucine-rich GliomaInactivated 1; LoC, Loss of Consciousness; LRR, Leucine-Rich Repeat; LTLE, Lateral
Temporal Lobe Epilepsy; MRI, Magnetic Resonance Imaging.
∗ Corresponding author. Istanbul University Institute of Experimental Medicine,
Department of Genetics, Vakif Gureba Cad. 34093, Fatih/Istanbul, Turkey.
Tel.: +90212 414 2000/33318 ext; fax: +90212 532 4171.
E-mail address: sibel.ugur@istanbul.edu.tr (S.A.U. Iseri).
http://dx.doi.org/10.1016/j.eplepsyres.2015.12.006
0920-1211/© 2015 Elsevier B.V. All rights reserved.

clinically characterized by focal seizures with typical involvement
of auditory symptoms and mostly benign outcomes (Michelucci
et al., 2009). Both conditions are reported to have homogenous clinical courses regarding frequency of seizures, response to treatment
and disease onset with a mean age of 18-19 years (Bisulli et al.,
2004a).
Heterozygous variations in leucine-rich, glioma-inactivated 1
(LGI1) gene have been implicated both in ADTLE and IPEAF (Dazzo
et al., 2015a). Substantial proportion of ADLTE families (up to 50%)
and only very rare IPEAF cases carry inherited or de novo point
mutations in LGI1, respectively (Michelucci et al., 2003; Bisulli et al.,
2004b; Dazzo et al., 2015a). Small LGI1 micro-rearrangements have
also been spotted in ADTLE (Fanciulli et al., 2012; Dazzo et al.,
2015a). LGI1 encodes a secreted protein that is expressed predominantly in hippocampal and cortical neurons (Senechal et al., 2005).
The LGI1 protein contains four leucine-rich repeat (LRR) motifs in
its N-terminal domain responsible for protein-protein interactions
(Kobe and Kajava, 2001) and a epitempin (EPTP) domain containing
seven EPTP repeats in its C-terminal domain, which has prominent role in the development of epileptic disorders (Staub et al.,
2002). Herein, we report clinical and genetic analyses of a cohort
of 26 patients from Turkey exhibiting focal epilepsy with auditory
features leading to identification of a novel de novo LGI1 mutation.

74

Y.F. Kesim et al. / Epilepsy Research 120 (2016) 73–78

Materials and Methods
Subjects and Clinical Investigations
A cohort of 26 unrelated patients with focal epilepsy and clearcut recurring auditory auras were enrolled to this study. This cohort
had been followed up between the years 1996-2013 at Istanbul University Epilepsy Center (EPIMER). All patients underwent
full clinical, neuroradiological and electroencephalography (EEG)
examinations. Informed consents were obtained from all patients
and their recruited family members in accordance with ethics
approval obtained for the study from Ethics Committee of Istanbul
Medical Faculty (2012/740-1058).
Clinical data from each patient was collected including details
of seizure types and frequency, nature of auditory aura, response to
treatment, antiepileptic drugs (AED) used, ictal and interictal EEG
recordings, and neuroradiological findings.

Genetic Analysis
All exons and exon-intron boundaries of LGI1 gene were analysed for sequence variants from genomic DNA extracted from
whole blood for all patients. All sequence variants presented herein
are named according to LGI1 gene transcript variant NM 005097.2.
Upon identification of a de novo variant in LGI1, the relevant trio
was analysed for relationship specification using the application
Graphical Representation of Relationships (Abecasis et al., 2001)
after whole genome genotyping with the GeneChip Mapping 250 K
Nsp Array (Affymetrix Inc., Santa Clara, Calif., USA).

Table 1
The characteristics of the cohort and associated phenotypes.
Patient Characteristics

Patients (Total: 26) N(%)

Gender: Female/Male
Mean age (±standard deviation)
Follow-up duration (years)
Age at onset of epilepsy (years)
Consanguinity of the parents
Family history of epilepsy
Family history of ADLTE
Comorbid diseases

13/13; (50%)/(50%)
34.8 ± 11.24
6.8 ± 5.5
16.83± 11.12
6 (23.1%)
10 (38.5%)
5 (19.2%)
Hypertension (n = 1); diabetes
mellitus (n = 1); Hashimoto’s
thyroiditis (n = 1); Hodgkin
lymphoma (n = 1)

Seizure Characteristics*
History of febrile seizures
Focal and bilateral convulsive seizures
Focal seizures with LOCa only
Bilateral convulsive seizures and focal
seizures with LOC
Seizure precipitation by noises
Seizure relapse after AED withdrawal
Elementary auditory aura
Complex auditory aura
Negative auditory aura (decrease of
sound etc.
Bilateral perception of auditory aura
Lateralized auditory aura
Other coexisting aura symptoms

Good prognosis (drug-responsive)
EEG Findings
Normal/nonspecific
Focal interictal epileptic discharges

6 (23.1%)
10 (38.5%)
5 (19.2%)
11 (42.3%)
2 (7.7%)
11 (42.3%)
9 (34.6%)
13 (50%)
4 (15.4%)
18 (69.2%)
8 (30.8%) (4 left -4 right-sided)
Déjà vu (n = 3), vertigo (n = 4),
paresthesia (n = 3), nausea (n = 1),
blurred vision (n = 1).
18 (69.2%)
78 routine EEG and 2 video-EEG
8 (30.8%)
18 (69.2%)

a

LOC, Loss of consciousness;
The seizure types were diagnosed according to the ILAE classification in 2010
(Berg et al., 2010)
*

Results
All 26 patients admitted to our clinic over the course of 17
years were non-lesional, i.e. their MRI findings were unremarkable
and/or unrelated to their seizures. The breakdown of familial origin
of LTLE in the cohort is as follows: ADTLE (5); LTLE with positive
family history of epilepsy (5); sporadic LTLE (16) (Table 1).
Sequence analysis of LGI1 in the cohort revealed a novel heterozygous variant only in a single case with a negative family
history of epilepsy. This transition, c.1013T > C resides in exon 8
and at the protein level results in substitution of the amino acid
phenylalanine at position 338 with a serine (p.Phe338Ser) in the 3rd
EPTP repeat. Upon detection of this novel variant in LGI1, the unaffected family members (parents and two siblings) were recruited
to the study. Their genetic screenings were accordingly negative for
c.1013T > C suggesting a de novo mechanism (Fig. 1a). The de novo
nature of the variant has prompted us to confirm parent offspring
relationship via whole genome SNP genotyping.
LGI1 c.1013T > C; p.Phe338Ser variant was not detected neither
in Ensembl Genome Browser (Human release 81), which retrieves
human variation information from a variety of sources including Database of Short Genetic Variations (dbSNP), the National
Heart Lung and Blood Institute Exome Sequencing Project (ESP)
and The Human Gene Mutation Database (HGMD-Public) or in The
Exome Aggregation Consortium (ExAC) Browser. The variant was
also found to be absent in 300 unrelated individuals from Turkey.
The amino acid p.Phe338 is found to be evolutionary conserved
from human to zebrafish (Fig. 1b) and the substitution is predicted
to be damaging by in silico prediction tools, including Mutation
Taster, SIFT and Polyphen. Substitution of hydrophobic and aromatic phenylalanine at position 338 with the uncharged serine
may alter the structure of the EPTP repeat domain and result in
a misfolded protein. This variant has been submitted to the freely
accessible NCBI ClinVar Database. 42 different LGI1 gene mutations

identified to date are presented in Table 2 along with the novel de
novo mutation in this study.
The 38-year-old male patient (E5 in Fig. 1a) with the novel variant is the youngest among three siblings of non-consanguineous
parents. He had a normal developmental period and had no history of febrile seizures. He had started experiencing elementary
auras (buzzing and ringing) and bilateral convulsive seizures at the
age of 12 years. He had mild hypertension, which was under control with antihypertensive drugs. Neurological examination was
unremarkable and his three Tesla MRI was normal. He had four
EEG investigations and one of them showed nonspecific abnormalities of theta range. He was seizure-free for 7 years under
carbamazepine treatment with a history of seizure recurrence
upon medication withdrawal. He has been currently using carbamazepine (800 mg/day) and has 2-3 short elementary auras per
month, not disturbing his quality of life.
Discussion
The present study describes LGI1 mutation screening in a cohort
of 26 patients selected on the basis of focal epilepsy with auditory auras and absence of a symptomatic etiology. Our inclusion
criterion was solely based on phenotypic distinction, rather than
having a positive or negative family history. Reduced penetrance
and variable expressivity of a potential LGI1 variant in the preceding generations as well as emergence of a de novo variant for the
first time in the family can bias familial clustering of the condition at the time of the study. Sporadic cases arising due to such
mechanisms may eventually result in dominant transmission of
the condition in suggestive generations, which in turn will lead
to reclassification of the condition as ADTLE. The two LGI1 mutations p.Arg136Trp and p.Arg474X (Table 2) each reported for both

Y.F. Kesim et al. / Epilepsy Research 120 (2016) 73–78

75

Fig. 1. A novel de novo mutation in LGI1. (A) DNA sequence analysis of c.1013T > C variant in the relevant family. (B) The evolutionary conservation of phenylalanine at
position 338 (marked with an arrow) is shown with multiple sequence alignments among human (H.sapiens; NP 005088.1), chimpanzee (P.troglodytes; NP 001065246.1),
Rhesus monkey (M.mulatta, XP 001093284.1), grey wolf (C.lupus; XP 534971.2), cattle (B.taurus; NP 001040056.2), mouse (M.musculus; NP 064674.1), rat (R. norvegicus;
NP 665712.1), chicken (G.gallus; NP 001038120.1), frog (X.tropicalis; NP 001072366.1) and zebrafish (D.rerio; NP 001122241.1 and NP 955921.1). (C) Schematic representation of the domain structure of LGI1 protein. LRR: leucine-rich repeat; LRRNT and LRRCT: Cysteine-rich domains residing N- and C-terminal to LRRs, respectively; EPTP:
epitempin (domains are plotted to scale).

sporadic and familial cases serve as good examples for this phenomenon. The single LGI1 mutation identified in this study is a novel
missense change (c.1013T > C; p.Phe338Ser) observed de novo in
a sporadic patient. Having identified the causative mutation, the
patient is now informed about the possible transmission of the
ADTLE phenotype in his future children.
It is interesting to note that in families with LGI1 mutations,
the most commonly reported type of auditory seizure symptoms
was simple, unformed sounds (Ottman et al., 2004), similar to
our patient positive for LGI1 mutation. Additionally, this patient

is responsive to therapy with recurrence after drug withdrawal,
which is a typical feature of reported patients with LGI1 mutations
(Berkovic et al., 2004).
None of the 10 LTLE patients from our cohort with a positive
family history of epilepsy had LGI1 mutations, even though LGI1
mutations account for almost 50% of ADLTE families. Nevertheless, copy number variations (CNVs) have not been tested for this
cohort, which are not a frequent cause of ADLTE. Dazzo et al., 2015a
reported identification of only one family with a novel microdeletion spanning LGI1 exon 2 in a group of 24 ADTLE families and 140

76

Y.F. Kesim et al. / Epilepsy Research 120 (2016) 73–78

Table 2
Current catalogue of LGI1 mutations (NM 005097.2) in ADLTE and IPEAF arranged according to mutation location. The variant descriptions are checked with the ‘Name
Checker’ or ‘Position Converter’ options from the Mutalyzer website (https://mutalyzer.nl/) and corrected accordingly, whenever required.
Region

Variation

Protein Change

F/S*

Reference

Exon 1
Exon 1
Exon 1
Exon 1
Exon 1
Exon 2
Exon 3
Exon 3
Intron 3-4
Exon 4
Exon 4
Exon 4
Exon 4
Exon 4
Intron 4-5
Intron 4-5 & Exon5
Exon 5
Exon 5
Exon 6
Exon 6
Exon 6
Exon 6
Exon 6
Exon 7
Exon 7
Intron 7-8
Exon 8
Exon 8
Exon 8
Exon 8
Exon 8
Exon 8
Exon 8
Exon 8
Exon 8
Exon 8
Exon 8
Exon 8
Exon 8
Exon 8
Exon 8
Exon 8

c.77T > C
c.124T > C
c.124T > G
c.136T > C
c.137G > T
c.245T > C
c.329C > A
c.329del
c.360-3C > A
c.365T > A
c.365T > C
c.367G > A
c.377 379del
c.406C > T
c.431 + 1G > A
c.432-2 436del
c.435C > G
c.461T > C
c.535T > C
c.598T > C
c.598del
c.611del
c.673G > T
c.695T > C
c.758del
c.839-2A > G
c.856T > C
c.893T > C
c.953T > G
c.1013T > C
c.1050 1051del
c.1075A > G
c.1118T > C
c.1148A > C
c.1219C > T
c.1295T > A
c.1418C > T
c.1420C > T
c.1421G > A
c.1477G > A
c.1636 1637del
c.1639dup

p.Leu26Ser
p.Cys42Arg
p.Cys42Gly
p.Cys46Arg
p.Cys46Phe
p.Ile82Thr
p.Ala110Asp
p.Ala110ValfsX8
Truncation
p.Ile122Lys
p.Ile122Thr
p.Glu123Lys
p.Asn126del
p.Arg136Trp
Truncation
Truncation
p.Ser145Arg
p.Leu154Pro
p.Cys179Arg
p.Cys200Arg
p. Cys200AlafsX40
p.Pro204GlnfsX36
p.Glu225X
p.Leu232Pro
p.Ala253ValfsX32
Truncation
p.Cys286Arg
p.Ile298Thr
p.Phe318Cys
p.Phe338Ser
p.Asp350GlufsX31
p.Ile359Val
p.Leu373Ser
p.Glu383Ala
p.Arg407Cys
p.Val432Glu
p.Ser473Leu
p.Arg474X
p.Arg474Gln
p.Gly493Arg
p.Gln546AspfsX8
p.Ile547AsnfsX8

F
F
F
F
F
F
F
F
F
F
F
F
F
S, F
F
F
F
F
F
F
F
F
F
F
F
F
S
F
F
S
F
F
F
F
F
F
F
F, S
F
F
F
F

Pizzuti et al., 2003
Ottman et al., 2004
Berkovic et al., 2004
Gu et al., 2002
Lee et al., 2014
Sadleir et al., 2013
Ottman et al., 2004
Hedera et al., 2004
Kalachikov et al., 2002
Striano et al., 2008
Di Bonaventura et al., 2011
Di Bonaventura et al., 2009
De Bellescize et al., 2009
Michelucci et al., 2007; Di Bonaventura et al., 2011
Chabrol et al., 2007
Sadleir et al., 2013
Hedera et al., 2004
Pisano et al., 2005
Di Bonaventura et al., 2011
Michelucci et al., 2003
Heiman et al., 2010
Kalachikov et al., 2002
Sadleir et al., 2013
Chabrol et al., 2007
Morante-Redolat et al., 2002
Kobayashi et al., 2003
Dazzo et al., 2015a
Ottman et al., 2004
Fertig et al., 2003
Current study
Kalachikov et al., 2002
Di Bonaventura et al., 2011
Dazzo et al., 2015a
Kalachikov et al., 2002
Striano et al., 2011
Michelucci et al., 2003
Berkovic et al., 2004; Kawamata et al., 2010
Morante-Redolat et al., 2002; Bisulli et al., 2004b
Kawamata et al., 2010
Heiman et al., 2010
Heiman et al., 2010
Kalachikov et al., 2002

sporadic cases with no evidence of point mutations in LGI1. Nevertheless, the clinical utility of diagnostic screening of CNVs in LGI1
are still debatable (Magini et al., 2014) (Dazzo et al., 2015a).
LGI1, unlike most of the other epilepsy related genes, encodes
a neuronal secreted protein instead of an ion channel subunit
(Senechal et al., 2005). Secreted LGI1 presumably acts as an
antiepileptogenic ligand that modulates AMPA-type glutamate
receptor mediated synaptic transmission (Fukata et al., 2010).
In vitro mutagenesis assays and in vivo studies with homozygous
and heterozygous null mice (Lgi1-/− and Lgi1+/− ) collectively suggest that heterozygous loss-of-function alleles contribute to disease
pathogenesis by haploinsufficiency (Senechal et al., 2005) (Fukata
et al., 2010). It is proposed that LGI1 protein secretion and stability are altered by LGI1 mutations (Senechal et al., 2005). A rat
model carrying a missense mutation (L385R) in Lgi1 has recently
been generated (Baulac et al., 2012), which probably serves as
a suitable model for LGI1-related epilepsies, where the majority
of human LGI1 mutations (66%) are missense (Ho et al., 2012).
In this model, the depletion of LGI1 protein in neurons has not
been attributed only to a failure of Lgi1 secretion, but also to
rapid degradation of Lgi1-L385R (Baulac et al., 2012). Interestingly,
heterozygous Lgi1+/L385R rats are shown to be more susceptible
to sound-induced seizures, which may be controlled by AEDs
such as carbamazepine, phenytoin and levetiracetam (Fumoto
et al., 2014). However, in contrast to the findings in the pertinent

rat model, two sporadic patients from our cohort describing
sound-induced seizures were detected negative for LGI1 mutations. In addition to haploinsufficiency, LGI1 mutations may have
pathogenic effects through dominant-negative mechanisms (Zhou
et al., 2009).
Analysis of genes related to dominant epilepsy syndromes
should both focus on familial and sporadic forms in order to get
a better picture of the mutation frequency, molecular diagnosis
and genetic counselling. For ADTLE, the distinctive features including auditory aura and non-lesional brain MRI findings are shared
among familial and sporadic cases pointing involvement of common genes and pathways. Recently, heterozygous mutations in
reelin (RELN) have been shown to be segregating in ADLTE-affected
families (Dazzo et al., 2015b). Secreted RELN and LGI1 co-localize
in rat brain, which support involvement of overlapping mechanisms in ADTLE pathogenesis. Nevertheless, RELN like LGI1 and
further ADTLE genes yet to be identified need to be screened
in large and well-defined cohorts for extensive analysis of the
genotype–phenotype correlations.

Conclusion
In conclusion, we report identification of a novel de novo
LGI1 mutation in a patient from Turkey, which both aids the

Y.F. Kesim et al. / Epilepsy Research 120 (2016) 73–78

diagnosis of the condition as ADTLE and brings up more solid
genetic counselling options for the patient.
Conflict of Interest
None of the authors has any conflicts of interest to disclose. We
confirm that we have read the Journal’s position on issues involved
in ethical publication and affirm that this report is consistent with
those guidelines.
Acknowledgements
The authors are grateful to the patients and their relatives for
their participation in this study. This work was supported by the
grants of Scientific Research Projects Coordination Unit of Istanbul
University, Project Numbers: 26263 and 26211; Istanbul Development Agency, Project Number: TR10/15/YNK/0093. FYK, EY and
OO have been fellows of The Scientific and Technology Research
Council of Turkey (TUBITAK) Project Number: 113S331. We also
thank Assoc. Prof. Ebru Altindag, Prof. Candan Gurses and Prof.
Aysen Gokyigit for referring their patients. We would also like
to acknowledge Advanced Genomics and Bioinformatics Research
Center (IGBAM), TUBITAK-BILGEM for kindly providing the exome
sequencing data for 300 individuals from Turkey with varying disorders, which was used as a population control, set for the novel
LGI1 mutation.
References
Abecasis, G.R., Cherny, S.S., Cookson, W.O., Cardon, L.R., 2001. GRR: graphical
representation of relationship errors. Bioinformatics 17, 742–743.
Baulac, S., Ishida, S., Mashimo, T., Boillot, M., Fumoto, N., Kuwamura, M., Ohno, Y.,
Takizawa, A., Aoto, T., Ueda, M., Ikeda, A., LeGuern, E., Takahashi, R., Serikawa,
T., 2012. A rat model for LGI1-related epilepsies. Hum. Mol. Genet. 21,
3546–3557.
Berg, A.T., Berkovic, S.F., Brodie, M.J., Buchhalter, J., Cross, J.H., van Emde Boas, W.,
Engel, J., French, J., Glauser, T.A., Mathern, G.W., Moshé, S.L., Nordli, D., Plouin,
P., Scheffer, I.E., 2010. Revised terminology and concepts for organization of
seizures and epilepsies: Report of the ILAE Commission on Classification and
Terminology, 2005-2009. Epilepsia 51, 676–685.
Berkovic, S.F., Izzillo, P., McMahon, J.M., Harkin, L.A., McIntosh, A.M., Phillips, H.A.,
Briellmann, R.S., Wallace, R.H., Mazarib, A., Neufeld, M.Y., Korczyn, A.D.,
Scheffer, I.E., Mulley, J.C., 2004. LGI1 mutations in temporal lobe epilepsies.
Neurology 62, 1115–1119.
Bisulli, F., Tinuper, P., Avoni, P., Striano, P., Striano, S., d’Orsi, G., Vignatelli, L.,
Bagattin, A., Scudellaro, E., Florindo, I., Nobile, C., Tassinari, C.A., Baruzzi, A.,
Michelucci, R., 2004a. Idiopathic partial epilepsy with auditory features
(IPEAF): a clinical and genetic study of 53 sporadic cases. Brain 127,
1343–1352.
Bisulli, F., Tinuper, P., Scudellaro, E., Naldi, I., Bagattin, A., Avoni, P., Michelucci, R.,
Nobile, C., 2004b. A de novo LGI1 mutation in sporadic partial epilepsy with
auditory features. Ann. Neurol. 56, 455–456.
Chabrol, E., Popescu, C., IGourfinkel-An, I., Trouillard, O., Depienne, C., Senechal, K.,
Baulac, M., LeGuern, E., Baulac, S.S., 2007. Two novel epilepsy-linked mutations
leading to a loss of function of LGI1: Arch Neurol 64, 217–222.
Dazzo, E., Santulli, L., Posar, A., Fattouch, J., Conti, S., Lodén-van Straaten, M.,
Mijalkovic, J., De Bortoli, M., Rosa, M., Millino, C., Pacchioni, B., Di Bonaventura,
C., Giallonardo, A.T., Striano, S., Striano, P., Parmeggiani, A., Nobile, C., 2015a.
Autosomal dominant lateral temporal epilepsy (ADLTE): novel structural and
single-nucleotide LGI1 mutations in families with predominant visual auras.
Epilepsy Res. 110, 132–138.
Dazzo, E., Fanciulli, M., Serioli, E., Minervini, G., Pulitano, P., Binelli, S., Di
Bonaventura, C., Luisi, C., Pasini, E., Striano, S., Striano, P., Coppola, G.,
Chiavegato, A., Radovic, S., Spadotto, A., Uzzau, S., La Neve, A., Giallonardo, A.T.,
Mecarelli, O., Tosatto, S.C., Ottman, R., Michelucci, R., Nobile, C., 2015b.
Heterozygous reelin mutations cause autosomal-dominant lateral temporal
epilepsy. Am. J. Hum. Genet. 96, 992–1000.
De Bellescize, J., Boutry, N., Chabrol, E., André-Obadia, N., Arzimanoglou, A.,
Leguern, E., Baulac, S., Calender, A., Ryvlin, P., Lesca, G., 2009. A novel three
base-pair LGI1 deletion leading to loss of function in a family with autosomal
dominant lateral temporal epilepsy and migraine-like episodes. Epilepsy Res
85, 118–122.
Di Bonaventura, C., Operto, F.F., Busolin, G., Egeo, G., D’Aniello, A., Vitello, L.,
Smaniotto, G., Furlan, S., Diani, E., Michelucci, R., Giallonardo, A.T., Coppola, G.,
Nobile, C., 2011. Low penetrance and effect on protein secretion of LGI1
mutations causing autosomal dominant lateral temporal epilepsy. Epilepsia
52, 1258–1264.

77

Di Bonaventura, C., Carni, M., Diani, E., Fattouch, J., Vaudano, E.A., Egeo, G., Pantano,
P., Maraviglia, B., Bozzao, L., Manfredi, M., Prencipe, M., Giallonardo, T.A.,
Nobile, C., 2009. Drug resistant ADLTE and recurrent partial status epilepticus
with dysphasic features in a family with a novel LGI1mutation: electroclinical,
genetic, and EEG/fMRI findings. Epilepsia 50, 2481–2486.
Fanciulli, M., Santulli, L., Errichiello, L., Barozzi, C., Tomasi, L., Rigon, L., Cubeddu, T.,
de Falco, A., Rampazzo, A., Michelucci, R., Uzzau, S., Striano, S., de Falco, F.A.,
Striano, P., Nobile, C., 2012. LGI1 microdeletion in autosomal dominant lateral
temporal epilepsy. Neurology 78, 1299–1303.
Fertig, E., Lincoln, A., Martinuzzi, A., Mattson, R.H., Hisama, F.M., 2003. Novel LGI1
mutation in a family with autosomal dominant partial epilepsy with auditory
features. Neurology 60, 1687–1690.
Fukata, Y., Lovero, K.L., Iwanaga, T., Watanabe, A., Yokoi, N., Tabuchi, K., Shigemoto,
R., Nicoll, R.A., Fukata, M., 2010. Disruption of LGI1-linked synaptic complex
causes abnormal synaptic transmission and epilepsy. Proc. Natl. Acad. Sci. USA
107, 3799–3804.
Fumoto, N., Mashimo, T., Masui, A., Ishida, S., Mizuguchi, Y., Minamimoto, S., Ikeda,
A., Takahashi, R., Serikawa, T., Ohno, Y., 2014. Evaluation of seizure foci and
genes in the Lgi1 (L385R/ + ) mutant rat. Neurosci. Res. 80, 69–75.
Gu, W., Brodtkorb, E., Steinlein, O.K., 2002. LGI1 is mutated in familial temporal
lobe epilepsy characterized by aphasic seizures. Ann Neurol 52, 364–367.
Hedera, P., Abou-Khalil, B., Crunk, A.E., Taylor, K.A., Haines, J.L., Sutcliffe, J.S., 2004.
Autosomal dominant lateral temporal epilepsy: two families with novel
mutations in the LGI1 gene. Epilepsia 45, 218–222.
Heiman, G.A., Kamberakis, K., Gill, R., Kalachikov, S., Pedley, T.A., Hauser, W.A.,
Ottman, R., 2010. Evaluation of depression risk in LGI1 mutation carriers.
Epilepsia 51, 1685–1690.
Ho, Y.Y., Ionita-Laza, I., Ottman, R., 2012. Domain-dependent clustering and
genotype-phenotype analysis of LGI1 mutations in ADPEAF. Neurology 78,
563–568.
Kalachikov, S., Evgrafov, O., Ross, B., Winawer, M., Barker-Cummings, C., Martinelli
Boneschi, F., Choi, C., Morozov, P., Das, K., Teplitskaya, E., Yu, A., Cayanis, E.,
Penchaszadeh, G., Kottmann, A.H., Pedley, T.A., Hauser, W.A., Ottman, R.,
Gilliam, T.C., 2002. Mutations in LGI1 cause autosomal-dominant partial
epilepsy with auditory features. Nat Genet 30, 335–341.
Kawamata, J., Ikeda, A., Fujita, Y., Usui, K., Shimohama, S., Takahashi, R., 2010.
Mutations in LGI1 gene in Japanese families with autosomal dominant lateral
temporal lobe epilepsy: the first report from Asian families. Epilepsia 51,
690–693.
Kobayashi, E., Santos, N.F., Torres, F.R., Secolin, R., Sardinha, L.A., Lopez-Cendes, I.,
Cendes, F., 2003. Magnetic resonance imaging abnormalities in familial
temporal lobe epilepsy with auditory auras. Arch Neurol 60, 1546–1551.
Kobe, B., Kajava, A.V., 2001. The leucine-rich repeat as a protein recognition motif.
Curr. Opin. Struct. Biol. 11, 725–732.
Lee, M.K., Kim, S.W., Lee, J.H., Cho, Y.J., Kim, D.E., Lee, B.I., Kim, H.M., Lee, M.G., Heo,
K., 2014. A newly discovered LGI1 mutation in Korean family with autosomal
dominant lateral temporal lobe epilepsy. Seizure 23, 69–73.
Magini, P., Bisulli, F., Baldassari, S., Stipa, C., Naldi, I., Licchetta, L., Menghi, V.,
Tinuper, P., Seri, M., Pippucci, T., 2014. LGI1 microdeletions are not a frequent
cause of partial epilepsy with auditory features (PEAF). Epilepsy Res. 108,
972–977.
Michelucci, R., Mecarelli, O., Bovo, G., Bisulli, F., Testoni, S., Striano, P., Striano, S.,
Tinuper, P., Nobile, C., 2007. A de novo LGI1 mutation causing idiopathic
partial epilepsy with telephone-induced seizures. Neurology 68,
2150–2151.
Michelucci, R., Pasini, E., Nobile, C., 2009. Lateral temporal lobe epilepsies: clinical
and genetic features. Epilepsia 50, 52–54.
Michelucci, R., Poza, J.J., Sofia, V., de Feo, M.R., Binelli, S., Bisulli, F., Scudellaro, E.,
Simionati, B., Zimbello, R., D’Orsi, G., Passarelli, D., Avoni, P., Avanzini, G.,
Tinuper, P., Biondi, R., Valle, G., Mautner, V.F., Stephani, U., Tassinari, C.A.,
Moschonas, N.K., Siebert, R., Lopez de Munain, A., Perez-Tur, J., Nobile, C., 2003.
Autosomal dominant lateral temporal epilepsy: clinical spectrum, new
epitempin mutations, and genetic heterogeneity in seven European families.
Epilepsia 44, 1289–1297.
Morante-Redolat, J.M., Gorostidi-Pagola, A., Piquer-Sirerol, S., Sáenz, A., Poza, J.J.,
Galán, J., Gesk, S., Sarafidou, T., Mautner, V.F., Binelli, S., Staub, E., Hinzmann, B.,
French, L., Prud’homme, J.F., Passarelli, D., Scannapieco, P., Tassinari, C.A.,
Avanzini, G., Martí-Massó, J.F., Kluwe, L., Deloukas, P., Moschonas, N.K.,
Michelucci, R., Siebert, R., Nobile, C., Pérez-Tur, J., López de, MunainA., 2002.
Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant
lateral temporal epilepsy. Hum Mol Genet 11, 1119–1128.
Ottman, R., Winawer, M.R., Kalachikov, S., Barker-Cummings, C., Gilliam, T.C.,
Pedley, T.A., Hauser, W.A., 2004. LGI1 mutations in autosomal dominant partial
epilepsy with auditory features. Neurology 62, 1120–1126.
Pisano, T., Marini, C., Brovedani, P., Brizzolara, D., Pruna, D., Mei, D., Moro, F.,
Cianchetti, C., Guerrini, R., 2005. Abnormal phonologic processing in familial
lateral temporal lobe epilepsy due to a new LGI1 mutation. Epilepsia 46,
118–123.
Pizzuti, A., Flex, E., Di Bonaventura, C., Dottorini, T., Egeo, G., Manfredi, M.,
Dallapiccola, B., Giallonardo, A.T., 2003. Epilepsy with auditory features: a LGI1
gene mutation suggests a loss-of-function mechanism. Ann Neurol 53,
396–399.
Sadleir, L.G., Agher, D., Chabrol, E., Elkouby, L., Leguern, E., Paterson, S.J., Harty, R.,
Bellows, S.T., Berkovic, S.F., Scheffer, I.E., Baulac, S., 2013. Seizure semiology in
autosomal dominant epilepsy with auditory features, due to novel LGI1
mutations. Epilepsy Res 107, 311–317.

78

Y.F. Kesim et al. / Epilepsy Research 120 (2016) 73–78

Senechal, K.R., Thaller, C., Noebels, J.L., 2005. ADPEAF mutations reduce levels of
secreted LGI1, a putative tumor suppressor protein linked to epilepsy. Hum.
Mol. Genet. 14, 1613–1620.
Staub, E., Pérez-Tur, J., Siebert, R., Nobile, C., Moschonas, N.K., Deloukas, P.,
Hinzmann, B., 2002. The novel EPTP repeat defines a superfamily of proteins
implicated in epileptic disorders. Trends Biochem Sci. 27, 441–444.
Striano, P., de Falco, A., Diani, E., Bovo, G., Furlan, S., Vitiello, L., Pinardi, F., Striano,
S., Michelucci, R., de Falco, F.A., Nobile, C., 2008. A novel loss-of-function LGI1
mutation linked to autosomal dominant lateral temporal epilepsy. Arch Neurol
65, 939–942.
Striano, P., Busolin, G., Santulli, L., Leonardi, E., Coppola, A., Vitiello, L., Rigon, L.,
Michelucci, R., Tosatto, S.C., Striano, S., Nobile, C., 2011. Familial temporal lobe
epilepsy with psychic auras associated with a novel LGI1 mutation. Neurology
76, 1173–1176.
Zhou, Y.D., Lee, S., Jin, Z., Wright, M., Smith, S.E., Anderson, M.P., 2009. Arrested
maturation of excitatory synapses in autosomal dominant lateral temporal
lobe epilepsy. Nat Med 15, 1208–1214.

Further reading
ClinVar: http://www.ncbi.nlm.nih.gov/clinvar/(last accession:
12 August 2015)
Ensembl Genome Browser: http://www.ensembl.org/index.
html (last accession: 12 August 2015)
The Exome Aggregation Consortium (ExAC) Browser: http://
exac.broadinstitute.org/(last accession: 12 August 2015)
Mutation Taster: http://www.mutationtaster.org/(last accession: 12 August 2015)
Polyphen: http://genetics.bwh.harvard.edu/pph2/(last accession: 12 August 2015)
SIFT: http://sift.jcvi.org/(last accession: 12 August 2015)