The clinical characters and gene detection in a familial temporal lobe epilepsy with auditory aura

Auditory aura was the very important clinical character in familial temporal Lobe epilepsy. LGI1 was the main pathogenic gene. The inheritance mode of this disease was autosomal dominant. We describes the clinical characters and gene detection in 7 patients in a temporal lobe epilepsy family with auditory aura. All patients in this family were diagnosed as temporal lobe epilepsy and had the same mutation: the splice site mutation in No. 2 base of the intron after the first exon in gene LGI1, c.215+2T>A, which induced the abnormal expression of peptide protein after the No. 71 amino acid encoded by LGI1. Some of the antiepileptic drugs, such as carbamazepine, oxcarbazepine, could be effective.     

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.     

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.     

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.     

Epilepsy gene LGI1 regulates postnatal developmental remodeling of retinogeniculate synapses

Retinogeniculate connections undergo postnatal refinement in the developing visual system. Here we report that non-ion channel epilepsy gene LGI1 (leucine-rich glioma-inactivated), mutated in human autosomal dominant lateral temporal lobe epilepsy (ADLTE), regulates postnatal pruning of retinal axons in visual relay thalamus. By introducing an ADLTE-associated truncated mutant LGI1 (836delC) or excess full-length LGI1 into transgenic mice, we found that mutant LGI1 blocks, whereas excess LGI1 accelerates, retinogeniculate axon pruning. The normal postnatal single fiber strengthening was arrested by mutant LGI1 and, contrastingly, was enhanced by excess wild-type LGI1. The maximum response of the retinogeniculate synapses, conversely, remained the same in mature LGI1 transgenic mice, indicating that mutant LGI1 blocks, whereas excess wild-type LGI1 promotes, weak axon fiber elimination. Heterozygous deletion of the LGI1 gene, as found in ADLTE patients, inhibited postnatal retinogeniculate synapse elimination, an effect similar to the ADLTE truncated mutant LGI1. The results identify sensory axon remodeling defects in a sensory aura-associated human epilepsy disorder.     

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.     

LGI1: a gene involved in epileptogenesis and glioma progression?

The leucine-rich, glioma inactivated gene 1 (LGI1) gene on human chromosome 10q24 was first identified as a candidate tumor suppressor gene for glioma. Surprisingly, mutations in LGI1 were also shown to cause an idiopathic epilepsy syndrome, autosomal dominant lateral temporal lobe epilepsy (ADLTE). LGI1 is one of the only two currently known non-ion channel genes whose mutations cause idiopathic epilepsy in humans. In this review we summarize the current data on structure and function of the LGI1 protein and discuss clinical aspects of ADLTE and their correlation with LGI1. We also propose that the evidence supporting the tumor suppressor role of LGI1 in malignant gliomas is weak and that further work is necessary to establish LGI1 role in glial cells.     

LGI1 gene mutation screening in sporadic partial epilepsy with auditory features

Abstract Partial epilepsy with auditory features occasionally segregates in families as an autosomal dominant trait. In some families mutations in the leucine-rich glioma inactivated (LGI1) gene have been identified. Sporadic cases might harbour either denovo or low-penetrant LGI1 mutations, which will substantially alter the family risk for epilepsy.We selected sixteen sporadic patients with cryptogenic temporal lobe epilepsy and partial seizures with auditory features. We compared clinical features of these patients with those of published autosomal dominant family cases. We screened these patients for LGI1 mutations.Comparing the sporadic patients with the published familial cases no difference in either the primary auditory features or in the other associated epileptic manifestations was identified. Sequence analysis of the whole LGI1 gene coding regions in sporadic patients did not reveal changes in the LGI1 gene.The genetic analysis demonstrates that LGI1 is not a major gene for sporadic cases of partial epilepsy with auditory features at least in the Italian population. Screening of sporadic patients for LGI1 mutations appears not useful in genetic counselling of these patients.     

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.     

Leucine-rich glioma inactivated 1 (Lgi1), an epilepsy-related secreted protein, has a nuclear localization signal and localizes to both the cytoplasm and the nucleus of the caudal ganglionic eminence neurons

Leucine-rich glioma inactivated 1 (Lgi1) is a secreted synaptic protein that organizes a transsynaptic protein complex throughout the brain. Mutations in the Lgi1 gene have been found in patients with autosomal dominant lateral temporal lobe epilepsy (ADLTE). Although a large number of studies have focused on the expression and function of Lgi1 in the postnatal brain, information regarding its functions and distribution during development remains sparse. Here we report that Lgi1 mRNA is preferentially expressed in the caudal ganglionic eminence (CGE) of the early embryonic telencephalon, and LGI1 protein is unexpectedly localized in the nucleus of dissociated CGE neurons. Using bioinformatics analysis, we found that LGI1 contains a putative nuclear localization signal (NLS) in its leucine-rich repeat C-terminal domain. Furthermore, we show that the transient expression of Lgi1 in CGE neurons resulted in nuclear translocation of the LGI1 protein, and a mutation in the NLS led to the retention of LGI1 in the cytoplasm. We also confirmed that the NLS sequence of LGI1 had the ability to mediate the nuclear localization by using the NLS-containing fusion protein. Interestingly, when Lgi1 was expressed in neurons obtained from the medial ganglionic eminence or cerebral cortex, almost no nuclear localization of LGI1 was observed. These results raise the possibility of a novel role of Lgi1 within embryonic neurons through nuclear translocation and may provide insight into its potential effects on the development of the central nervous system and ADLTE pathogenesis.     

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.     

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.     

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.     

Absence of mutations in the LGI1 receptor ADAM22 gene in autosomal dominant lateral temporal epilepsy

Mutations in the LGI1 (leucine-rich, glioma inactivated 1) gene are found in less than a half of the families with autosomal dominant lateral temporal epilepsy (ADLTE), suggesting that ADLTE is a genetically heterogeneous disorder. Recently, it was shown that LGI1 is released by neurons and becomes part of a protein complex at the neuronal postsynaptic density where it is implicated in the regulation of glutamate-AMPA neurotransmission. Within this complex, LGI1 binds selectively to a neuronal specific membrane protein, ADAM22 (a disintegrin and metalloprotease). Since ADAM22 serves as a neuronal receptor for LGI1, the ADAM22 gene was considered a good candidate gene for ADLTE. We have therefore sequenced all coding exons and exon-intron flanking sites in the ADAM22 gene in the probands of 18 ADLTE families negative for LGI1 mutations. Although, we identified several synonymous and non-synonymous polymorphisms, we failed to identify disease-causing mutations, indicating that ADAM22 gene is probably not a major gene for this epilepsy syndrome.     

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.     

A family with autosomal dominant temporal lobe epilepsy accompanied by motor and sensory neuropathy]

We report a 20-year-old man with temporal lobe epilepsy (TLE) accompanied by hereditary motor and sensory neuropathy (HMSN). He had experienced complex partial seizures (CPS), which started with a nausea-like feeling, followed by loss of consciousness and automatism, since he was 6 years old. The frequency of attacks was at first decreased by phenytoin. However, attacks increased again when he was 18 years old. On admission, neurological examination showed mild weakness of the toes, pes cavus, hammer toe and mildly impaired vibratory sensation in his legs. Ten people in four generations of his family showed a history of epilepsy in the autosomal dominant inheritance form. His younger sister and mother had a history of epilepsy accompanied with pes cavus, hammer toe, weakness of toe and finger extension and mildly impaired vibratory sensation as well. Direct sequencing of the glioma-inactivated leucine-rich gene (LGI1), in which several mutations were reported in patients with familial lateral temporal lobe epilepsy, showed no specific mutation in this family. On consecutive video-EEG monitoring, paroxysmal rhythmic activity was confirmed in his left fronto-temporal region when he showed automatism, and then a generalized slow burst activity was detected when he lost consciousness. For his seizures, TLE with secondary generalization was diagnosed. In the nerve conduction study, delayed nerve conduction, distal motor latency and decreased amplitudes of the compound muscle action potentials (CMAP) of bilateral peroneal nerves were observed, indicating the existence of mild axonal degeneration. Based on these data, we consider that this family to be a new phenotype of autosomal dominant TLE accompanied by motor and sensory neuropathy.     

Asymmetry of long-latency auditory evoked potentials in LGI1-related autosomal dominant lateral temporal lobe epilepsy

PURPOSE: To investigate auditory processing with cortical long-latency auditory evoked potentials (AEPs) in patients with autosomal dominant lateral temporal lobe epilepsy (ADTLE). METHODS: Eight patients with LGI1-related ADTLE belonging to a family with predominantly aphasic seizures were studied. Sixty-five individuals without epilepsy served as controls. AEPs (N1-P2 amplitudes) to binaural tones were recorded over the left and the right hemispheres. Brainstem auditory evoked potentials (BAEPs) to monaural rarefaction clicks also were analyzed. Group differences were statistically assessed with Student's t test and repeated-measures analysis of variance. RESULTS: Left N1-P2 AEP amplitudes were moderately reduced in ADTLE patients (p = 0.005). No group differences in BAEP were found, indicating unaffected cochlear system and auditory brainstem pathways. CONCLUSIONS: A moderate, but highly significant reduction in N1-P2 AEP amplitudes over the left hemisphere was demonstrated in patients with ADTLE. This finding corresponds to the cardinal symptom of aphasia in this family, and also to the generally prevailing left-sided EEG abnormalities in this condition. The background for this electrophysiologic lateralization in LGI1-related epilepsy is unknown. It may be related to a specific function of LGI1 in the dominant hemisphere.     

Genetics of the epilepsies

PURPOSE OF REVIEW: This article reviews the most significant advances in the field of genetics of the epilepsies during the past year, with emphasis on newly identified genes and functional studies leading to new insights into the pathophysiology of epilepsy. RECENT FINDINGS: Mutations in the chloride channel gene CLCN2 have been associated with the most common forms of idiopathic generalized epilepsies. A mutation in the ATP1A2 sodium potassium ATPase pump gene has been described in a family in which familial hemiplegic migraine and benign familial infantile convulsions partly co-segregate. The leucine-rich, glioma-inactivated 1 gene (LGI1) (also known as epitempin) was found to be responsible for autosomal-dominant lateral temporal lobe epilepsy in additional families. The serine-threonine kinase 9 gene (STK9) was identified as the second gene associated with X-linked infantile spasms. Mutations in the Aristaless-related homeobox gene (ARX) have been recognized as a cause of X-linked infantile spasms and sporadic cryptogenic infantile spasms. A second gene underlying progressive myoclonus epilepsy of Lafora, NHLRC1, was shown to code for a putative E3 ubiquitin ligase. SUMMARY: Genes associated with idiopathic generalized epilepsies remain within the ion channel family. Mutations in non-ion channel genes are responsible for autosomal-dominant lateral temporal lobe epilepsy, a form of idiopathic focal epilepsy, malformations of cortical development, and syndromes that combine X-linked mental retardation and epilepsy. Most genetic epilepsies have a complex mode of inheritance, and genes identified so far account only for a minority of families and sporadic cases. Functional studies are leading to a better understanding of the mechanisms underlying hyperexcitability and seizures.     

Drug resistant ADLTE and recurrent partial status epilepticus with dysphasic features in a family with a novel LGI1mutation: electroclinical, genetic, and EEG/fMRI findings

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.