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Keywords:

  • Autosomal dominant lateral temporal epilepsy ;
  • LGI1;
  • Penetrance;
  • Mutated families;
  • Nonmutated families

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information

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 déjà 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).

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 LGI1-mutated pedigrees, suggesting that a complex inheritance pattern may underlie a proportion of these 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.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information

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. 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 copy-number 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.

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information

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.

Table 1. Clinical details of affected families
Clinical findingsF1F2F3F4F5F6F7F8F9F10F11F12F 13F14F15F16F17
(A)
N° patients (a/d)3/04/04/03/16/12/25/23/24/16/23/02/13/03/32/02/02/0
Male/female3/03/13/11/33/42/25/21/43/26/22/11/20/31/50/21/10/2
Age (years) at onset (range)12–1918–5010–1333–3714–3019–199–229–1517–4312–3422–468–818–2019–2020–2420–3026–uk
Seizure types                 
EPS or CPS (n°)33225153363232222
SGTC (n°)33213152363221211
UOTC (n°)12223222214
Ictal symptoms                 
Auditory (n°)3215143352132122
Aphasia (n°)21132121
Complex visual (n°)111111
Other (n°)1112143111221
Reflex seizures (n°)3121221
Seizure free (n°/affected)3/34/42/21/32/31/22/4uk2/40/52/30/21/23/31/12/21/2
EEG (n°)33214254232123222
Ictal (findings n°)lt se 1
Interictal (findings n°)bt sa 3bt sa 3n 2lt ea 1n 3, lt ea1n 2n 3, bt ea 2n 1, bt sa 1, lt ea 2lt ea 2bt sa 1, lbt ea 2n 1, rt ea 1, lt ea 1rt ea 1n 2n 3rt ea 2rt ea 1, bt ea 2n 2
MRI (n°)3322322uk222122222
Normal (n°)3322322221121211
Abnormal (findings n°)1111
LGI1 mutations1295 T>A598 T>C406 C>T367 G>A365 T>A365 T>C461 T>C136 T>C1138T>CDeletion
Clinical findingsF18F19F20F21F22F23F24F25F26F27F28F29F30F31F32F33
  1. n normal; b, bilateral. left; t, temporal; sa, slow abnormalities; ea, epileptiform abnormalities; se, status epilepticus.

(B)
N° patients (a/d)2/02/05/02/03/03/33/14/03/02/12/03/04/04/03/13/1
Male/female1/12/04/10/22/13/31/31/31/21/20/21/22/22/23/12/2
Age (years) at onset (range)11–1814–1815–2723–uk11–136–1010–1111–166–4315–602–92–2312–2514–2511–328–30
Seizure types                
EPS or CPS (n°)2232333423224423
SGTC (n°)122133342123423
UOTC (n°)2–311121
Ictal symptoms                
Auditory (n°)2132233323223323
Aphasia (n°)2111111
Complex visual (n°)1141
Other (n°)2211211132
Reflex seizures (n°)11211211
Seizure free (n°/affected)0/22/22/20/11/22/21/22/40/21/30/21/20/31/33/30/2
EEG (n°)12232142123423
Ictal (findings n°)
Interictal (findings n°)rt ea 1rt ea 1, lt ea 1rt ea 2bt ea 1, lt ea 2bt ea 2lt ea 1rt ea 3, rt sa 1rt sa 1, lt ea 1lt ea 1rt sa 1, lt sa 1n 1, lt ea 1, lt sa 1lt ea 3, lt sa 1bt ea 1, lt ea 1n 1, lt sa 2
MRI (n°)1211221422221432
Normal (n°)111211421221332
Abnormal (n°)11111
LGI1 mutations     
image

Figure 1. Pedigree structures of mutated (A) and nonmutated (BD) 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.

Download figure to PowerPoint

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 (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, déjà vu and other symptoms in single cases, whereas auditory aura was preceded by other symptoms (nausea, vertigo, déjà 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, déjà 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. 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.

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.

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).

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–LGI1-mutated 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 carriers of families with mutations in other, as yet unknown, ADLTE-related genes (OR 2.94, CI 1.2–7.21).

Table 2. Penetrance estimate in mutated families
FamilyFamily membersObligate carriersPenetrance estimate (%)
Total affectedTotalAffected
14311100
21942150
3194600
45422100
51374375
6843267
722733100
86511100
91555247
1024844100
Total13551311961.3
Table 3. Penetrance estimate in nonmutated families
FamilyFamily membersObligate carriersPenetrance estimate (%)
Total AffectedTotalAffected
11732150
12532150
13932150
141564375
1572100
16122400
17102200
1872300
19152200
20415700
21722150
224311100
231565480
24943133
25184200
26832150
272833133
28322150
294311100
30642150
31264400
3222422100
331142150
Total28976602135

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information

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).

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 percentage 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 LGI1-negative 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 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

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information

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

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information

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.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information
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Supporting Information

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information
FilenameFormatSizeDescription
epi12194-sup-0001-TableS1.docxWord document18KTable S1. Characteristics of auras.

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