Drs. Pisano and Marini contributed equally to the article.
Address corresponding and reprint requests to Dr. R. Guerrini at Division of Child Neurology and Psychiatry, University of Pisa & IRCCS Fondazione Stella Maris, via dei Giacinti 2, 56018 Calambrone, Pisa, Italy. E-mail: firstname.lastname@example.org
Summary: Purpose: Autosomal dominant lateral temporal lobe epilepsy (ADLTLE) is a rare familial epilepsy with onset in adolescence or early adulthood, associated with mutations of LGI1 in most families. We describe the clinical, neuropsychological, and molecular genetic study of a new ADLTLE Italian family.
Methods: A four-generation family from Sardinia was studied. Clinical, neuropsychological, and genetic analysis were performed in eight living affected family members.
Results: Nine family members had seizures over four generations; four of them had auditory auras and aphasia followed by secondarily generalized tonic–clonic seizures (SGTCs). One individual in addition had visual symptoms, and one family member had only vertigo followed by SGTCs. The side of seizure onset could not be determined in these five patients with focal seizures. The proband had febrile and afebrile tonic–clonic seizures. Two family members had only febrile seizures. Inheritance was autosomal dominant with 59% penetrance. Genetic molecular analysis showed a new LGI1 missense mutation causing a Leu154Pro substitution in six affected and one unaffected individuals. Dichotic listening performance was abnormal in four affected individuals compared with controls. Fluency and lexical abilities also were pathological in three patients. These findings showed that in patients, the left temporal lobe was less specialized in the auditory processing function than in controls.
Conclusions: In this ADLTLE family, both seizure semiology and neuropsychological findings point to a lateral temporal lobe dysfunction. The newly identified LGI1 mutation might underlie both the seizure disorder and the neuropsychological deficits.
Autosomal dominant lateral temporal lobe epilepsy (ADLTLE) (1) or autosomal dominant partial epilepsy with auditory features (ADPEAF) (2), first described in 1995 by Ottman et al. (3), is a rare familial epilepsy with mendelian inheritance. Several families with similar phenotypes have been reported (1–7). Auditory auras are present in 50–100% of affected family members, but other sensory auras also were frequently described, including visual, psychic, epigastric, vertiginous, and aphasic symptoms. In addition, three families with predominantly aphasic seizures were reported (5,6,8). Auditory and other sensory auras suggest the involvement of the lateral temporal cortex in the seizure origins (9). However, extratemporal epilepsies with auditory symptoms also have been reported (9). Studies of cortical stimulations and intracranial recordings in humans have shown that elementary and complex auditory auras predominantly originate from the transverse temporal gyri of Heschl, corresponding to the primary auditory cortex and to the associative cortex in the superior and lateral aspects of the superior temporal gyrus (Brodmann areas 41, 22, and 42) (9).
ADLTLE has been associated with mutations in the leucine-rich, glioma-inactivated 1 (LGI1) gene with 70–80% penetrance (10,11). Similar to other genetic epilepsies, ADLTLE has a genetic heterogeneity, and the absence of LGI1 mutations in some families suggests that at least one other gene, yet to be found, is involved in causing the same phenotype (6,12).
LGI1 is the first epilepsy gene not related to ion channels, and its pathogenetic mechanism is yet to be understood. A reduced LGI1 expression was reported in glioblastoma multiform and low-grade gliomas, suggestive of its function in the glial tumor progression (13). A plausible hypothesis is that mutations in one copy of LGI1 could cause epilepsy, whereas mutations in both copies of LGI1 could enable glial tumor metastasis through loss of an inhibitory signal. However, no evidence indicates that LGI1 is associated with a serious risk for malignancies in ADLTE families (14).
A possible pathogenetic mechanism for LGI1 in epileptogenesis could be subtle alteration of the neuronal migration in the developing brain, which may result in a microdysgenic lesion not detectable with magnetic resonance imaging (MRI). The possibility of an underlying mild temporal abnormality on the lateral temporal cortex in ADLTLE was suggested by Kobayashi et al. (15). However, the authors could not demonstrate a clear association between the LGI1 mutation and the temporal lobe structural abnormalities. In case of an abnormal lateral temporal cortex, one might expect that specific functions relying on an integral lateral temporal cortex, including processing of phonologic auditory inputs, could be affected. To test this hypothesis, we conducted a clinical, molecular, and neuropsychological study in a family with ADLTLE caused by a new LGI1 mutation.
The family was ascertained through the proband (Fig. 1, IV-1), referred to the Epilepsy Unit (Department of Child Neurology and Psychiatry) of the Cagliari Hospital when he was initially seen with tonic–clonic seizures (TCSs). All participating individuals and parents, in the case of minors, gave informed consent. This study was undertaken with the approval of the Human Research Ethics Committee of the IRCCS Stella Maris Foundation, Pisa, Italy.
Twelve family members were personally interviewed by using a validated seizures questionnaire (16) to obtain clinical and genealogic information. Previous medical records of affected individuals were reviewed when possible. Six family members underwent neurologic examination. EEG recordings during wakefulness, photic stimulation, and hyperventilation were performed for family members II-2, III-2, III-3, III-4, and IV-1. Computed tomography (CT) scan or MRI of the brain was obtained in five individuals. Blood samples were collected for genetic analysis.
Classification of epilepsy phenotypes
Seizure types and epilepsy syndromes were classified according to the International Classifications of Seizures and Epilepsy Syndromes (17,18). Individuals with a history of seizures but insufficient information to identify a specific phenotype were designated as unclassified epilepsy.
Genomic DNA from peripheral blood leukocytes was extracted from nine family members (II-2, III-1, III-2, III-3, III-4, III-5, III-6, III-7, and IV-1) by using a standard protocol. The eight exons covering the coding regions of LGI1 and their respective intron–exon boundaries were amplified by polymerase chain reaction (PCR). Most of the primer sequences have been described previously (11). PCR products were purified (GenElute PCR Clean-Up Kit, Sigma, St. Louis, MO, U.S.A.) and subjected to cycle sequencing in both forward and reverse directions (BigDye v1.1 and ABI prism 310, Applied Bioscience, LaJolla, CA, U.S.A.).
Neuropsychological evaluation was undertaken in the five patients who agreed to participate (III-2; III-3; III-4; III-6; and IV-1). Their performance was matched to controls of approximately the same age, same gender, comparable low educational and socioeconomic levels (all were semiskilled or unskilled laborers), and of estimated intelligence (Progressive Matrices, Series 1, and CPM, if children) (19,20). Patients' performance was compared with matched controls and with Italian norms. Evaluators were blind as to patient/control status. The neuropsychological evaluation comprised a measure of lateralization for language. Receptive and expressive language measures were administered to ensure that patients did not have receptive or expressive aphasic disorders: (a) receptive: syllable discrimination, lexical decision, all taken from the BADA (Batteria per l'analisi dei deficit afasici, Italian battery for assessing aphasic deficits) (21), lexical decision task for children (22), and Token Test (23,24); (b) expressive: nonword repetition, picture naming of words and verbs (BADA); verbal fluency (phonologic: letters F, P, L, and semantic: animals, fruits, automobile brands (25,26), picture-naming task for children (27). For the BADA errors, scores >4 are considered cutoff points for pathologic performance (Miceli et al., personal communication); for all other tests, means and standard deviations are provided (Table 3). For children in the Token Test, a score <25.5 (5th percentile) is considered impaired performance (24).
Table 3. Normative data
See text for normative data of other tests.
Lateralization for language was assessed by means of the Fused Dichotic Listening task (28,29). The procedure consists of the simultaneous presentation to both ears of 30 pairs of fused words through headphones: 25 pairs differ for the first consonant, and five pairs differ for the first vowel. The word pairs are presented twice, and in the second session, the assignment of stimuli to ears is reversed. Furthermore, all 55 stimuli are presented separately to the right and to the left ear. Overall, each subject is presented with 115 stimuli to each ear. The instructions are to repeat, after each presentation, all words heard. A laterality index (lambda) was calculated as Ln [(right-ear responses + 1)/(left-ear responses + 1)]. A positive lambda is indicative of a right-ear advantage corresponding to a left-hemisphere specialization, whereas a negative lambda, of a left-ear advantage corresponding to right-hemisphere specialization. Mean lambda scores for normal 10 year-olds are 0.46 with a standard deviation of 0.40 (30), mean lambda scores for young adults are 0.63 with a standard deviation of 0.61 (unpublished data). A 20-item handedness questionnaire (Edinburgh Inventory) (31) also was administered and a Laterality Quotient calculated, with positive scores >70 and negative scores >–70 indicating right or left handedness, respectively.
The family pedigree is shown in Fig. 1. Nine family members had a history of seizures. Clinical details are presented in Table 1.
Table 1. Clinical details of affected family members
Sequencing of LGI1 in the proband (IV-1) and his father (III-2) revealed a T → C nucleotide substitution in exon 5 at position 461, numbering from the start codon of LGI1 cDNA sequence (GenBank M_005097) (Fig. 1). This nucleotide changed a highly conserved leucine to a proline at residue 154 (Leu154Pro) of the mature protein. T461C falls in one of three leucine-rich repeats domains of the protein. Four affected family members, including the one with febrile seizures (FSs) only (III-3, III-4, III-6, and II-2), and one unaffected individual (III-7), had the T461C substitution (Fig. 1). We did not detect the T461C change in 60 control chromosomes of Sardinian origin and in 250 chromosomes of mixed ethnic origin tested by DHPLC or sequencing or both. Conservation of the residue leucine at position 461 in all known human and mice LGI proteins and the absence of the nucleotide substitution in 135 controls provide circumstantial evidence for the functional importance of this residue.
A summary of the neuropsychological findings is presented in Table 2.
Table 2. Neuropsychological results in both patients and controls
Hand Edinburgh laterality quotient
Language Laterality Index (lambda)
Repetition Nonword repetition no. errors
Phonological no. correct
Semantic no. correct
Nouns no. errors
Verbs no. errors
Syllable discrimination no. errors
Lexical decision no. errors
Token test no. correct
aImpaired performance (>1.5 SD from mean); breduced (approaching 0) or atypical (negative) lambda values; na, not available.
Control IV-1 (prob)
The reduced number of patients in this family did not allow statistical analyses. Estimated intelligence scores for all subjects except the two children were in the low-average–borderline range (fewer than six correct responses for adults) (Table 2).
Overall, patients' performance was normal in tasks requiring single-word repetition and syllable discrimination, but it was impaired in tasks requiring access to stored lexical knowledge (either verbal fluency, naming, or lexical decision). Patients III-3, III-4, and III-6 were impaired in at least two of these tasks. In the phonologic fluency tasks, patients III-3, III-4, and III-6 fell in the deficit range (z score, >1.5), two of whom also had an impaired performance in the semantic task (compared with matched controls and normative data). Two patients and one control were impaired in the Token test (Table 2). Lateralization for phonologic processing, as assessed by the fused dichotic listening task, revealed that although all control values were positive and fell within the mean, patients' laterality indices, except for the proband's, were distributed around 0 or were in the negative range. Low lambda scores (approaching zero), indicative of a reduced specialization for language, were present in patients III-3 and III-4. Negative lambda scores were obtained in patients III-2 and III-6, indicative of a right hemisphere specialization for phonologic processing. Negative lambda value can be found in a small percentage of left-handers; thus it cannot be completely ruled out that the negative lambda value of the left-handed patient III-2 is not linked to hand preference.
This Sardinian family had seizures semiology consistent with ADLTLE (1–7). An auditory aura was the initial symptom in four of the nine affected individuals. Three of them also had ictal aphasic symptoms, and individual III-4 had visual symptoms and postictal aphasia. Vertigo, malaise, and weakness also were common symptoms in this family.
The proband had generalized tonic–clonic seizures not preceded by aura, and two family members had only had FSs (III-6 and III-8). One of them (III-6) carried the LGI1 mutation, unlike individuals with FSs in previously reported families (9) and in unrelated individuals with FS only in the Japanese population (32). However, our patient was only 22 years old and could develop other seizure types. Patient III-6, the older brother who also had only FS, refused testing. The LGI1 mutation also was found in the remaining affected living family members and in one unaffected individual. The T461C change is the first reported mutation affecting a leucine in one of three leucine-rich repeats domains of the LGI1 protein. Its pathogenetic role also was supported by the absence of the nucleotide substitution in healthy controls with mixed ethnic origin including a sample from Sardinia.
Epilepsy was very mild in our patients with low seizure frequency throughout their lives, and most of them were seizure free at the time of the study. This made them good candidates for neuropsychological evaluation, because we did not expect that their performances could be influenced by seizure activity.
The neuropsychological evaluation showed that the patients did not have clinical signs of aphasia although they had reduced scores in some language tasks compared with controls. The fused dichotic listening task, stressing phonologic processing under bilateral competing auditory input, and not linked to culture-dependent knowledge, showed a reduced (lambda values approaching zero) or atypical (negative lambda) indices of lateralization in four affected family members. These results, although based on a small sample size, suggest that ADLTLE with the LGI1 mutation is associated with a reduced capacity of the lateral temporal neuronal network of the left hemisphere to process phonologic information without impairment in language tasks. The deficit shown also in fluency tasks requiring search in the phonologic lexicon under time constraints, also may be compatible with an inefficient lateralized neural network encompassing language areas of the left hemisphere involved in the access of stored lexical knowledge.
In conclusion, both seizure semiology and neuropsychological testing are concordant with a lateral temporal lobe dysfunction. LGI1 mutations could determine subtle structural changes in the lateral temporal cortex underlying focal epileptogenesis and impaired phonologic processing. More individuals with ADLTLE with and without LGI1 mutations must be tested to confirm our findings.