A de novo LGI1 mutation in sporadic partial epilepsy with auditory features

University of Bologna, Bolonia, Emilia-Romagna, Italy
Annals of Neurology (Impact Factor: 11.91). 09/2004; 56(3):455-6. DOI: 10.1002/ana.20218
Source: PubMed
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    ABSTRACT: The γ-aminobutyric acid receptor type A (GABAA receptor) is a ligand-gated chloride channel that mediates major inhibitory functions in the central nervous system. GABAA receptors function mainly as pentamers containing α, β, and either γ or δ subunits. A number of antiepileptic drugs have agonistic effects on GABAA receptors. Hence, dysfunctions of GABAA receptors have been postulated to play important roles in the etiology of epilepsy. In fact, mutations or genetic variations of the genes encoding the α1, α6, β2, β3, γ2, or δ subunits (GABRA1, GABRA6, GABRB2, GABRB3, GABRG2, and GABRD, respectively) have been associated with human epilepsy, both with and without febrile seizures. Epilepsy resulting from mutations is commonly one of following, genetic (idiopathic) generalized epilepsy (e.g., juvenile myoclonic epilepsy), childhood absence epilepsy, genetic epilepsy with febrile seizures, or Dravet syndrome. Recently, mutations of GABRA1, GABRB2, and GABRB3 were associated with infantile spasms and Lennox-Gastaut syndrome. These mutations compromise hyperpolarization through GABAA receptors, which is believed to cause seizures. Interestingly, most of the insufficiencies are not caused by receptor gating abnormalities, but by complex mechanisms, including endoplasmic reticulum (ER)-associated degradation, nonsense-mediated mRNA decay, intracellular trafficking defects, and ER stress. Thus, GABAA receptor subunit mutations are now thought to participate in the pathomechanisms of epilepsy, and an improved understanding of these mutations should facilitate our understanding of epilepsy and the development of new therapies.
    Progress in brain research 01/2014; 213C:55-85. DOI:10.1016/B978-0-444-63326-2.00003-X · 5.10 Impact Factor
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    ABSTRACT: Mutations in the LGI1 gene predispose to autosomal dominant lateral temporal lobe epilepsy, a rare hereditary form with incomplete penetrance and associated with acoustic auras. LGI1 is not a structural component of an ion channel like most epilepsy-related genes, but is a secreted protein. Mutant null mice exhibit early-onset seizures, and electrophysiological analysis shows abnormal synaptic transmission. LGI1 binds to ADAM23 on the presynaptic membrane and ADAM22 on the postsynaptic membrane, further implicating it in regulating the strength of synaptic transmission. Patients with limbic encephalitis show autoantibodies against LGI1 and develop seizures, supporting a role for LGI1 in synapse transmission in the post developmental brain. LGI1, however, also seems to be involved in aspects of neurite development and dendritic pruning, suggesting an additional role in corticogenesis. LGI1 is also involved in cell movement and suppression of dendritic outgrowth in in vitro systems, possibly involving actin cytoskeleton dynamics. Expression patterns in embryonic development correspond to areas of neuronal migration. Loss of LGI1 expression also impacts on myelination of the central and peripheral nervous systems. In zebrafish embryos, knockdown of lgi1a leads to a seizure-like behavior and abnormal brain development, providing a system to study its role in early embryogenesis. Despite being implicated in a role in both synapse transmission and neuronal development, how LGI1 predisposes to epilepsy is still largely unknown. It appears, however, that LGI1 may function differently in a cell context-specific manner, implying a complex involvement in brain development and function that remains to be defined.
    Progress in brain research 01/2014; 213C:159-179. DOI:10.1016/B978-0-444-63326-2.00009-0 · 5.10 Impact Factor
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    ABSTRACT: Autosomal dominant partial epilepsy with auditory features (ADPEAF) is a rare familial partial epilepsy syndrome with onset in the second or third decades of life characterized by recurrent auditory auras and/or other symptoms suggesting a lateral temporal onset. Mutations in the leucine-rich, glioma inactivated 1 gene (LGI1) on chromosome 10q have been identified in approximately 50% of families with ADPEAF. In the literature a total of 25 LGI1 mutations have been described. The mechanisms by which LGI1 mutations cause epilepsy remain unclear. Among the various diagnostic techniques it is important to obtain an electroencephalogram and long-latency auditory evoked potentials. The prognosis is good and the treatment is based on carbamazepine, phenytoin and valproate.
    Audiological Medicine 05/2012; 10(2). DOI:10.3109/1651386X.2012.683291