A de novo LGI1 mutation causing idiopathic partial epilepsy with telephone-induced seizures

University of Naples Federico II, Napoli, Campania, Italy
Neurology (Impact Factor: 8.29). 07/2007; 68(24):2150-1. DOI: 10.1212/01.wnl.0000264932.44153.3c
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    • "In some patients, seizures are induced by acoustic stimuli such as sudden noises or answering the phone (Winawer et al., 2000; Michelucci et al., 2003, 2007), indicating a lateral temporal lobe onset. Some MRI studies have reported developmental abnormalities in the left Abbreviations: ADLTE, autosomal dominant lateral temporal lobe epilepsy; AGS, audiogenic seizures; EEG, electroencephalography; ENU, N-ethyl-N-nitrosourea; GTCS, generalized tonic–clonic seizures; IR, immunoreactivity; Lgi1, leucine-rich, glioma inactivated 1. * Corresponding author at: Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. "
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    ABSTRACT: Mutations in the leucine-rich, glioma inactivated 1 (LGI1) gene have been identified in patients with autosomal dominant lateral temporal lobe epilepsy (ADLTE). We previously reported that Lgi1 mutant rats, carrying a missense mutation (L385R) generated by gene-driven N-ethyl-N-nitrosourea (ENU) mutagenesis, showed generalized tonic-clonic seizures (GTCS) in response to acoustic stimuli. In the present study, we assessed clinically-relevant features of Lgi1 heterozygous mutant rats (Lgi1(L385R/+)) as an animal model of ADLTE. First, to explore the focus of the audiogenic seizures, we performed electroencephalography (EEG) and brain Fos immunohistochemistry in Lgi1(L385R/+) and wild type rats. EEG showed unique seizure patterns (e.g., bilateral rhythmic spikes) in Lgi1(L385R/+) rats with GTCS. An elevated level of Fos expression indicated greater neural excitability to acoustic stimuli in Lgi1(L385R/+) rats, especially in the temporal lobe, thalamus and subthalamic nucleus. Finally, microarray analysis revealed a number of differentially expressed genes that may be involved in epilepsy. These results suggest that Lgi1(L385R/+) rats are useful as an animal model of human ADLTE.
    Neuroscience Research 01/2014; 80(1). DOI:10.1016/j.neures.2013.12.008 · 1.94 Impact Factor
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    • "Interestingly, 50% of ADLTE families did not show any LGI1 mutations [12]. Moreover, de novo LGI1 mutations in unrelated sporadic TLE cases with auditory features, also called idiopathic partial epilepsy with auditory features (IPEAF) [13], account for about 2% of cases only [14]. A recent study, evaluating LGI1 promoter, prodynorphin (PDYN), and GABA (B) receptor 1 (GABBR1) genes in 104 sporadic IPEAF, did not show any statistically significant differences between patients and controls [15] "
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    ABSTRACT: Temporal lobe epilepsy (TLE) is usually regarded as a polygenic and complex disorder. To understand its genetic component, numerous linkage analyses of familial forms and association studies of cases versus controls have been conducted since the middle of the nineties. The present paper lists genetic findings for TLE from the initial segregation analysis to the most recent results published in May 2011. To date, no genes have been clearly related to TLE despite many efforts to do so. However, it is vital to continue replication studies and collaborative attempts to find significant results and thus determine which gene variant combination plays a definitive role in the aetiology of TLE.
    02/2012; 2012(2090-1348):863702. DOI:10.1155/2012/863702
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    • "The LGI1 R136W mutation that segregates in family D is not novel. It was previously reported to occur de novo in a sporadic case of telephone-induced partial epilepsy with typical lateral temporal lobe semiology (Michelucci et al., 2007). Because it causes seizures without any triggering factors in this family, the R136W mutation seems to be responsible for the lateral temporal semiology rather than the pathophysiologic mechanisms underlying the reflex nature of telephone-induced seizures. "
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    ABSTRACT: To describe the clinical and genetic findings of four families with autosomal dominant lateral temporal epilepsy. 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. 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. 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.
    Epilepsia 04/2011; 52(7):1258-64. DOI:10.1111/j.1528-1167.2011.03071.x · 4.57 Impact Factor
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