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Keywords:

  • LGI1/Epitempin;
  • ADLTE;
  • EEG/fMRI

Summary

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

Purpose: We characterized a family with autosomal dominant lateral temporal epilepsy (ADLTE) whose proband presented uncommon electroclinical findings such as drug-resistant seizures and recurrent episodes of status epilepticus with dysphasic features.

Methods: The electroclinical characteristics and LGI1 genotype were defined in the family. In the proband, the ictal pattern was documented during video-EEG monitoring and epileptic activity was mapped by EEG/fMRI.

Results: The affected members who were studied had drug-resistant seizures. In the proband, seizures with predominant dysphasic features often occurred as partial status epilepticus. The video-EEG-documented ictal activity and fMRI activation clearly indicated the elective involvement of the left posterior lateral temporal cortex. Sequencing of LGI1 exons revealed a heterozygous c.367G>A mutation in exon 4, resulting in a Glu123Lys substitution in the protein sequence.

Conclusions: The uncommon clinical pattern (high seizure frequency, drug-resistance) highlights the variability of the ADLTE phenotype and extends our knowledge of the clinical spectrum associated with LGI1 mutations.

Autosomal dominant lateral temporal epilepsy (ADLTE, OMIM#600512) is a partial epilepsy characterized by juvenile-adult onset, rare seizures, and a good response to antiepileptic treatments. The main feature in ADLTE is the recurrence of auditory symptoms during epileptic aura (Ottman et al., 1995), which suggests a lateral temporal origin of the seizures. Other epileptic features of probable lateral temporal origin, such as aphasic or visual phenomena, may also be present, either in isolation or accompanying the auditory symptoms (Poza et al., 1999; Gu et al., 2002; Michelucci et al., 2003). Magnetic resonance imaging (MRI) findings are usually normal and electroencephalography (EEG) recordings reveal unilateral or bilateral slow waves and/or epileptiform activity over the temporal–occipital regions in a small proportion of cases. Mutations causing ADLTE have been found in the LGI1/Epitempin gene (Kalachikov et al., 2002; Morante-Redolat et al., 2002). These were the first mutations in epilepsy to affect a gene encoding neither an ion channel nor a neurotransmitter receptor. Overall, LGI1/Epitempin mutations account for about 50% of ADLTE families (Michelucci et al., 2003) suggesting genetic heterogeneity in ADLTE.

The function of the LGI1/Epitempin gene is unclear. The structure of the encoded protein consists of an N-terminal LRR domain (Kobe & Kajava, 2001) and C-terminal EPTP (beta-propeller) domain (Pfam no. PF03736), both of which mediate protein–protein interactions.

We describe an Italian family with ADLTE carrying a novel mutation in LGI1/Epitempin, whose proband presented uncommon electroclinical findings such as drug-resistant seizures and recurrent episodes of status epilepticus with dysphasic features. In this patient, the ictal pattern was documented during video-EEG monitoring and epileptic activity was mapped by EEG/fMRI.

Patients and Methods

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

The family had four affected members (three alive) spanning three generations (Fig. 1). All participants gave written, informed consent to a protocol approved by the local ethics committee. A medical history was obtained by interviewing each subject, and information on the occurrence and frequency of seizures, age at onset, presence and nature of aura and semiology, and possible risk factors was collected. Subjects underwent a neurologic examination.

image

Figure 1.   (A) Family pedigree. Circles denote females; squares denote males. Individuals carrying one mutant and one normal allele are denoted by M/−. Ictal semiology in the family members: I:1—Rare generalized tonic–clonic seizures, no information about subjective phenomena; II:2—complex partial seizures (impairment of consciousness with automatisms, no prodromic phenomena); II:3—single generalized tonic–clonic seizure; III:1—partial seizures/status epilepticus with dysphasic features. (B) Original sequence tracings used to detect the disease allele. Variant allele is denoted by an arrow.

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Video-EEG and EEG/fMRI study performed on proband

The patient underwent video-EEG monitoring (Telefactor System, 21 channels, International 10–20 System, Astromed Inc, West Warwick, RI, U.S.A.) to evaluate ictal activity. We performed a thorough clinical evaluation during the recording, paying particular attention to aphasic and apraxic disorders (comprehension, denomination, verbal fluency and repetition, writing and reading, as well as tasks to reveal ideomotor and constructive apraxic features) and the patient’s acoustic deficit (diapason test). Because of the large amount of interictal epileptiform abnormalities present the day after the dysphasic/dyspraxic status, an EEG/fMRI study (1.5-T Philips EEG Gyroscan magnet, Micromed recording system; technical details are reported in the Supporting Information) was also performed on the patient.

Molecular genetic studies

DNA was extracted from blood by standard methods and LGI1 exons were polymerase chain reaction (PCR) amplified as described previously (Michelucci et al., 2003). Sequencing of PCR products was performed using the Big Dye Terminator Cycle Sequencing kit (ABI PRISM; Applied Biosystems, Carlsbad, CA, U.S.A.) and ABI3730 automatic sequencer (Applied Biosystems).

Results

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

Clinical descriptions of family members

The family pedigree is shown in Fig. 1A.

Patient I:1, a detailed clinical history of the proband’s grandfather is lacking. As far as we could gather, while alive he had very rare, generalized tonic–clonic seizures. No information regarding subjective phenomena is available.

Patient II:1, the proband’s mother, is a 67-year-old right-handed woman affected by partial epilepsy. Her seizures began at the age of 37 years and became drug-resistant precociously. They are characterized by a sudden impairment of consciousness with staring, and gestural and oroalimentary automatic activities; she has never referred prodromic subjective phenomena. Her neurologic examination and MRI scan were normal. She is currently on polytherapy consisting of topiramate 400 mg/day, levetiracetam 3,000 mg/day, and zonisamide 300 mg/day (a partial effect on seizure frequency was achieved when this last drug was added), although seizures continue to occur at a monthly rate. The drugs tried previously, including valproate, phenytoin, carbamazepine, phenobarbital, and primidone, had no effect on seizures.

Patient II:3, the proband’s aunt’s medical history contains a single generalized tonic–clonic seizure, during which no aura was reported. The EEG and MRI scan were normal. She is not currently taking antiepileptic therapy.

Proband III:1, is a 42-year-old right-handed woman affected by partial epilepsy. Seizures began at the age of 33 years and were initially characterized by prodromic symptoms consisting of a acoustic manifestation (“a whistle…”) followed by speech disorder (“I can’t speak well… I sometimes can’t understand…”), deviation of the head and eyes to the right, and secondary generalization. The partial seizures persisted after she started antiepileptic treatment, becoming drug-resistant.

The various EEG studies always showed slow waves and epileptiform abnormalities in the left temporal lobe; neurologic examination and MRI scan were normal. After several therapy changes, this patient’s ictal semiology became monomorphic and stereotyped, predominantly consisting of dysphasic features with expressive and receptive ictal language disorder. A very atypical feature of these seizures was their prolonged duration, which ranged from 2 to 12 hours. When the patient was referred to our unit because of status epilepticus, she was receiving therapy with topiramate 400 mg/day, pregabalin 450 mg/day, phenobarbital 150 mg/day; several drugs had been tried previously, including valproate, carbamazepine, acetazolamide, barbexaclone, and levetiracetam, with no effect on seizures.

Electroclinical findings in proband

We video-EEG recorded a prolonged seizure cluster lasting several hours and treated with benzodiazepines. The clinical features consisted of a predominant aphasic disorder. More specifically, the evaluation of the main language functions performed during the status epilepticus allowed us to define the ictal language disorder as a sensory or, less frequently, mixed transcortical aphasia (see the Table 1). In addition to dysphasic features, the clinical periictal evaluation documented ideomotor dyspraxic findings consisting of the inability to perform complex motor sequences. An alternating worsening/improving pattern of the dysphasic/dyspraxic features was closely related to the recurrent seizures observed on the EEG. During the periictal state, the patient referred to a “difficulty in speaking” and a right hearing impairment (clinically evaluated by means of the diapason test), probably due to auditory agnosia. The EEG pattern consisted of recurrent seizures consisting of low-voltage fast activity followed by delta activity and rhythmic sharp waves clearly located in the anterior and middle left temporal lobes (phase reversal on F7-T3 channel), followed by propagation to the homolateral centroparietal regions (Fig. 2). Fifty-nine partial seizures were recorded during the 45-min video-EEG session. The status epilepticus was interrupted by the administration of sublingual clonazepam at a dose of 20 mg.

Table 1.   Language functions examined in the proband during the periictal state
 FluencyContentComprehensionRepetitionNamingSpellingReadingAssociated signs
  1. SE, status epilepticus.

Ictal phasePoorPoorPoorMildly impairedPoorPoorPoorNot evaluable
Post-ictal phaseMildly impairedFair goodMildly impairedFair goodFair goodFair goodMildly impairedIdeomotor dyspraxia Auditory agnosia
After SE resolutionGoodGoodGoodGoodGoodGoodGoodNone
image

Figure 2.   Interictal abnormalities well located on the left temporal lobe recorded in the patient during awaking (A) and sleep (B); seizure predominantly involving left temporal lobe with secondary propagation to homolateral centroparietal regions: a well-localized low-voltage fast activity followed by delta activity and rhythmic sharp waves is evident on the anterior and middle temporal lobe (phase reversal on F7-T3 channel) with subsequent involvement of the homolateral centroparietal regions (C); the seizure shown is one of the 59 events recorded in almost 45 min.

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EEG/fMRI data

By using EEG/fMRI, we were able to map the regions underlying the epileptic spikes and study related hemodynamic changes. During the sessions, we recorded a large amount of epileptic activity consisting of spikes, isolated or in brief runs, which were clearly located in the left posterior temporal regions. fMRI analysis showed significant activation clusters in the same regions, which were highly concordant with the interictal and ictal electroclinical features (Fig. 3).

image

Figure 3.   Epileptic activity–related activated areas in electroencephalography/functional magnetic resonance imaging (EEG/fMRI) study. Significant activation clusters in the middle and posterior temporal regions (coordinates −52, −54, −4 in the Montreal Neurological Institute space; middle and superior temporal gyri; Brodmann areas 37, 21, 19, 20, 39) are evident. Statistical parametric maps thresholded at p < 0.05 (corrected for multiple comparisons) are superimposed on a structural image (A) and on a template’s brain surface (B). EEG tracing recorded inside the scanner (after the artifact subtraction) showing the epileptiform activity well located on the left temporal region (C). Technical details. fMRI data were acquired using a clinical 1.5-T magnet Philips Gyroscan (20 axial slices, 5 mm thickness, TR/TE = 3000/50 ms, image matrix 64 × 64; 2 series of 200 temporal dynamics). Simultaneous EEG signal was acquired by means of a digital recording system by Micromed, Italy (EEG recorded using an 18-channel MR-compatible cap, connected to a nonferrous shielded head-box; EEG signals—sampling rate 1024 Hz—transmitted through a fiberoptic cable to a digital recording system; gradient-induced artifact on EEG data digitally removed on-line using a custom-developed software). fMRI data preprocessed and analyzed using the SPM5 software (http://www.fil.ion.ucl.ac.uk/spm, Welcome Department of Cognitive Neurology, London, UK).

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Genetic study

Sequencing of LGI1 exons in the proband III:1 revealed a heterozygous c.367G > A mutation in exon 4 (numbering from the start codon), resulting in a glutamic acid to lysine substitution at position 123 of the protein sequence (Glu123Lys; Fig. 1B). The mutation was present in the affected proband’s mother II:2, but was not found in 125 unrelated healthy controls of Italian ancestry. The Glu123 residue occurs in the third LRR repeat and is conserved in many species, including mouse, rat, chicken, and zebrafish. Replacement of this negatively charged amino acid with the positively charged lysine likely hampers the function of the LRR domain in the mutated protein.

Discussion

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

The ADLTE family we describe, which carries a novel LGI1 mutation, c.367G > A, has several unusual clinical features. The proband had seizures that occurred in a cluster or status epilepticus. This clinical feature allowed us to perform a thorough ictal evaluation using video-EEG recording, which showed not only a dysphasic disorder, already reported in other families (Brodtkorb et al., 2002; Michelucci et al., 2003), but also ideomotor dyspraxic features and an apparent right auditory deficit (probably auditory agnosia). These clinical features, combined with the location of the ictal EEG pattern, point to the involvement of posterior regions of the left lateral temporal cortex. This is in keeping with published data, most of which are based on anamnestic information; few seizures having been recorded in patients affected by ADLTE (Winawer et al., 2002; Brodtkorb et al., 2005a). The study described herein is a rare example of a well-documented electroclinical pattern that may shed light on the ictal characteristics of this specific syndrome.

The EEG/fMRI findings in the proband confirm the crucial role of the posterior temporal neocortex. The involvement of this cortical subregion fits well with the clinical findings, particularly with the dysphasic and dyspraxic features. The hemodynamic changes we describe, which to our knowledge is the first such report in ADLTE, may help to define the epileptogenic anatomofunctional network in this peculiar syndrome. These data are in keeping with anatomic and functional data based on clinical and neurophysiologic (including EEG, long-latency brainstem acoustic evoked potentials (BAEPs)) (Brodtkorb et al., 2005a,b) and diffusion tensor imaging (DTI) MRI studies (Tessa et al., 2007), which show the involvement of the lateral temporal cortex in this condition. From a clinical point of view, this elective topography does not necessarily imply, as confirmed by this family, the occurrence of auditory features, a concept that may influence the nomenclature of the syndrome. Indeed, our findings may, from a terminological point of view, lend further support to the term “ADLTE,” as opposed to the previously used term “autosomal dominant partial features with auditory features” (ADPEAF).”

This family is also interesting on account of the refractoriness of the seizures observed in the proband and her mother, and the high number of related interictal epileptiform abnormalities. High seizure frequency and drug-resistance are not normally associated with this syndrome, which is usually characterised by rare seizures and a good response to antiepileptic treatments (Winawer et al., 2002; Michelucci et al., 2003).

Within the clinical context, another relatively original finding in this family is the seizure semiology of the proband’s mother: the rapid impairment of consciousness not preceded by a specific aura may represent, as has previously been observed, a wider primitive involvement of the temporo–parietal–occipital junction.

The severity of the disorder in the proband and the drug-resistance in both affected members suggest that knowledge of the clinical spectrum of ADLTE is incomplete, that this syndrome may manifest itself through different phenotypes, and that its genetic etiology does not necessarily imply a benign evolution.

LGI1 represents a new class of epilepsy genes because it differs structurally from ion channel genes implicated in other inherited forms of epilepsies. The replacement of the negatively charged Glu123 with a positively charged lysine likely alters the binding properties of the LRR domain and/or interactions between different LRR repeats, thereby affecting the function of the mutated protein. It is not clear why this particular amino acid change is responsible for the unusually more severe phenotype displayed by the proband. The identification of additional LGI1 mutations and characterization of their phenotypic consequences and functional effects may shed light on both the clinical spectrum of ADLTE and normal function of the LGI1 protein and its role in epileptogenesis.

Acknowledgments

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

We thank the patients for their participation, Dr Valter Nucciarelli for technical assistance, and Mr Lewis Baker for his help in editing the manuscript. This work was supported in part by the Genetic Commission of the Italian League Against Epilepsy (specifically, ED received financial support from the same Commission).

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.

References

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

Supporting Information

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

EEG/fMRI procedures and data analysis.

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