Mutations in LGI1 gene in Japanese families with autosomal dominant lateral temporal lobe epilepsy: The first report from Asian families

Autosomal dominant lateral temporal lobe epilepsy (ADLTE) caused by LGI1 (leucine‐rich gene, glioma‐inactivated‐1) mutations is a rare familial epileptic syndrome characterized by the auditory ictal manifestation and rare nocturnal generalized seizures. We have examined the sequence of the LGI1 gene in four Japanese families with lateral temporal lobe epilepsy having characteristic auditory features, and identified one novel (1421G>A), and one reported (1418C>T) point mutation each in two families. These two mutations were 3 bp apart in the LGI1 gene and caused adjoining amino acid substitutions. The two families presented different clinical phenotypes and seizure control to drug treatment. These findings suggest that LGI1 mutations in Japanese ADLTE families may not be uncommon, and that diverse clinical phenotypes make adequate diagnosis of ADLTE difficult when only based on clinical information.     

Autosomal dominant lateral temporal epilepsy: clinical spectrum, new epitempin mutations, and genetic heterogeneity in seven European families

PURPSOE: To describe the clinical and genetic findings of seven additional pedigrees with autosomal dominant lateral temporal epilepsy (ADLTE). METHODS: A personal and family history was obtained from each affected and unaffected member, along with a physical and neurologic examination. Routine and sleep EEGs, computed tomography (CT), or magnetic resonance imaging (MRI) were performed in almost all the patients. DNAs from family members were typed with several microsatellite markers localized on either side of LGI1 at 10q24 and screened for LGI1 mutations. RESULTS: The seven families included a total of 34 affected individuals (10 deceased). The age at onset ranged between 8 and 50 years (average, 22 years). Twenty-six patients had clear-cut focal (elementary, complex, or secondarily generalized) seizures, characterized by prominent auditory auras in 68% of the cases. Less frequent ictal symptoms were visual, psychic, or aphasic seizures, the latter occurring in isolation in one family. The attacks were rare and well controlled by antiepileptic drug treatment but recurred after drug discontinuation. Interictal EEGs were usually unrevealing. MRI or CT scans were negative. Analysis of LGI1/Epitempin exons failed to show mutations in three pedigrees. Linkage analysis strongly suggested exclusion of linkage in one of these families. We found two novel missense mutations, a T-->C substitution in exon 6 at position 598, and a T-->A transition in exon 8 at position 1295, the latter being detected in a family with aphasic seizures. CONCLUSIONS: Our data confirm the inclusion of aphasic seizures within the ADLTE clinical spectrum, suggest the existence of locus heterogeneity in ADLTE, and provide new familial cases with LGI1 missense mutations associated with the disease.     

Autosomal dominant lateral temporal epilepsy: two families with novel mutations in the LGI1 gene

PURPOSE: Mutations in the leucine rich, glioma inactivated gene (LGI1) were recently described in a small number of families with autosomal dominant lateral temporal epilepsy (ADLTE). ADLTE is characterized by partial seizures with symptoms suggestive of a lateral temporal onset, including frequent auditory aura. Here we report the results of clinical and genetic analyses of two newly identified families with ADTLE. METHODS: We identified two families whose seizure semiology was suggestive of ADLTE. Evaluation included a detailed history and neurologic examination, as well as collection of DNA. The coding sequence of the LGI1 gene from affected subjects from both families was analyzed for evidence of mutation. RESULTS: Each patient had a history of partial seizures, often with secondary generalization earlier in the course. Auditory aura was reported by approximately two thirds of affected patients in each pedigree. Novel mutations in LGI1 were detected in both families. A heterozygous single-nucleotide deletion at position 329 (del 329C) was detected in affected individuals from one family, whereas patients from the second family had a nonsynonymous variation, corresponding to C435G. CONCLUSIONS: We identified two novel mutations in the LGI1 gene. The phenotype of these two families was similar to that of other kindreds with ADLTE, as auditory aura was absent in one third of affected individuals. Our results further support that LGI1 mutations should be considered in patients with a history of partial seizures if the semiology of seizures is consistent with the onset in the lateral temporal lobe.     

Diffusion-weighted magnetic resonance imaging in patients with partial status epilepticus

Purpose:   Diffusion-weighted magnetic resonance imaging (DWI) is used to detect changes in the distribution of water molecules in regions affected by various pathologies. Like other conditions, ictal epileptic activity, such as status epilepticus (SE), can cause regional vasogenic/cytotoxic edema that reflects hemodynamic and metabolic changes. This study describes the electroclinical and neuroimaging findings in 10 patients with partial SE whose DWI evaluation disclosed periictal changes related to sustained epileptic activity.
Patients and Methods:   In this retrospective study we selected 10 patients with partial SE of different etiologies (six acute symptomatic SE; four with previous epilepsy and concomitant precipitating factors) who underwent video-EEG (electroencephalography) monitoring and a DWI study during the periictal phase. We analyzed ictal electroclinical features and DWI changes in the acute phase and during the follow-up period.
Results:   DWI images revealed significant signal alterations in different brain regions depending on the location of ictal activity. DWI changes were highly concordant with the electroclinical findings in all 10 patients. As the SE resolved and the clinical conditions improved, DWI follow-up showed that the signal alterations gradually disappeared, thereby documenting their close relationship with ictal activity.
Conclusions:   This study confirms the usefulness of DWI imaging in clinical practice for a more accurate definition of the hemodynamic/metabolic changes occurring during sustained epileptic activity.     

Eyelid fluttering, typical EEG pattern, and impaired intellectual function: A homogeneous epileptic condition among the patients presenting with eyelid myoclonia

Purpose:   This retrospective study aims to review the electroclinical features of patients presenting with eyelid myoclonia (EM) with and without absences.
Methods:   The Italian chapter of the International League Against Epilepsy (ILAE) has been conducting an electroclinical study of patients with EM. Among these, we searched for and selected the patients presenting with both impairment of intellectual functions and a peculiar ictal electroencephalography (EEG) pattern, that is, a discharge of fast generalized polyspikes/polyspikes and waves.
Results:   We found 18 patients matching this electroclinical picture. All the patients were photosensitive. All of them had associated generalized, mostly nocturnal, tonic–clonic seizures. During the evolution, 13 patients presented episodes of EM status. Despite adequate antiepileptic treatment, the patients remained drug resistant for many years or throughout the evolution. The degree of impairment of intellectual functions varied from borderline level to moderate mental retardation.
Discussion:   The patients we described herein can be considered a homogeneous group in the more heterogeneous group of patients presenting with EM. Further clinical and, more probably, genetic studies will clarify whether this condition could be considered a specific and homogeneous condition in the more heterogeneous group of patients presenting with EM.     

Lateral temporal lobe epilepsies: Clinical and genetic features

Lateral temporal epilepsies are still a poorly studied group of conditions, covering lesional and nonlesional cases. Within nonlesional cases, autosomal dominant lateral temporal epilepsy (ADLTE) is a well-defined, albeit rare, condition characterized by onset in adolescence or early adulthood of lateral temporal seizures with prominent auditory auras sometimes triggered by external noises, normal conventional magnetic resonance imaging (MRI), good response to antiepileptic treatment, and overall benign outcome. The same phenotype is shared by sporadic and familial cases with complex inheritance. Mutations in the LGI1 gene are found in about 50% of ADLTE families and 2% of sporadic cases. LGI1 shows no homology with known ion channel genes. Recent findings suggest that LGI1 may exert multiple functions, but it is not known which of them is actually related to lateral temporal epilepsy.     

No evidence for a seriously increased malignancy risk in LGI1-caused epilepsy

The Leucine-rich Glioma Inactivated-1 (LGI1) gene is supposed to be a tumor suppressor gene involved in glial tumors. Mutations in this gene were recently found to cause autosomal dominant lateral temporal lobe epilepsy (ADLTE). We have now analysed the comorbidity in a large Norwegian ADLTE family. No evidence was found that LGI1 is a high-penetrance tumor suppressor gene associated with a serious risk for malignancies in ADLTE families.     

Ictal electroencephalograms in neonatal seizures: characteristics and associations

The characteristics of ictal electroencephalograms in 160 neonatal seizures of 43 babies were correlated with mortality and neurodevelopmental outcomes. Neonatal seizures are focal at onset, most frequently temporal, and often occur during sleep. Twenty-one percent of babies with seizures died, and 76% of survivors manifested neurodevelopmental impairment during 2-6-year follow-up. A low-amplitude ictal electroencephalogram discharge was associated with increased mortality, and a frequency of <2 Hz with increased morbidity. Status epilepticus, ictal fractions, multiple foci, and bihemispheric involvement did not influence outcomes. Of 160 seizures, 99 exhibited no associated clinical features (electrographic seizures). Neonatal seizures with clinical correlates (electroclinical seizures) exhibited a higher amplitude and frequency of ictal electroencephalogram discharge than electrographic seizures. During electroclinical seizures, the ictal electroencephalogram was more likely to involve larger areas of the brain and to cross the midline. Mortality and morbidity were similar in babies with electroclinical and electrographic seizures, emphasizing the need to diagnose and treat both types. Ictal electroencephalogram topography has implications for electrode application during limited-channel, amplitude-integrated electroencephalograms. We recommend temporal and paracentral electrodes. Video electroencephalograms are important in diagnosing neonatal seizures and providing useful information regarding ictal electroencephalogram characteristics.     

Early-Onset Benign Occipital Seizure Susceptibility Syndrome

Summary: Purpose: Childhood epilepsy with occipital paroxysms (CEOP) is characterised by ictal visual hallucinations and occipital epileptiform activity on interictal EEG. A variant has been described with nonvisual symptoms including tonic head and eye deviation, vomiting, and episodes of partial status epilepticus. We fully documented the electroclinical features of such patients to determine whether classification separate from CEOP is justified.
Methods: This was a multicentre study with participating investigators submitting details of patients with idiopathic occipital seizures characterised by ictal head or eye deviation and vomiting.
Results: One hundred thirteen patients were recruited. Seizures began in early childhood (mean, 4.6 years) and occurred infrequently (mean total seizures, 3); 30% of patients had only a single seizure. Two thirds of seizures were nocturnal. Ictal eye deviation occurred in 79%, vomiting in 70%, and head deviation in 35%. Seizures were predominantly complex partial in type. Partial status epilepticus occurred in 44% of patients. Seventy-four percent of patients had occipital interictal EEG epileptiform activity, predominantly right sided, with fixation-off sensitivity. Extraoccipital EEG abnormalities occurred in 35% of patients. Prognosis was excellent: the mean duration of active seizures was 1 year.
Conclusions: Although the two groups shared identical EEG features, the distinct clinical symptoms probably justify separate classification. Early-onset benign occipital seizure syndrome (EBOSS) is suggested as an appropriate name for the variant group.     

A newly discovered LGI1 mutation in Korean family with autosomal dominant lateral temporal lobe epilepsy

PurposeA new leucine-rich glioma-inactivated 1 gene (LGI1) mutation inducing an amino acid sequence substitution was found in a Korean family with autosomal dominant lateral temporal lobe epilepsy (ADLTE). We report the clinical features and characteristics of this newly identified LGI1 mutation.MethodsClinical data were collected from a large ADLTE family. All exons and flanking regions of the LGI1 gene were directly sequenced. 243 healthy controls were screened for the putative mutation. The ‘Sorting Tolerant From Intolerant’ algorithm was employed for the prediction of mutated LGI1 protein stability. LGI1 protein secretion was confirmed in vitro by immunoblotting assay.ResultsThe main clinical characteristics included a young age at onset (mean, 12.4 years), diverse phenotypic manifestations, the occurrence of generalized tonic–clonic seizures, and a favorable prognosis. The genetic analysis detected a nonsynonymous single nucleotide polymorphism of c.137G > T coding for p.C46F in the five affected family members. This variant was not found in the normal control population and one unaffected family member. All the amino acids substituted for cysteine at position 46 of the LGI1 protein were predicted to damage protein stability in in silico analysis. Mutated C46F protein was retained within the cell at the immunoblotting assay.ConclusionWe identified a new LGI1 mutation in a large Korean ADLTE family which appeared to be involved in the development of epilepsy through suppressing LGI1 protein secretion.     

Genetic analysis of the LGI/Epitempin gene family in sporadic and familial lateral temporal lobe epilepsy

Mutations in the LGI1/Epitempin gene cause autosomal dominant lateral temporal lobe epilepsy (ADLTE), a partial epilepsy characterized by the presence of auditory seizures. However, not all the pedigrees with a phenotype consistent with ADLTE show mutations in LGI1/Epitempin, or evidence for linkage to the 10q24 locus. Other authors as well as ourselves have found an internal repeat (EPTP, pfam# PF03736) that allowed the identification of three other genes sharing a sequence and structural similarity with LGI1/Epitempin. In this work, we present the sequencing of these genes in a set of ADLTE families without mutations in both LGI1/Epitempin and sporadic cases. No analyzed polymorphisms modified susceptibility in either the familial or sporadic forms of this partial epilepsy.     

Abnormal phonologic processing in familial lateral temporal lobe epilepsy due to a new LGI1 mutation

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.     

Temporal Lobe Epilepsy in Children: Electroclinical Study of 77 Cases

Summary:  Purpose: Temporal lobe epilepsy (TLE) is probably more difficult to recognize in children than in adults. In fact, ictal symptoms in children are less stereotyped and less obvious, and the neuropathological substrate is more heterogeneous than in adults. The aim of this study is to examine the relationships between etiology, age at onset and electroclinical findings in 77 children with TLE, 32 of whom were surgically treated.
Methods: Electroclinical study including video-EEG recording of seizures in 77 children with TLE. The investigation focused on the first five initial ictal symptoms.
Results: Age at onset was less than 3 years in 39 cases, between 3 and 6 years in 17 cases and older than 6 years in 21 cases. Auras also occurred in younger children but were more common after the age of 6 years. A peculiar initial ictal semiology consisted in staring with arrest, lip cyanosis, and very slight oral automatisms. In some cases, EEG recordings documented seizures starting independently on both temporal lobes. Based on electroclinical and neuroradiological features, we recognized three subgroups: symptomatic TLE due to cortical malformations or nonevolutive tumors, TLE with mesial temporal sclerosis, and cryptogenic TLE.
Conclusions: A correct electroclinical and neuroradiological approach allows in several cases early recognition of TLE even when onset is earlier than the age of 6 years. A correct definition of the localization relies primarily on video-EEG recording of the seizures, possibly repeated during follow up in cases lacking obvious neuroradiological correlation.     

Panayiotopoulos syndrome: a prospective study of 192 patients

OBJECTIVES: To characterize the electroclinical features and evolution of Panayiotopoulos Syndrome (PS). METHODS: Children with electroclinical criteria of PS were prospectively identified and followed-up clinically, and with sleep and awake EEGs between February 1990 and 2006. RESULTS: We identified 192 patients with PS. In the same length of time 398 children with benign childhood epilepsy with centro-temporal spikes (BCECTS) were registered. PS had a peak age at onset of 5 years. Autonomic manifestations were one of the most common ictal event. Ictal deviation of the eyes and progression to generalized convulsions were also quite frequent. Approximately one third had partial status epilepticus. In all patients except five, the seizures occurred during sleep. One-third also had fits while awake. Sixteen children had concomitant symptoms of rolandic epilepsy and eight developed rolandic seizures after remission of PS seizures. Prognosis was excellent. Eighty-four (44.2%) had a single seizure, 79 (41.2%) had 2-5 fits, and 28 (14.6%) had frequent seizures. CONCLUSION: PS is less common than BCECTS, but is well defined and easily recognizable by clinical and EEG features, with autonomic manifestations as one of the most common ictal event.     

Status epilepticus in a patient with fragile X syndrome: electro-clinical features and peri-ictal neuroimaging.

Fragile X syndrome (Fra-X) is a common cause of mental retardation that can be associated with partial epilepsy characterized by a variety of electro-clinical features. A wide spectrum of interictal activities are reported, although no data regarding ictal EEG activity have as yet been published. Drug-resistant seizures are uncommon, and the occurrence of clustering seizures or status epilepticus has only been reported anecdotally. We describe a Fra-X patient with refractory partial epilepsy related to a malformation of cortical development who experienced a partial status epilepticus that was well documented by video-EEG and MRI. We report the electro-clinical features and peri-ictal neuroimaging data.     

Ictal vocalizations occur more often in temporal lobe epilepsy with dominant (left-sided) epileptogenic zone

Objective:   To investigate the lateralization value of ictal vocalizations in temporal lobe epilepsy (TLE).
Methods:   We reviewed video-recordings of 97 patients who had undergone presurgical evaluation programs with video-EEG (electroencephalography)–recorded complex partial seizures (CPS) and high-resolution magnetic resonance imaging (MRI). All patients had surgery due to TLE and became seizure-free. In 57 patients, determination of speech dominance was necessary by using Wada tests or functional MRI (fMRI). To reevaluate the archived seizures, we reviewed one to three consecutively recorded CPS of each patient. Altogether 223 archived seizures were analyzed. Ictal vocalization was considered to be present in a particular patient if it occurred in at least one of the recorded seizures.
Results:   Ictal vocalizations occurred in 22 patients. They occurred in 37% of left-sided and in 11% of right-sided patients with TLE (p = 0.003). In patients with determined speech lateralization, ictal vocalizations occurred in 37% of the dominant and in 14% in patients with nondominant epileptogenic zone (p = 0.04). In patients with ictal vocalizations, epilepsy began at age 8.7 ± 6, whereas in the remaining patients, epilepsy started at age 14.0 ± 9 (p = 0.017). Logistic regression showed that both hemispheric dominance and age at onset were independently associated with pure ictal vocalization (PIV).
Conclusions:   Ictal vocalization is a frequent phenomenon, occurring in 23% of patients with TLE. It is more often associated with left-sided and early onset TLE. Our results may improve the lateralization of the epileptogenic zone and suggest that nonspeech vocalizations in humans are related to the dominant (left-sided) hemisphere. Our study is a further argument that there are different subtypes of TLE depending on the age at onset.     

Autosomal dominant lateral temporal epilepsy: absence of mutations in ADAM22 and Kv1 channel genes encoding LGI1-associated proteins

Mutations in the LGI1 gene are linked to autosomal dominant lateral temporal epilepsy (ADTLE) in about half of the families tested, suggesting that ADLTE is genetically heterogeneous. Recently, the Lgi1 protein has been found associated with different protein complexes and two distinct molecular mechanisms possibly underlying ADLTE have been hypothesized: the one recognizes Lgi1 as a novel subunit of the presynaptic Kv1 potassium channel implicated in the regulation of channel inactivation, the other suggests that Lgi1 acts as a ligand that selectively binds to the postsynaptic receptor ADAM22, thereby regulating the glutamate-AMPA neurotransmission. Both mechanisms imply that LGI1 mutations result in alteration of synaptic currents, though of different types. Since their protein products have been found associated with Lgi1, the Kv1 channel subunit genes KCNA1, KCNA4, and KCNAB1 and ADAM22 can be considered strong candidates for ADLTE. We sequenced their coding exons and flanking splice sites in the probands of 9 carefully ascertained ADLTE families negative for LGI1 mutations. We failed to detect any mutation segregating with the disease, but identified several previously unreported polymorphisms. An association study of four non-synonymous variants (three found in ADAM22, one in KCNA4) in a population of 104 non-familial lateral temporal epilepsy cases did not show any modification of susceptibility to this disorder. Altogether, our results suggest that neither ADAM22 nor any of the three Kv1 channel genes are major causative genes for ADLTE.     

Beta activity in status epilepticus

Focal beta activity on scalp EEG is a rare seizure pattern that has most extensively been studied in patients undergoing evaluation for epilepsy surgery. However, ictal beta activity is uncommon beyond this population and has not been reported in human status epilepticus. We observed ictal focal beta activity as the predominant seizure pattern in a patient with refractory status epilepticus. Continuous left temporal beta activity clinically correlated with complex partial semiology on video-EEG.     

Effects of thyrotropin-releasing hormone (TRH) on status epilepticus in rats

Recent studies have demonstrated that intramuscular administration of thyrotropin-releasing hormone (TRH) or its analogue improves various clinical aspects of intractable epilepsy such as Lennox-Gastaut syndrome, West syndrome, and myoclonus epilepsy. Other clinical studies reported efficient property of intravenous TRH against status epilepticus. However, it is also true that intravenous TRH produces epileptic seizures in patients with epilepsy or organic brain damage. Thus, the utility of intravenous TRH for the treatment of status epilepticus seems to be equivocal. To further explore the problem in this regard, we examined the effect of TRH on limbic status epilepticus in rats. Thirty-eight male Wistar rats weighing 180-220g were used. Status epilepticus was induced by intracerebral injection of a combination of 200 micrograms of dibutyryl-cAMP (db-cAMP) and 67.2ng of ethylenediaminetetraacetic acid (EDTA) into the amygdala (AM) through an implanted cannula. 30 min later, TRH or vehicle (distilled water) was administered intravenously (i.v.) or intracerebroventricularly (i.c.v.). Although 3 mg/kg of TRH (n = 9), when injected i.v., did not alter the pattern of electroclinical ictal responses induced by db-cAMP/EDTA, 25 mg/kg (n = 5) and 50 mg/kg (n = 5) of TRH significantly exaggerated EEG and/or behavioral ictal seizures, beginning immediately after the injection and lasting for more than 30 min. With 50 mg/kg of TRH, the exaggerated seizure patterns were followed by marked suppression of electroclinical seizures. 50 micrograms of i.c.v. TRH (n = 5), like higher doses of i.v. TRH, caused a slight, but not a significant, build up of electroclinical ictal seizures, beginning immediately after the injection and lasting for about 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mutation analysis of the leucine-rich, glioma inactivated 1 gene (LGI1) in Japanese febrile seizure patients

Mutations in the leucine-rich, glioma inactivated 1 gene (LGI1) were recently identified in some families with autosomal dominant lateral temporal epilepsy (ADLTE). To investigate whether the LGI1 gene is a susceptibility gene for febrile seizures (FS), we performed a systematic search for mutations in 94 unrelated Japanese patients with FS. We detected two intronic polymorphisms (IVS2 + 19 A/G and IVS6 - 18 T/C). No non-synonymous mutation was detected. We genotyped these polymorphisms and performed a case-control study and transmission disequilibrium testing (TDT) of 62 FS families (n = 230) and 105 control subjects. None of the polymorphisms was significantly associated with FS. Our results indicate that genomic variations in the LGI1 gene are not likely to be substantially involved in the etiology of FS in the Japanese population.