Epilepsia, 54(7):1288–1297, 2013
doi: 10.1111/epi.12194
FULL-LENGTH ORIGINAL RESEARCH
Low penetrance of autosomal dominant lateral temporal
epilepsy in Italian families without LGI1 mutations
*Roberto Michelucci, *Elena Pasini, †Sandro Malacrida, ‡Pasquale Striano,
§Carlo Di Bonaventura, ¶Patrizia Pulitano, #Francesca Bisulli, §Gabriella Egeo, **Lia Santulli,
††Vito Sofia, ‡‡Antonio Gambardella, §§Maurizio Elia, ¶¶Arturo de Falco, ##Angela la Neve,
***Paola Banfi, †††Giangennaro Coppola, #Patrizia Avoni, ‡‡‡Simona Binelli,
§§§Clementina Boniver, ¶¶¶Tiziana Pisano, ###Marco Marchini, ****Emanuela Dazzo,
††††Manuela Fanciulli, *Yerma Bartolini, *Patrizia Riguzzi, *Lilia Volpi,
¶¶Fabrizio A. de Falco, §Anna Teresa Giallonardo, ¶Oriano Mecarelli, **Salvatore Striano,
#Paolo Tinuper, and ****Carlo Nobile
*Unit of Neurology, IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy; †Department of Biology,
University of Padua, Padova, Italy; ‡Muscular and Neurodegenerative Disease Unit, Institute “G. Gaslini”, University of Genova,
Genova, Italy; §Department of Neurological Sciences, University of Rome “Sapienza”, Roma, Italy; ¶Department of Neurology and
Psychiatry, Sapienza University, Umberto 1° Hospital, Roma, Italy; #Neurological Clinic, Bellaria Hospital IRCCS Institute of
Neurological Sciences of Bologna and Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy;
**Department of Neurological Sciences, Federico II University, Napoli, Italy; ††Department of Neurosciences, University of Catania,
Catania, Italy; ‡‡Institute of Neurology, University “Magna Græcia”, Catanzaro, Italy; §§Oasi Institute for Research on Mental
Retardation and Brain Aging (IRCCS), Troina, Italy; ¶¶Division of Neurology New, Loreto Hospital, Napoli, Italy; ##Neurology Clinic,
University of Bari, Bari, Italy; ***Unit of Neurology, Circolo Hospital, Varese, Italy; †††Child and Adolescent Neuropsychiatry, Medical
School, University of Salerno, Salerno, Italy; ‡‡‡C. Besta Foundation Neurological Institute, Milano, Italy; §§§Department of
Pediatrics, Clinical Neurophysiology, Padova, Italy; ¶¶¶A. Meyer Children’s Hospital – University of Florence, Pediatric Neurology,
Firenze, Italy; ###Division of Neurology, “C. Poma” Hospital, Mantova, Italy; ****Section of Padua, CNR-Institute of Neurosciences,
Padova, Italy; and ††††Porto Conte Researches, Alghero, Italy
SUMMARY
Purpose: In relatively small series, autosomal dominant
lateral temporal epilepsy (ADLTE) has been associated
with leucine-rich, glioma-inactivated 1 (LGI1) mutations
in about 50% of the families, this genetic heterogeneity
being probably caused by differences in the clinical characteristics of the families. In this article we report the overall clinical and genetic spectrum of ADLTE in Italy with
the aim to provide new insight into its nosology and
genetic basis.
Methods: In a collaborative study of the Commission of
Genetics of the Italian League Against Epilepsy (LICE)
encompassing a 10-year period (2000–2010), we collected
33 ADLTE families, selected on the basis of the following
criteria: presence of at least two members concordant
for unprovoked partial seizures with prominent auditory
and or aphasic symptoms, absence of any known structural brain pathology or etiology, and normal neurologic
examination. The clinical, neurophysiologic, and neuroradiologic findings of all patients were analyzed and a
genealogic tree was built for each pedigree. The probands’
DNA was tested for LGI1 mutations by direct sequencing
and, if negative, were genotyped with single-nucleotide
polymorphism (SNP) array to search for disease-linked
copy-number variation CNV. The disease penetrance in
mutated and nonmutated families was assessed as a
proportion of obligate carriers who were affected.
Key Findings: The 33 families included a total of 127
affected individuals (61 male, 66 female, 22 deceased).
The age at onset ranged between 2 and 60 years (mean
18.7 years). Ninety-one patients (72%) had clear-cut focal
(elementary, complex, or secondarily generalized) seizures, characterized by prominent auditory auras in 68%
of the cases. Other symptoms included complex visual
hallucinations, vertigo, and d
ej
a vu. Aphasic seizures,
associated or not with auditory features, were observed in
20% of the cases, whereas tonic–clonic seizures occurred
in 86% of the overall series. Sudden noises could precipitate the seizures in about 20% of cases. Seizures, which
usually occurred at a low frequency, were promptly controlled or markedly improved by antiepileptic treatment
in the majority of patients. The interictal electroencephalography (EEG) studies showed the epileptiform temporal
abnormalities in 62% of cases, with a slight predominance
over the left region. Magnetic resonance imaging (MRI) or
computerized tomography (CT) scans were negative.
LGI1 mutations (missense in nine and a microdeletion in
one) were found in only 10 families (30%). The patients
belonging to the mutated and not mutated groups did not
differ except for penetrance estimate, which was 61.3%
and 35% in the two groups, respectively (chi-square,
p = 0.017). In addition, the disease risk of members of
families with mutations in LGI1 was three times higher
than that of members of LGI1-negative families (odds
ratio [OR] 2.94, confidence interval [CI] 1.2–7.21).
1288
1289
Low Penetrance in Non–LGI1-Related ADLTE
Significance: A large number of ADLTE families has
been collected over a 10-year period in Italy, showing a
typical and homogeneous phenotype. LGI1 mutations
have been found in only one third of families, clinically
indistinguishable from nonmutated pedigrees. The estimate of penetrance and OR, however, demonstrates a
significantly lower penetrance rate and relative disease
risk in non–LGI1-mutated families compared with LGI1mutated pedigrees, suggesting that a complex inheritance pattern may underlie a proportion of these families.
KEY WORDS: Autosomal dominant lateral temporal
epilepsy, LGI1, Penetrance, Mutated families, Nonmutated families.
Autosomal dominant lateral temporal epilepsy (ADLTE),
also known as autosomal dominant partial epilepsy with
auditory features (ADPEAF), is a relatively new familial
epileptic condition, with <40 families having been reported
in Europe, United States, South America, Australia, and
Japan (Ottman et al., 1995; Poza et al., 1999; Brodtkorb
et al., 2002; Winawer et al., 2002; Kalachikov et al., 2002;
Morante-Redolat et al., 2002; Gu et al., 2002; Michelucci
et al., 2003, 2009; Kobayashi et al., 2003; Berkovic et al.,
2004; Ottman et al., 2004; Hedera et al., 2004; Chabrol
et al., 2007a; Kawamata et al., 2010; Heiman et al., 2010;
Ho et al., 2012). The real prevalence of ADLTE is
unknown, but it may account for about 19% of familial idiopathic focal epilepsies (Ottman et al., 2004).
The syndrome segregates with an autosomal dominant
inheritance pattern, and its penetrance, which ranges
between 50% and 85% in different families, has been estimated at 67% (Rosanoff & Ottman, 2008). It is characterized by a variable age of onset (with a mean of 18 years),
focal seizures with distinctive auditory auras or aphasic
symptoms, secondarily generalized tonic–clonic seizures,
almost invariable good response to treatment, mild interictal
electroencephalography (EEG) temporal abnormalities, and
negative conventional magnetic resonance imaging (MRI)
findings. Similar clinical findings are shared by sporadic
cases referred to as idiopathic partial epilepsy with auditory
features (Bisulli et al., 2004a).
More than 30 mutations in the leucine-rich, glioma-inactivated 1 (LGI1) gene have been associated with ADLTE,
representing the genetic hallmark of this syndrome (Nobile
et al., 2009). LGI1 mutations have also been found in 2 of
>200 sporadic cases (Bisulli et al., 2004b; Michelucci
et al., 2007).
In relatively small series, LGI1 mutations have been
found in about 50% of ADLTE families (Michelucci et al.,
2003; Berkovic et al., 2004; Ottman et al., 2004), and additional ADLTE-related loci or genes have not been identified. It may be hypothesized that this genetic heterogeneity
is also related to differences in the clinical characteristics in
the families.
Over the last 10 years, we have been collecting ADLTE
families in the context of a collaborative study promoted by
the Commission of Genetics of the Italian League Against
Epilepsy (LICE) and studied the clinical and genetic features of these pedigrees. In the present article we report the
overall clinical and genetic spectrum of ADLTE in Italy,
with the aim of providing new insight into the nosology and
genetic basis of this condition.
Accepted March 12, 2013; Early View publication April 26, 2013.
Address correspondence to Roberto Michelucci, Unit of Neurology,
IRCCS Institute of Neurological Sciences, Bellaria Hospital, Via Altura 3,
40139 Bologna, Italy. E-mail: roberto.michelucci@ausl.bo.it
Wiley Periodicals, Inc.
© 2013 International League Against Epilepsy
Methods
In a collaborative study of the LICE Commission of
Genetics encompassing a 10-year period (2000–2010), we
invited Italian epileptologists to refer families with suspected ADLTE, selected on the basis of the following criteria: presence of at least two members concordant for
unprovoked partial seizures with prominent auditory and or
aphasic symptoms, absence of any known structural brain
pathology or etiology as demonstrated by negative conventional MRI findings of the brain and normal neurologic
examination.
Each proband and affected individual was interviewed
directly and examined by the referring clinician, either at
the hospital or during a visit to the patient’s home. The
clinical interview included personal and family history,
as well as details concerning the following features: age
at onset of seizures, description of ictal semiology
(obtained from the patient and an external observer), verbatim of auras, triggering factors of seizures, seizure
occurrence in relation to the sleep–wake cycle, seizure
frequency and response to treatment, and past and present therapy. Each affected individual also had a physical
and neurologic examination. Medical records describing
results of neurophysiologic, neuroimaging, and history
data were collected whenever possible to supplement the
clinical visits.
Routine and sleep (after afternoon nap) EEG studies were
available in 77 (73%) of the living patients and a few unaffected members. An MRI scan of the brain was available
in 66 (62%) of the living patients and in all the probands.
Each pedigree was discussed during regular meetings of
the LICE Commission of Genetics and, if accepted, was
reported in detail by the referring physician by filling out a
standardized form aimed at collecting detailed information
on family history, and clinical, neurophysiologic, and
neuroradiologic, data of all available affected individuals.
Epilepsia, 54(7):1288–1297, 2013
doi: 10.1111/epi.12194
1290
R. Michelucci et al.
A genealogic tree was built for each pedigree, and overall
data were reviewed by two epileptologists (RM, PS), who
asked for additional information if needed, and also analyzed original EEG and/or MRI findings if available.
Thirty-three pedigrees meeting the above inclusion criteria and with satisfactory clinical/neurophysiologic/neuroradiologic information were selected for the aims of this
study. After informed consent was obtained, blood samples
were drawn from each proband and DNA was extracted
using standardized methods. The probands’ DNA samples
were tested for LGI1 mutations by direct sequencing; some
of the LGI1-negative ADLTE families were genotyped with
the HumanOmni1-Quad v1.0 single-nucleotide polymorphism (SNP) array to search for disease-linked copynumber variation (CNV).
Penetrance in mutated and nonmutated families was
calculated as a proportion of affected versus nonaffected
obligate carriers. Obligate carriers were defined as individuals who were inferred to have carried a disease-causing
mutation because they had one or more affected descendants (going back to the common ancestors of all affecteds
shown in the pedigree). This definition differed slightly
from that proposed by Rosanoff and Ottman (2008), who
counted only individuals with affected offspring. This
method avoids the selection bias that would have occurred
by the inclusion of all available family members. It is well
known, in fact, that affected individuals are more likely to
be included in the pedigree than nonaffected members.
Moreover, obligate carrier analysis includes only those
individuals who are beyond the disease risk-age, since all
obligate carriers have at least one affected child or descendant. Penetrance values were estimated for each pedigree,
for all families combined, and for the family subgroups
with or without LGI1 mutations, and the differences
between subgroups were evaluated using the chi-square
test. In addition, we estimated phenotype–genotype associations by odds ratio (OR) and 95% confidence interval
(CI), to provide a measure of the relative disease risk conferred by LGI1 mutations compared to that associated with
mutations in genes other than LGI1. All statistical analyses
have been performed for probability >95% (p 0.05).
Analyses were carried out using GRAPHPAD Software,
Inc. (http://www.graphpad.com/quickcalcs/) and SISA
server (http://www.quantitativeskills.com/sisa/).
Because our study also included some published
mutated families, we used the information from published
pedigree figures. Of the 33 families included in this series, 12 pedigrees (9 showing LGI1 mutations and 3 were
without mutations) have been described in detail elsewhere (Michelucci et al., 2000, 2003; Bisulli et al., 2002;
Pizzuti et al., 2003; Pisano et al., 2005; Striano et al.,
2008; Di Bonaventura et al., 2009, 2011; Fanciulli et al.,
2012), whereas the remaining 21 pedigrees have not been
published so far.
Epilepsia, 54(7):1288–1297, 2013
doi: 10.1111/epi.12194
Results
Overall there were 127 subjects (22 deceased) with epilepsy belonging to these 33 families. An additional seven
family members had febrile convulsions during infancy,
and one further subject had had one isolated tonic–clonic
seizure in adulthood. The clinical, EEG, and neuroimaging
findings of each family are reported in detail in Table 1(A,B),
and the individual pedigrees are shown in Fig. 1.
Clinical findings
Sex
Among affected individuals, both sexes were equally
involved (61 male and 66 female).
Age of onset
The age of seizure onset ranged between 2 and 60 years,
with a mean of 18.7 years. In most cases, however, the disease began in adolescence or early adulthood. Of interest, in
one family (n° 14, Table 1A) all the six affected individuals
began their seizure history at the same age, that is, around
20 years.
Personal antecedents and associated illnesses
There was no history of significant personal antecedent
or pathology in any affected member. Three patients died
from malignancy (Hodgkin lymphoma, lung cancer, pancreatic carcinoma) and one patient underwent surgery for a
skull base meningioma. Two patients belonging to the same
family had obsessive-compulsive disorder, one patient had
depression, and one additional case had severe cognitive
impairment since infancy. Common migraine was reported
by four patients. Movement-induced dystonia and dyskinesia was present in one affected member carrying an LGI1
mutation.
Three patients (2.4%) had typical febrile seizures in their
infancy.
Epilepsy/seizure classification and semiology
Patients were classified as having idiopathic focal
epilepsy (n° 91, 72%), epilepsy with recurrent tonic–clonic
seizures, undetermined whether focal or generalized, as the
only seizure type (n° 25, 19%) and epilepsy not otherwise
specified (because of the lack of sufficient clinical/neurophysiologic/neuroradiologic information) (n° 11, 9%).
Among the 91 patients with idiopathic focal epilepsy, 19
(21%) had only secondarily generalized tonic–clonic
seizures, 14 (15%) had only elementary or complex partial
seizures, and 58 (64%) had both secondarily generalized
tonic–clonic seizures and elementary or complex partial
seizures. Overall, of the 116 patients with sufficient clinical
information, simple partial seizures were reported by 47
patients (41%), complex partial seizures by 27 patients
1291
Low Penetrance in Non–LGI1-Related ADLTE
Figure 1.
Pedigree structures of mutated (A) and nonmutated (B–D) ADLTE families. The colors refer to the following diagnostic categories:
blue, idiopathic partial epilepsy; yellow, tonic–clonic seizures, undetermined whether focal or generalized; red, epilepsy not otherwise specified;
gray, febrile seizures; green, isolated seizure. Circles – females; squares – males. Open symbols – healthy family members. Arrows indicate probands. Aud, auditory aura; Aph, aphasic symptoms; m, mutation in LGI1.
Epilepsia ILAE
(23%), and secondarily generalized tonic–clonic seizures by
77 patients (66%). By adding those patients with tonic–
clonic seizures undetermined whether focal or generalized,
a total of 100 patients (86%) had convulsive seizures.
Auras were reported by all the 91 patients with idiopathic
focal epilepsy and allowed classifying seizures as focal.
Auras were distinguished in two groups: auditory and nonauditory (Table S1).
Auditory auras were the most common type, being
observed in 79 cases (68%) and occurring in isolation
(n° 41, 35%) or associated with some kind of receptive
aphasia (n° 18, 16%). Other symptoms following the
auditory phenomena included complex visual hallucinations, vertigo, deja vu and other symptoms in single
cases, whereas auditory aura was preceded by other
symptoms (nausea, vertigo, deja vu and visual features)
in five cases (Table S1).
Nonauditory auras occurring in isolation were less frequent (n° 12, 10%) and consisted of visual hallucinations,
aphasia, deja vu, and vertigo.
Aphasic seizures, associated or not with auditory features, were reported by 21 cases (18%), and were the second
ictal symptom in frequency. Aphasia was described as
receptive aphasia with difficulty of comprehension, and verbal and semantic paraphasias.
Semiology of auditory auras
The auditory symptoms were reported as elementary and
unformed sounds in 49 cases (42%) (usually hooting, buzzing, or humming). Sixteen patients (14%) described structured voices and an additional four cases (3%) reported
music or songs. Negative auditory symptoms, such as sudden decrease or disappearance of the surrounding noises,
were reported by 8 (7%) and 4 (3%) patients, respectively.
Epilepsia, 54(7):1288–1297, 2013
doi: 10.1111/epi.12194
Epilepsia, 54(7):1288–1297, 2013
doi: 10.1111/epi.12194
2/0
2/0
14–18
2
2
–
1
2
2/0
1/1
11–18
2
1
–
2
–
F19
F18
(B)
N° patients
(a/d)
Male/female
Age (years) at
onset (range)
Seizure types
EPS or CPS (n°)
SGTC (n°)
UOTC (n°)
Ictal symptoms
Auditory (n°)
Aphasia (n°)
Clinical findings
3
–
bt sa 3
3
–
bt sa 3
598 T>C
1
3
4/4
1
–
3/3
1295 T>A
3
1
–
–
2
–
3
3
–
3
3
1
3
3
–
3
3
–
4/0
3/1
18–50
F2
3/0
3/0
12–19
F1
MRI (n°)
Normal (n°)
Abnormal
(findings n°)
LGI1 mutations
N° patients (a/d)
Male/female
Age (years) at
onset (range)
Seizure types
EPS or CPS (n°)
SGTC (n°)
UOTC (n°)
Ictal symptoms
Auditory (n°)
Aphasia (n°)
Complex
visual (n°)
Other (n°)
Reflex seizures (n°)
Seizure free
(n°/affected)
EEG (n°)
Ictal (findings n°)
Interictal
(findings n°)
(A)
Clinical findings
3
–
3
2
2–
4/1
15–27
5/0
F20
406 C>T
2
2
–
2
1
2
1
–
0/2
23–uk
2/0
F21
367 G>A
2
2
–
1
lt se 1
lt ea 1
1
–
1/3
–
–
2/2
2
1
2
1
1
–
2
–
n2
F4
3/1
1/3
33–37
2
–
–
2
2
2
4/0
3/1
10–13
F3
2
–
3
3
–
2/1
11–13
3/0
F22
365 T>A
3
3
–
4
–
n 3, lt ea1
2
1
2/3
5
–
–
5
3
2
6/1
3/4
14–30
F5
3
–
3
3
3
3/3
6–10
3/3
F23
365 T>C
2
2
–
2
–
n2
1
–
1/2
1
–
–
1
1
3
2/2
2/2
19–19
F6
3
1
3
3
1
1/3
10–11
3/1
F24
3
–
2
1
3
–
2
–
2
1
–
0/2
2–9
2/0
F28
Deletion
2
2
–
3
–
bt sa 1,
lbt ea 2
1
–
0/5
5
–
–
6
6
2
1/2
15–60
3
2
–
F10
6/2
6/2
12–34
F27
2/1
1138T>C
2
2
–
2
–
lt ea 2
1
1
2/4
3
–
–
3
3
2
1/2
6–43
2
–
1
F9
4/1
3/2
17–43
F26
3/0
136 T>C
4
–
n 1,
bt sa 1,
lt ea 2
uk
3
–
uk
3
2
–
3
2
2
1/3
11–16
4
4
–
F8
3/2
1/4
9–15
F25
4/0
461 T>C
2
2
–
5
–
n 3,
bt ea 2
4
2
2/4
4
3
1
5
5
2
5/2
5/2
9–22
F7
Table 1. Clinical details of affected families
–
–
2
1
2
2
1
1/2
2–23
3/0
F29
1
1
–
F30
–
2
2
–
2
–
n2
2
2
1/2
3
2
–
3
2
–
3/0
0/3
18–20
F 13
3
1
4
3
–
2/2
12–25
4/0
1
–
rt ea 1
2
2
0/2
1
–
1
2
2
1
2/1
1/2
8–8
F12
2
–
n 1,
rt ea 1,
lt ea 1
2
1
1
1
–
2/3
2
1
1
3
3
–
3/0
2/1
22–46
F11
–
2
1
1
F31
3
1
4
4
–
2/2
14–25
4/0
3
–
n3
–
–
3/3
2
–
–
2
1
4
3/3
1/5
19–20
F14
–
2
2
–
–
2
1
1
2
–
–
2
1
1
2
–
n2
–
–
1/2
2
1
1
2
1
–
2/0
0/2
26–uk
F17
F33
Continued
3
–
3
3
1
2/2
8–30
3/1
2
–
rt ea 1,
bt ea 2
–
–
2/2
2
–
1
2
1
–
3/1
11–32
2
2
2
F16
2/0
1/1
20–30
F32
3/1
2
–
rt ea 2
1
1
1/1
1
–
1
2
2
–
2/0
0/2
20–24
F15
1292
R. Michelucci et al.
1293
0/2
3
–
3/3
2
–
bt ea 1,
lt ea 1
3
3
–
4
–
lt ea 3,
lt sa 1
4
3
1
3
–
n 1, lt ea 1,
lt sa 1
1
1
–
2
–
rt sa 1,
lt sa 1
2
2
–
–
–
–
2
1
1
–
1
1
–
–
2
1
1
–
1
1
–
–
1
–
1
–
1
1
–
–
n normal; b, bilateral. left; t, temporal; sa, slow abnormalities; ea, epileptiform abnormalities; se, status epilepticus.
rt sa 1,
lt ea 1
2
2
–
–
lt ea 1
bt ea 1,
lt ea 2
2
2
–
–
–
rt ea 1,
lt ea 1
2
1
1
–
rt ea 1
rt ea 2
bt ea 2
rt ea 3,
rt sa 1
4
4
–
–
1
–
2
–
4
–
1
–
2
–
3
–
–
–
2
–
2
–
1
–
0/2
Triggering stimuli
Sudden noises (such as telephone ringing, slamming the
doors, entering a noisy room), listening to the radio, or
answering the phone could precipitate the seizures in 22
cases (19%), 3 of them belonging to the same family (n° 2,
Table 1A). In these cases seizures occurred also spontaneously.
2
2
–
–
1/3
0/3
1/2
0/2
1/3
0/2
1/2
1/2
2/2
2/2
0/1
2/2
2/4
lt ea 1
3
–
1
1
–
–
1
–
1
2
2
–
1
1
–
1
–
–
1
2
2
–
–
–
–
1
2
1
Some patients (n° 8, 7%) had two or three different auditory
symptoms combined in the same seizures, and others 6 (5%)
reported that the hooting or buzzing sensation grew louder
and louder during the ictal event.
Feelings such as getting far from the environmental
noises or voices were not strictly considered auditory auras.
2
2
–
–
1
2
–
n 1, lt sa 2
–
1
F28
F27
–
F26
–
F25
4
F24
1
F23
–
F22
1
–
F21
F20
–
Complex
visual
(n°)
Other (n°)
Reflex
seizures (n°)
Seizure free
(n°/affected)
EEG (n°)
Ictal
(findings n°)
Interictal
(findings n°)
MRI (n°)
Normal (n°)
Abnormal (n°)
LGI1 mutations
F19
–
F18
–
Clinical findings
Table 1. Continued.
–
–
F29
F30
–
F31
F32
–
F33
Low Penetrance in Non–LGI1-Related ADLTE
Seizure frequency and response to treatment
Seizures occurred typically at a low frequency, with
tonic–clonic seizures (either secondarily generalized or
unknown whether focal or generalized) being sporadic (one
to two times per year, mostly during sleep) and elementary
or complex partial seizures occurring at a variable frequency (on a weekly 13%, monthly 26%, or annual basis
42%), usually during wakefulness. In one family (n° 4,
Table 1A), recurrent episodes of status epilepticus with
auditory semiology and secondarily generalized tonic–clonic seizures were reported in one patient.
Seizures were promptly controlled by antiepileptic treatment in more than one half of the cases (53%), sometimes at
low doses. The remaining patients (47%) were not seizure
free, although seizures usually improved and were only sporadic. Seizure recurrence after drug discontinuation was
observed in three cases that had been seizure-free for many
years.
Neurophysiologic findings
Routine EEG studies were available in 77 (73%) of 105
living patients. The interictal recordings showed epileptiform abnormalities in 48 cases (62%) (usually sharp waves
or slow spikes) over the temporal regions, involving the left
side in 23 patients (30%), the right side in 15 (20%), and
both sides in 10 (13%). In 29 patients (38%), EEG studies
were normal or showed aspecific abnormalities.
One ictal EEG tracing, showing a left focal temporal status with auditory symptoms, was available (Di Bonaventura
et al., 2009).
Neuroradiologic findings
A conventional MRI scan was available in 66 (62%) of
105 living patients. The examinations were normal in most
patients (85%), but results disclosed minor abnormalities in
10 unrelated cases (15%), consisting of mild temporal atrophy (2), temporal arachnoidal cysts (2), mild ventricular
asymmetry (3), cerebral asymmetry (1), and white matter
gliotic changes (2).
Epilepsia, 54(7):1288–1297, 2013
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R. Michelucci et al.
Genetic findings
Mutation analysis of LGI1 coding exons and flanking intronic splice sites, performed by direct sequencing, failed to
show mutations in 23 families (70%) (Fig. 1). Missense
mutations were found in nine families by means of direct
sequencing (Michelucci et al., 2003; Pizzuti et al., 2003;
Pisano et al., 2005; Striano et al., 2008; Di Bonaventura
et al., 2009, 2011), and a microdeletion mutation was discovered in one family by SNP-array genotyping and semiquantitative polymerase chain reaction (PCR) analysis
(Fanciulli et al., 2012).
Overall, 10 families (30%) had LGI1 mutations (Fig. 1).
The details of LGI1 mutations are given in Table 1(A,B).
Clinical comparison between mutated and nonmutated
families
The clinical features of the patients belonging to the
mutated and nonmutated groups did not differ substantially
as to age at onset (19.7 vs. 18.2 years), frequency of auditory auras (62% vs. 73%), ictal aphasic symptoms (20% vs.
17%), occurrence of secondarily generalized tonic–clonic
seizures (63% vs. 68%), and response to therapy (58% vs.
50% of seizure freedom) (Table S1). Febrile seizures were
also equally distributed in both groups (four and six cases,
respectively).
The mean number of affected members per family was
higher in mutated than in nonmutated families (5.1 vs. 3.5).
Penetrance estimate
Results of penetrance estimation analysis are shown in
Tables 2 and 3. The penetrance was 43.9% (range 0–100%)
for all the pedigrees combined. When penetrance estimate
was calculated separately in LGI1-mutated and non–LGI1mutated families, it was significantly different in the two
groups, being 61.3% and 35%, respectively (chi-square,
p = 0.017). In addition, we estimated the relative disease
risk by odds ratio and found that obligate carriers of families
with mutations in LGI1 had a risk three times higher than
Table 2. Penetrance estimate in mutated families
Family members
Obligate carriers
Family
Total
affected
Total
Affected
Penetrance estimate (%)
1
2
3
4
5
6
7
8
9
10
Total
4
19
19
5
13
8
22
6
15
24
135
3
4
4
4
7
4
7
5
5
8
51
1
2
6
2
4
3
3
1
5
4
31
1
1
0
2
3
2
3
1
2
4
19
100
50
0
100
75
67
100
100
47
100
61.3
Epilepsia, 54(7):1288–1297, 2013
doi: 10.1111/epi.12194
carriers of families with mutations in other, as yet unknown,
ADLTE-related genes (OR 2.94, CI 1.2–7.21).
Discussion
In this article, we report 127 patients belonging to 33 Italian pedigrees with ADLTE, collected over a 10-year period
under the auspices of the Commission of Genetics of the
Italian League Against Epilepsy. Although almost one third
of the families have been published separately over the last
decade, this is the largest ADLTE series so far reported in
the world.
Clinical findings included absence of any relevant personal history or associated illnesses, no sex predominance, a
mean age at onset of 18.7 years with a range spanning from
infancy to late adulthood, focal seizures (elementary, complex, or secondarily generalized) with prominent auditory
auras (sometimes triggered by sudden external noises),
tonic–clonic seizures as the only seizure type in one third of
cases, relative low frequency of seizures and good response
to conventional treatment in most cases, absence of any neurologic or mental abnormality, mild temporal EEG paroxysmal abnormalities, and normal neuroimaging. These data
were similar to those described in previous series. In the
families we studied, 68% of the patients for whom sufficient
clinical data were available had auditory symptoms and
18% had aphasia (either isolated or in combination with
auditory aura). These frequencies are of course inflated
because families were selected for study only if they had
auditory symptoms or aphasia. However, there was no bias
in collection of information on the specific types of auditory
and other symptoms. In particular, we observed that auditory auras were usually described as elementary (42%) or,
more rarely, complex auditory hallucinations (14%), the
distortion of sounds (becoming louder and louder or suddenly low) being a possible feature. In individual seizures,
auditory auras could be followed in about half of the cases
by other ictal symptoms, such as aphasia, visual hallucinations, and vertigo. When auditory symptoms were not
reported, the usual auras were visual hallucinations or
aphasia.
Overall, the above data suggest that the ictal discharge
engages, either primarily or secondarily, other areas located
within or close to the lateral temporal cortex in addition to
the primary auditory cortex, supporting the view that we are
dealing with a true focal epilepsy with a lateral temporal
onset. Furthermore, in our series, tonic–clonic seizures
occurred in the majority of cases (86%), as expected in epilepsies originating from the lateral temporal cortex (Williamson & Engel, 2008).
Interictal EEG findings show temporal paroxysmal
abnormalities in about 62% of cases. At variance with what
was previously suggested (Brodtkorb et al., 2005), a left
predominance of the abnormalities was not statistically
more frequent than other localizations (right or bilateral).
1295
Low Penetrance in Non–LGI1-Related ADLTE
Table 3. Penetrance estimate in nonmutated families
Family members
Obligate carriers
Family
Total
Affected
Total
Affected
Penetrance estimate (%)
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Total
7
5
9
15
7
12
10
7
15
41
7
4
15
9
18
8
28
3
4
6
26
22
11
289
3
3
3
6
2
2
2
2
2
5
2
3
6
4
4
3
3
2
3
4
4
4
4
76
2
2
2
4
1
4
2
3
2
7
2
1
5
3
2
2
3
2
1
2
4
2
2
60
1
1
1
3
0
0
0
0
0
0
1
1
4
1
0
1
1
1
1
1
0
2
1
21
50
50
50
75
0
0
0
0
0
0
50
100
80
33
0
50
33
50
100
50
0
100
50
35
Conventional MRI was also normal in most of the
patients, this finding being necessary for the definition of
the disease and selection of the probands. In mutated families, however, the use of nonconventional techniques
allowed for demonstration of focal changes coherent with
the postulated epileptogenic area on diffusion tensor imaging (Tessa et al., 2007) or abnormalities of speech paradigms on functional MRI (fMRI) (Ottman et al., 2008),
suggesting that LGI1 mutations may cause structural, albeit
subtle, cerebral damage.
The genetic study performed in our 33 pedigrees disclosed LGI1 mutations in 10 families (30%), a percentage
significantly lower than hitherto reported. Of interest, missense mutations were found in nine families by means of
direct sequencing and a microdeletion was discovered in
one family by means of high-density SNP array genotyping
and CNV analysis, suggesting that the latter or other appropriate methods should also be performed before excluding
LGI1 mutations in ADLTE families (Fanciulli et al.,
2012).
The comparison between the subgroups of families with
or without mutations in LGI1 did not disclose any significant clinical difference, at least in terms of age of onset, frequency of auditory auras, ictal aphasic symptoms, and
secondarily generalized tonic–clonic seizures. The only
difference was a lower number of affected members in
families with no LGI1 mutation, suggesting that the penetrance of the condition could be different in the two family
subgroups. In fact, penetrance estimate by means of the per-
centage of affected obligate carriers disclosed a significant
difference between the two subgroups, the families with
LGI1 mutations having a penetrance of 61.3% compared to
35% in families without LGI1 mutations. This finding
implies that although ADLTE with LGI1 mutations segregates with an autosomal dominant inheritance pattern with
incomplete penetrance (Rosanoff & Ottman, 2008), the pedigrees without LGI1 mutations may genetically be of two
different kinds: those with dominant mutations in genes
other than LGI1, and those with lower intrafamilial recurrence and likely complex inheritance of the syndrome. The
latter group should account for a substantial proportion of
the LGI1-negative families, thus resulting in an overall
reduction of penetrance. This admixture of pedigrees with
different genetic structures might explain why attempts at
identifying a second gene for ADLTE by cumulative
genetic linkage studies of LGI1-mutation–free families have
so far failed to map a statistically significant novel ADLTE
locus (Carlo Nobile, unpublished data). This heterogeneous
genetic architecture, accounting for a complex inheritance,
was also shown in another relatively large series of LGI1negative families (Chabrol et al., 2007b).
The penetrance in our families with LGI1 mutations
(61.3%) is similar to that reported by Rosanoff and Ottman
(2008) (67%). However, because some families were
included in both studies, our finding cannot be regarded as
an independent confirmation of that reported by Rosanoff
and Ottman (2008). The penetrance we calculated in our
families, which were ascertained on the basis of containing
Epilepsia, 54(7):1288–1297, 2013
doi: 10.1111/epi.12194
1296
R. Michelucci et al.
two or more affected individuals, is inflated with respect to
the true penetrance in general population, which should be
estimated in a large sample of individuals unselected on the
basis of family history of lateral temporal epilepsy (Begg,
2002). However, within these limitations, it provides a measure of the risk for developing the disorder in members of
ADLTE families who carry mutations in LGI1 or other, as
yet unknown, related genes. Notably, our data support a significantly higher relative risk (OR 2.94) for developing
ADLTE conferred by LGI1 mutations than that conferred
by mutations in other ADLTE genes. Our finding also
implies that the term ADLTE/ADPEAF, as it is currently
used to define any family with two patients with lateral
temporal epilepsy irrespective of family structure and overall number of patients, may not be suitable for all families
with lateral temporal epilepsy. In general terms, families
with low recurrence of epilepsy are less likely to have a
major gene as a genetic cause than families with numerous
members affected with lateral temporal epilepsy over two or
more generations. According to this distinction, only the latter subgroup of families should be termed ADLTE/ADPEAF, whereas the former familial cases may lie
somewhere between ADLTE families and sporadic cases,
and are better referred to as familial lateral temporal epilepsy. The analysis of the genetic architecture and clinical
findings of our families suggests that the selection of families with more patients (three or more) over at least two generations would increase the likelihood of finding LGI1
mutations. However, a clear conclusion cannot be drawn
because pedigrees bearing LGI1 mutations, although more
commonly showing an autosomal dominant inheritance,
may also demonstrate an unexpected low penetrance (Di
Bonaventura et al., 2011).
We conclude that a large number of ADLTE families
have been collected over a 10-year period in Italy, showing
a typical and homogeneous phenotype. LGI1 mutations
have been found only in one third of families, clinically
indistinguishable from nonmutated pedigrees. The estimate
of penetrance, however, demonstrates a significantly lower
penetrance rate in non–LGI1 -mutated families compared
with LGI1-mutated pedigrees, suggesting that a complex
inheritance pattern may underlie a proportion of these
families.
Acknowledgments
This work was supported by the Commission of Genetics of the Italian
League Against Epilepsy (grant to R.M. and C.N.), and by the Fondazione
Cassa di Risparmio di Padova e Rovigo (grant to C.N.). M.F. was the recipient of a fellowship by Regione Autonoma della Sardegna (L.R.7/2007).
Disclosure
None of the authors has any conflict 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.
Epilepsia, 54(7):1288–1297, 2013
doi: 10.1111/epi.12194
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Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Table S1. Characteristics of auras.
Epilepsia, 54(7):1288–1297, 2013
doi: 10.1111/epi.12194