LGI1 mutations in temporal lobe epilepsies

Epilepsy Research Institute and Department of Medicine, University of Melbourne, Victoria, Australia.
Neurology (Impact Factor: 8.29). 04/2004; 62(7):1115-9. DOI: 10.1212/01.WNL.0000118213.94650.81
Source: PubMed


A number of familial temporal lobe epilepsies (TLE) have been recently recognized. Mutations in LGI1 (leucine-rich, glioma-inactivated 1 gene) have been found in a few families with the syndrome of autosomal dominant partial epilepsy with auditory features (ADPEAF). The authors aimed to determine the spectrum of TLE phenotypes with LGI1 mutations, to study the frequency of mutations in ADPEAF, and to examine the role of LGI1 paralogs in ADPEAF without LGI1 mutations.
The authors performed a clinical and molecular analysis on 75 pedigrees comprising 54 with a variety of familial epilepsies associated with TLE and 21 sporadic TLE cases. All were studied for mutations in LGI1. ADPEAF families negative for LGI1 mutations were screened for mutations in LGI2, LGI3, and LGI4.
Four families had ADPEAF, 22 had mesial TLE, 11 had TLE with febrile seizures, two had TLE with developmental abnormalities, and 15 had various other TLE syndromes. LGI1 mutations were found in two of four ADPEAF families, but in none of the other 50 families nor in the 21 individuals with sporadic TLE. The mutations were novel missense mutations in exons 1 (c.124T-->G; C42G) and 8 (c.1418C-->T; S473L). No mutations in LGI2, LGI3, or LGI4 were found in the other two ADPEAF families.
In TLE, mutations in LGI1 are specific for ADPEAF but do not occur in all families. ADPEAF is genetically heterogeneous, but mutations in LGI2, LGI3, or LGI4 did not account for families without LGI1 mutations.

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    • "The causal gene was initially mapped to chromosome 10q [4] [5] [6] [7], then identified by two groups [8] [9]. To date, mutations in the leucinerich glioma-inactivated 1 (LGI1) gene have been found in about 50% of families with ADLTE [10] [11] [12]. Attention-deficit/hyperactivity disorder (ADHD) is more frequent in children with epilepsy than in the general pediatric population. "
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    ABSTRACT: Autosomal dominant lateral temporal lobe epilepsy (ADLTE) is characterized by focal seizures with auditory features or aphasia. Mutations in the leucine-rich glioma-inactivated 1 (LGI1) gene have been reported in up to 50% of families with ADLTE. Attention-deficit/hyperactivity disorder (ADHD) symptoms have not yet been reported in these families. Clinical data were collected from a family with five affected members. Leucine-rich glioma-inactivated 1 exons and boundaries were sequenced by standard methods. Attention-deficit/hyperactivity disorder symptoms were scored based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. Affected members had seizures with auditory features and psychic auras, and some experienced nightmares. A heterozygous c.431+1G>A substitution in LGI1 was detected in all members. Significantly more hyperactivity symptoms were found in family members carrying the LGI1 mutation. This study expands the phenotypic spectrum associated with ADLTE due to LGI1 mutation and underlines the need for more systematic evaluation of ADHD and related symptoms.
    Epilepsy & Behavior 05/2013; 28(1):41-46. DOI:10.1016/j.yebeh.2013.03.032 · 2.26 Impact Factor
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    • "Numerous additional LGI1 mutations resulting in either protein truncation or single amino acid substitutions have been reported subsequently (see Ottman et al. 2004), including a de novo mutation (Bisulli et al. 2004). Overall, LGI1 mutations have been found in about 50% of ADLTE families (Michelucci et al. 2003; Berkovic et al. 2004; Ottman et al. 2004). LGI1, which has been renamed Epitempin, is mostly expressed in the brain (Chernova et al. 1998). "
    Dataset: J NEUROCHEM

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    • "Hippocampal sclerosis was not an exclusion criterion though hippocampal sclerosis was not seen in this series. Third, no identified genetic cause [such as mutation in LGI1 (Berkovic et al., 2004a) or sodium channel beta-1 subunit gene (SCN1B; Scheffer et al., 2007)] has been found. Diagnosis of temporal lobe epilepsy was made on clinical and electrographic grounds. "
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    ABSTRACT: Temporal lobe epilepsy is the commonest partial epilepsy of adulthood. Although generally perceived as an acquired disorder, several forms of familial temporal lobe epilepsy, with mesial or lateral seizure semiology, have been described. Descriptions of familial mesial temporal lobe epilepsy have varied widely from a benign epilepsy syndrome with prominent déjà vu and without antecedent febrile seizures or magnetic resonance imaging abnormalities, to heterogeneous, but generally more refractory epilepsies, often with a history of febrile seizures and with frequent hippocampal atrophy and high T₂ signal on magnetic resonance imaging. Compelling evidence of a genetic aetiology (rather than chance aggregation) in familial mesial temporal lobe epilepsy has come from twin studies. Dominant inheritance has been reported in two large families, though the usual mode of inheritance is not known. Here, we describe clinical and neurophysiological features of 20 new mesial temporal lobe epilepsy families including 51 affected individuals. The epilepsies in these families were generally benign, and febrile seizure history was infrequent (9.8%). No evidence of hippocampal sclerosis or dysplasia was present on brain imaging. A single individual underwent anterior temporal lobectomy, with subsequent seizure freedom and histopathological evidence of hippocampal sclerosis was not found. Inheritance patterns in probands' relatives were analysed in these families, together with 19 other temporal lobe epilepsy families previously reported by us. Observed frequencies of epilepsies in relatives were lower than predicted by dominant Mendelian models, while only a minority (8/39) of families could be compatible with recessive inheritance. These findings strongly suggest that complex inheritance, similar to that widely accepted in the idiopathic generalized epilepsies, is the usual mode of inheritance in familial mesial temporal lobe epilepsy. This disorder, which appears to be relatively common, and not typically associated with hippocampal sclerosis, is an appropriate target for contemporary approaches to complex disorders such as genome-wide association studies for common genetic variants or deep sequencing for rare variants.
    Brain 11/2010; 133(11):3221-31. DOI:10.1093/brain/awq251 · 9.20 Impact Factor
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