Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the LGI1 gene predispose to a hereditary epilepsy syndrome and is the first gene associated with this disease which does not encode an ion channel protein. In zebrafish, there are two paralogs of the LGI1 gene, lgi1a and lgi1b. Knockdown of lgi1a results in a seizure-like hyperactivity phenotype with associated developmental abnormalities characterized by cellular loss in the eyes and brain. We have now generated knockdown morphants for the lgi1b gene which also show developmental abnormalities but do not show a seizure-like behavior. Instead, the most striking phenotype involves significant enlargement of the ventricles (hydrocephalus). As shown for the lgi1a morphants, however, lgi1b morphants are also sensitized to PTZ-induced hyperactivity. The different phenotypes between the two lgi1 morphants support a subfunctionalization model for the two paralogs.
 ...
PMID:Loss of zebrafish lgi1b leads to hydrocephalus and sensitization to pentylenetetrazol induced seizure-like behavior. 2205 18

For diagnosis of seizure type and epilepsy syndrome, we always take all the three aspects of 1) history and symptoms (symptomatology), 2) EEG (clinical neurophysiology) and 3) neuroimaging into account, and thus an appropriate treatment approach based on both short- and long-term concerns is individualized. Recent advances in clinical epileptology on the three aspects (i, ii, iii) and on genetic analysis (iv, v) are briefly introduced as follows. i) Wide-band EEG analysis Clinical EEG provides us with diagnostic information of epileptogenicity by epileptiform discharges, i.e., spikes, sharp waves, which reflects the paroxysmal depolarization shifts (PDS) in the epileptic neurons. Currently advanced technology has enabled us to record wide-band EEG: direct current (DC) shifts (Ikeda et al., 1996) and high frequency oscillation (HFO) (Bragin et al., 1999). The both conditions occurred together as early as electrodecremental pattern occurred or earlier than conventional ECoG changes, and that ictal DC shifts happened earlier than HFO on some occasions, that may suggest more active role of glia (Imamura et al., 2011). ii) Amygdalar enlargement in patients with temporal lobe epilepsy (TLE). With absence of hippocampal atrophy (HA), some patients with TLE clearly showed amygdalar enlargement on focus side; they had older onset age and better seizure control than HA. It may be a subtype of TLE (Mitsueda-Ono et al., 2011). iii) Focal epilepsy syndrome as antibody-mediated gray matter disease? Recently delineated antibodies to cell surface antigens such as anti-VGKC antibody, anti-GAD antibody or anti-NMDA receptor antibody could develop chronic epileptic condition, being apart from so-called acute limbic encephalitis with ovarian teratoma. iv) Gentic abnormality in epilepsy other than channelopathy Abnormality of LGI1 gene is responsible for autosomal dominant lateral temporal lobe epilepsy (ADLTE), where synaptic transmission could be impaired. Clinically significant divergence in symptoms and the degree of abnormality within family as well as between families remains to be solved (Kawamata et al., 2010). v) Genetic polymorphism in CYP2C19 in drug choice Information of genetic polymorphism in CYP2C19 could individualize drug choice and its dose in advance (Yasuda et al., 2009).
 ...
PMID:[The leading edge of epilepsy research]. 2227 54

Limbic encephalitis with LGI1 antibodies may cause drug-resistant temporal lobe epilepsy. We report a case of a young man with progressive drug-resistant focal epilepsy, hyperhidrosis, and memory impairment associated with a left mesial temporal lesion. Epilepsy surgery was performed with the provisional diagnosis of cortical dysplasia or tumour. A neuropathological study following amygdalohippocampectomy revealed limbic encephalitis and LGI1 antibodies were identified in the serum. Two and a half years after surgery, the patient remains seizure-free without medication, with normal memory and without hyperhidrosis. Although immunosuppression is the first-line therapy for autoimmune limbic encephalitis, this case suggests that, in selected cases, a lasting response can be achieved with surgery.
 ...
PMID:Surgical control of limbic encephalitis associated with LGI1 antibodies. 2294 Jul 85

Genetic mutations causing dysfunction of both voltage- and ligand-gated ion channels make a major contribution to the cause of many different types of familial epilepsy. Key mechanisms comprise defective Na(+) channels of inhibitory neurons, or GABA(A) receptors affecting pre- or postsynaptic GABAergic inhibition, or a dysfunction of different types of channels at axon initial segments. Many of these ion channel mutations have been modelled in mice, which has largely contributed to the understanding of where and how the ion channel defects lead to neuronal hyperexcitability. Animal models of febrile seizures or mesial temporal epilepsy have shown that dendritic K(+) channels, hyperpolarization-activated cation channels and T-type Ca(2+) channels play important roles in the generation of seizures. For the latter, it has been shown that suppression of their function by pharmacological mechanisms or in knock-out mice can antagonize epileptogenesis. Defects of ion channel function are also associated with forms of acquired epilepsy. Autoantibodies directed against ion channels or associated proteins, such as K(+) channels, LGI1 or NMDA receptors, have been identified in epileptic disorders that can largely be included under the term limbic encephalitis which includes limbic seizures, status epilepticus and psychiatric symptoms. We conclude that ion channels and associated proteins are important players in different types of genetic and acquired epilepsies. Nevertheless, the molecular bases for most common forms of epilepsy are not yet clear, and evidence to be discussed indicates just how much more we need to understand about the complex mechanisms that underlie epileptogenesis.
 ...
PMID:Ion channels in genetic and acquired forms of epilepsy. 2309 Sep 47

The detection of antineural autoantibodies in patients with epilepsy has led to the new concept of "autoimmune epilepsy." A particularly important implication is that knowledge of the antigenic target of the underlying antibody permits prognostic estimates. Patients with antibodies to the potassium channel complex (mostly to its leucine-rich glioma inactivated 1 [LGI1] component) have a high chance of becoming seizure free within days to months upon immunotherapy but less so with antiepileptic drug (AED) treatment alone. Seizures in the setting of antibodies to the N-methyl-d-aspartate receptor also have a high likelihood to remit, again especially with rapid institution of immunotherapy. In contrast to these antibodies to neuronal surface molecules, antibodies directed to intracellular antigens (onconeural antibodies, antibodies to glutamic acid decarboxylase) portend a low likelihood of seizure remission, regardless of the treatments chosen. These outcome differences are probably related to the underlying pathophysiology--with largely reversible functional effects of antibodies to surface antigens and irreversible destructive sequelae (probably caused by T cells) in patients with antibodies to intracellular antigens. With ongoing experience with these conditions, clinical and paraclinical clues to the diagnosis of autoimmune epilepsies are emerging.
 ...
PMID:Value of autoantibodies for prediction of treatment response in patients with autoimmune epilepsy: review of the literature and suggestions for clinical management. 2364 71

Mutations in LGI1 are found in 50% of families with autosomal dominant epilepsy with auditory features (ADEAF). In ADEAF, family members have predominantly lateral temporal lobe seizures but mesial temporal lobe semiology may also occur. We report here three families with novel LGI1 mutations (p.Ile82Thr, p.Glu225*, c.432-2_436del). Seven affected individuals reported an auditory aura and one a visual aura. A 10-year old boy described a cephalic aura followed by an unpleasant taste and oral automatisms without auditory, visual or psychic features.
...
PMID:Seizure semiology in autosomal dominant epilepsy with auditory features, due to novel LGI1 mutations. 2420 7

More than 30 mutations in LGI1, a secreted neuronal protein, have been reported with autosomal dominant lateral temporal lobe epilepsy (ADLTE). Although LGI1 haploinsufficiency is thought to cause ADLTE, the underlying molecular mechanism that results in abnormal brain excitability remains mysterious. Here, we focused on a mode of action of LGI1 autoantibodies associated with limbic encephalitis (LE), which is one of acquired epileptic disorders characterized by subacute onset of amnesia and seizures. We comprehensively screened human sera from patients with immune-mediated neurological disorders for LGI1 autoantibodies, which also uncovered novel autoantibodies against six cell surface antigens including DCC, DPP10, and ADAM23. Our developed ELISA arrays revealed a specific role for LGI1 antibodies in LE and concomitant involvement of multiple antibodies, including LGI1 antibodies in neuromyotonia, a peripheral nerve disorder. LGI1 antibodies associated with LE specifically inhibited the ligand-receptor interaction between LGI1 and ADAM22/23 by targeting the EPTP repeat domain of LGI1 and reversibly reduced synaptic AMPA receptor clusters in rat hippocampal neurons. Furthermore, we found that disruption of LGI1-ADAM22 interaction by soluble extracellular domain of ADAM22 was sufficient to reduce synaptic AMPA receptors in rat hippocampal neurons and that levels of AMPA receptor were greatly reduced in the hippocampal dentate gyrus in the epileptic LGI1 knock-out mouse. Therefore, either genetic or acquired loss of the LGI1-ADAM22 interaction reduces the AMPA receptor function, causing epileptic disorders. These results suggest that by finely regulating the synaptic AMPA receptors, the LGI1-ADAM22 interaction maintains physiological brain excitability throughout life.
...
PMID:Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors. 2422 25

Over the last few years, various autoantibodies against cell surface or intracellular antigens were identified in association with several forms of encephalitis, i.e. autoimmune encephalitis. Immunoprecipitaion and sequence analysis of the target protein (proteomics) provided the identification of the antigens corresponding to autoantibodies in autoimmune encephalitis. Appropriate preparation of antigens (synthesized peptides, or recombinant proteins prepared in E.coli or cultured mammalian cells) and assay systems (immunoblot, ELISA, immunoprecipitation or cell-based assay) should be selected for detection of each autoantibodies.Limbic encephalitis characterized by psychosis, dementia, seizures and abnormal movements is a common form of autoimmune encephalitis. Autoantibodies against the NMDA receptor, the AMPA receptor or the VGKC complex (LGI1 and Caspr2) were identified in limbic encephalitis with or without tumor association. Especially, limbic encephalitis associated with anti-NMDA receptor and ovarian teratoma became a distinct neurologic disorder to date.The intracellular antigens are also involved in several forms of encephalitis. Cerebellar ataxia is a common form of autoimmune encephalitis (cerebellits). The autoimmune cerebellar ataxia consists of paraneoplastic ataxia (anti-Yo etc.), anti-GAD-autoantibodies associated ataxia, gluten ataxia (anti-gliadin) and ataxic form of Hashimoto's encephalitis (anti-NAE).The early and accurate diagnosis of autoimmune encephalitis is important because most patients show responses to immunotherapy.
...
PMID:[Autoimmune encephalitis and its related-disorders]. 2429 79

A 5-year-old, female client-owned cat presented with acute onset of focal epileptic seizures with orofacial twitching and behavioural changes. Magnetic resonance imaging showed bilateral temporal lobe hyperintensities and the EEG was consistent with ictal epileptic seizure activity. After antiepileptic and additional corticosteroid treatment, the cat recovered and by 10 months of follow-up was seizure-free without any problem. Retrospectively, antibodies to LGI1, a component of the voltage-gated potassium channel-complex, were identified. Feline focal seizures with orofacial involvement have been increasingly recognised in client-owned cats, and autoimmune limbic encephalitis was recently suggested as a possible aetiology. This is the first report of EEG, MRI and long-term follow-up of this condition in cats which is similar to human limbic encephalitis.
...
PMID:EEG-confirmed epileptic activity in a cat with VGKC-complex/LGI1 antibody-associated limbic encephalitis. 2466 92

Antibodies against LGI1 (leucin-rich glioma-inactivated 1 protein) are associated with limbic encephalitis (LE), which is characterized by a favorable outcome following immunotherapy. Here, we present two cases, where antibodies against LGI1 were detected in the sera 36 and 53 months after acute LE, respectively, and none of the patients received immunotherapy. LE showed characteristics of LGI1 encephalitis in both cases, including low sodium content in the sera; disorientation, hallucination, short-term memory loss; and epileptic seizures. One patient had faciobrachial tonic seizures. MRI indicated bilateral inflammation of the hippocampus in one case. We reviewed longitudinal clinical and MRI data covering 53 and 36 months after LE without immunotherapy, respectively. Both patients became seizure-free and spontaneously recovered with mild/moderate cognitive impairment. No relapses have been observed. Follow-up brain MRI indicated early hippocampal sclerosis and global brain atrophy in one case characterized by more pronounced cognitive deficit. Memory and verbal fluency were affected most during the natural course of LGI1 encephalitis. LGI1 encephalitis had a monophasic course and spontaneously improved, suggesting that a relatively benign natural course may contribute to the favorable outcome observed after immunotherapy. Our data also indicate that LGI1 antibodies can be present in the sera without clinical disease activity.
 ...
PMID:Natural course of LGI1 encephalitis: 3-5 years of follow-up without immunotherapy. 2492 80


<< Previous 1 2 3 4 5 6 7 8 Next >>