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.     

Autosomal dominant partial epilepsy with auditory features: description of a new family

PURPOSE: To report the clinical and genetic study of a new family with autosomal dominant partial epilepsy with auditory features (ADPEAF). METHODS: All the living affected members underwent a full clinical, neurophysiological, and magnetic resonance imaging (MRI) study. Genetic analysis was performed by typing their DNA with seven microsatellite markers previously found to cosegregate with ADPEAF on chromosome 10q24. RESULTS: The three living affected members had a childhood onset of rare and drug-responsive tonic-clonic seizures constantly preceded by a humming sensation. Routine and sleep electroencephalograms revealed rare and inconstant focal abnormalities over both temporal regions. MRI detected atrophy with increased T2 signal in the subcortical lateral portion of the right temporal lobe in one case. Analysis of 10q24 polymorphic alleles showed the same haplotype in all three affected members but different alleles in unaffected individuals. CONCLUSIONS: ADPEAF is a distinct condition with homogeneous clinical features. Genetic findings are consistent with linkage of ADPEAF to chromosome 10q24.     

Familial temporal lobe epilepsy with aphasic seizures and linkage to chromosome 10q22-q24

PURPOSE: To describe the phenotypic expression of a new family with familial lateral temporal lobe epilepsy with aphasic seizures, and to compare the findings with the clinical features of previously reported families linked to chromosome 10q22-q24. METHODS: Medical records were collected from 12 living affected members. The patients underwent a personal interview and a clinical neurologic examination. Results from interictal scalp EEGs and neuroimaging examinations were obtained. RESULTS: The cardinal ictal symptom was a brief sensory aphasia in eight of the patients. In four, this was accompanied by auditory symptoms, usually in the form of monotonous unformed sounds. Simple partial seizures with psychic or somatosensory seizures also were present. Visual ictal symptoms and complex partial seizures were absent. All patients had generalized tonic-clonic seizures. Magnetic resonance imaging (MRI) or computed tomography (CT) did not reveal morphologic correlates. Improvement with age seemed to occur in many patients. Significant linkage to chromosome 10q22-q24 was established by testing 17 polymorphic microsatellite markers. CONCLUSIONS: The epilepsy of this family appears to represent a variety of autosomal dominant lateral temporal lobe epilepsy. Aphasic seizures and a peculiar seizure-precipitating effect of the activation of speech (initiation or perception) may serve as markers for identifying further families with this phenotype.     

Partial and generalized epilepsy with febrile seizures plus and a novel SCN1A mutation.

BACKGROUND: Generalized epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant syndrome characterized by febrile seizures (FS) and a variety of afebrile generalized seizure types. GEFS+ has previously been linked to mutations in two genes encoding the voltage-gated sodium channel alpha-subunit (SCN1A) and beta1-subunit (SCN1B). We studied a large family with FS and partial as well as generalized seizure types. METHODS: All but two living affected family members were interviewed and examined. Information on deceased affected family members was sought. EEG for 11 affected family members and one unaffected family member were obtained. Genetic linkage analysis and mutation screening of SCN1A were performed on blood samples from 16 affected individuals and their first-degree relatives. RESULTS: There were 27 affected family members; 18 were alive at the time of the study. All affected family members had FS; seven had FS only, and 19 also had afebrile seizures. Eleven individuals continued to have FS beyond 6 years of age. FS were complex in 12 family members, usually with prolonged duration. The index patient had right temporal lobe epilepsy and hippocampal sclerosis. Four other patients had strong historical evidence of temporal lobe epilepsy, and three others had nonlocalizing evidence of partial epilepsy. Pedigree analysis indicated autosomal dominant transmission. All affected individuals who were tested and one asymptomatic individual had a sodium channel mutation of SCN1A, an A-->C transversion at nucleotide 3809 resulting in the substitution of lysine 1270 by threonine in the D3/S2 segment (designated as K1270T). CONCLUSIONS: Our findings indicate that partial epilepsy preceded by FS can be associated with sodium channel mutations and may represent a variant of GEFS+.     

Electroclinical features of a family with simple febrile seizures and temporal lobe epilepsy associated with SCN1A loss-of-function mutation

PURPOSE: To report in detail the electroclinical features of a large family in which we recently identified a missense mutation (M145T) of a well-conserved amino acid in the first transmembrane segment of domain I of the human SCN1A. We showed that the mutation is associated with a loss of SCN1A function. METHODS: The family originates from southern Italy and contains 35 members spread over four generations. Of the 14 affected individuals, the 13 still living members (7 males, mean age 36.6 +/- 20.4) underwent a complete electroclinical evaluation. RESULTS: All 13 affected family members had febrile seizures (FS) up to the age of 6 years. Age at onset of FS ranged from 5 to 45 months with a mean age of 12.8 +/- 12.9 months. One of the 13 was affected by post-traumatic epilepsy. Three of the 13 later developed temporal lobe epilepsy (TLE) with both simple focal seizures, and also very rare focal complex or nocturnal secondary generalized tonic-clonic seizures. In two of the three patients who later developed TLE, the MRI studies revealed mesial temporal sclerosis. CONCLUSIONS: Our findings illustrate that SCN1A mutations can cause simple FS associated with TLE, which differ from the characteristic clinical spectrum of GEFS+. It is open to conjecture if this unusual phenotype might at least in part be related to the fact that M145T is the first missense mutation found in DIS1 of SCN1A.     

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.     

Low penetrance and effect on protein secretion of LGI1 mutations causing autosomal dominant lateral temporal epilepsy

Purpose: To describe the clinical and genetic findings of four families with autosomal dominant lateral temporal epilepsy. Methods: A personal and family history was obtained from each affected and unaffected subject along with a physical and neurologic examination. Routine electroencephalography and magnetic resonance imaging (MRI) studies were performed in almost all patients. DNAs from family members were screened for LGI1 mutations. The effects of mutations on Lgi1 protein secretion were determined in transfected culture cells. Key Findings: The four families included a total of 11 patients (two deceased), six of whom had lateral temporal epilepsy with auditory aura. Age at onset was in the second decade of life; seizures were well controlled by antiepileptic treatment and MRI studies were normal. We found two pathogenic LGI1 mutations with uncommonly low penetrance: the R136W mutation, previously detected in a sporadic case with telephone‐induced partial seizures, gave rise to the epileptic phenotype in three of nine mutation carriers in one family; the novel C179R mutation caused epilepsy in an isolated patient from a family where the mutation segregated. Another novel pathogenic mutation, I122T, and a nonsynonymous variant, I359V, were found in the two other families. Protein secretion tests showed that the R136W and I122T mutations inhibited secretion of the mutant proteins, whereas I359V had no effect on protein secretion; C179R was not tested, because of its predictable effect on protein folding. Significance: These findings suggest that some LGI1 mutations may have a weak penetrance in families with complex inheritance pattern, or isolated patients, and that the protein secretion test, together with other predictive criteria, may help recognize pathogenic LGI1 mutations.     

LGI1 is mutated in familial temporal lobe epilepsy characterized by aphasic seizures

Autosomal dominant lateral temporal lobe epilepsy previously has been linked to chromosome 10q22-q24, and recently mutations in the LGI1 gene (Leucine-rich gene, Glioma Inactivated) have been found in some autosomal dominant lateral temporal lobe epilepsy families. We have now identified a missense mutation affecting a conserved cysteine residue in the extracellular region of the LGI1 protein. The C46R mutation is associated with autosomal dominant lateral temporal lobe epilepsy in a large Norwegian family showing unusual clinical features like short-lasting sensory aphasia and auditory symptoms.     

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.     

Idiopathic familial temporal lobe epilepsy with febrile convulsions.

Efforts to duplicate the genetic and molecular breakthroughs of autosomal dominant frontal lobe epilepsy have lead to increased interest in familial temporal lobe epilepsy. In this report we describe three kindreds. The epilepsy syndrome described manifests after the teenage years and was generally mild and treatment responsive. The predominant seizure types were simple and complex partial seizures, typical of mesial temporal onset. Some family members had febrile convulsions only and others had epilepsy without preceding febrile convulsions. Three patients had both febrile convulsions and temporal lobe epilepsy. High-resolution quantitative and qualitative MRI was normal. The syndrome in these three kindreds is distinct from temporal lobe epilepsy due to mesial temporal sclerosis and febrile convulsions and is probably a form of idiopathic localization related epilepsy. Its relation to other familial temporal lobe epilepsy phenotypes is discussed.