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

We report a family with complex febrile seizures (FS). The proband is a 15-year-old boy with seizures that persisted beyond 6 years of age. His father, aunt, and cousin also have the histories of FS until 8, 9, and 8 years old, respectively. A base substitution 5569G-->T of voltage-gated sodium channel alpha-1 subunit gene was found in DNA derived from the affected members of this family.
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PMID:A family of generalized epilepsy with febrile seizures plus type 2-a new missense mutation of SCN1A found in the pedigree of several patients with complex febrile seizures. 1571 99

Zolpidem is a short acting hypnotic drug belonging to imidazopyridine family. It produces its hypnotic effects via the GABA-A benzodiazepine receptor complex, and binds preferentially to those receptors containing the alpha-1 subunit. In comparison with benzodiazepines this mechanism is thought to reduce liability to induce dependence. Several case reports of zolpidem abuse and dependence have been published along with a small number of cases demonstrating seizures after sudden zolpidem withdrawal. We describe a case of a 29-year-old Caucasian woman who developed a generalized seizure following sudden zolpidem withdrawal subsequent to drug dependence to 160mg of zolpidem. The clinical effects of zolpidem seem to be comparable to those of benzodiazepines and abuse, dependence and withdrawal seizures belong to the spectrum of its adverse drug reactions.
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PMID:Seizure following sudden zolpidem withdrawal. 1695 May 52

Severe myoclonic epilepsy (SMEI) or Dravet syndrome is caused by mutations of the SCN1A gene that encodes voltage-gated sodium channel alpha-1 subunit. Recently, we generated and characterized a knock-in (KI) mice with an SCN1A nonsense mutation that appeared in three independent SMEI patients. The SCN1A-KI mice well reproduced the SMEI disease phenotypes. Both homozygous and heterozygous knock-in mice developed epileptic seizures within the first postnatal month. In heterozygous knock-in mice, trains of evoked action potentials in inhibitory neurons exhibited pronounced spike amplitude decrement late in the burst but not in pyramidal neurons. We further showed that in wild-type mice the Nav1.1 protein is expressed dominantly in axons and moderately in somata of parbalbumin (PV) - positive inhibitory interneurons. Our immunohistochemical observations of the Nav1.1 are clearly distinct to the previous studies, and our findings has corrected the view of the Nav1.1 protein distribution. The data indicate that Nav1.1 plays critical roles in the spike output from PV interneurons and further, that the specifically altered function of these inhibitory circuits may contribute to epileptic seizures in the mice. These information should contribute to the understanding of molecular pathomechanism of SMEI and to develop its effective therapies.
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PMID:Molecular basis of severe myoclonic epilepsy in infancy. 1920 54

An 11 months old boy, developed liver failure after febrile status epilepticus while being treated with valproic acid for myoclonic epilepsy and recurrent partial and generalized seizures. The diagnosis of Alpers-Huttenlocher disease was considered. A muscle biopsy showed mitochondrial dysfunction. Mitochondrial DNA depletion was ruled out. Sequencing of the polymerase gamma gene (POLG1) did not detect any mutations. Sequencing of the alpha-1 subunit gene of the voltage-gated neuronal sodium channel (SCN1A) revealed a novel, de novo amino acid change p.Val 1637 Glu. This case expands the spectrum of clinical presentations related to mutations in SCN1A. We warn that children with SCN1A mutations may be at risk for developing liver failure following status epilepticus, due to mitochondrial dysfunction.
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PMID:Hepatic coma culminating in severe brain damage in a child with a SCN1A mutation. 2039 57

Dravet syndrome is caused by mutations of the SCN1A gene that encodes voltage-gated sodium channel alpha-1 subunit. SCN1A-knock-in mouse with a disease-relevant nonsense mutation that we generated well reproduced the disease phenotypes. Both homozygous and heterozygous knock-in mice developed epileptic seizures within the first postnatal month. In heterozygotes, trains of evoked action potentials in fast-spiking, inhibitory cells exhibited pronounced spike amplitude decrement late in the burst but not in pyramidal neurons. Furthermore, our immunohistochemical studies showed that in wild-type mice Nav1.1 is expressed in parvalbumin-positive inhibitory interneurons (PV cells), dominantly in its axons and moderately in somata, and not expressed in pyramidal cells nor other types of interneurons including somatostatin-positive and calretinin-positive cells. These results so far suggest that Nav1.1 expression is largely confined to PV cells and plays critical roles in their spike output, and that impaired function of PV cells would be the cellular basis of Dravet syndrome.
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PMID:Molecular and cellular basis: insights from experimental models of Dravet syndrome. 2146 84

Dravet syndrome is a severe infantile-onset epilepsy syndrome with a distinctive but complex electroclinical presentation. A healthy, developmentally normal infant presents at around 6 months of age with convulsive status epilepticus, which may be hemiclonic or generalized; seizures may be triggered by fever, illness or vaccination. The infant typically has further episodes of status epilepticus every month or two, often triggered by fever. Other seizure types including focal dyscognitive seizures, absence and myoclonic seizures develop between 1 and 4 years. Atonic drop attacks and episodes of non-convulsive status may occur. Early development is normal but slows in the second year. Developmental regression may occur, particularly with status epilepticus. EEG studies are initially normal, but after 2 years they show generalized spike-wave and polyspike-wave activity with multifocal discharges. Photosensitivity may be seen. Imaging is normal or shows non-specific findings such as atrophy. Dravet syndrome is associated with mutations of the gene encoding the alpha-1 subunit of the sodium channel, SCN1A, in >70% of patients. These include sequencing mutations and copy number variant anomalies; 90% of mutations arise de novo. PCDH19 mutational analysis is a second-tier test for girls with a Dravet-like picture who do not have SCN1A mutations. Outcome is poor, with intellectual disability in most patients and ongoing seizures. Intellectual impairment varies from severe in 50% patients, to moderate and mild intellectual disability each accounting for 25% cases. Rare patients have normal intellect. The long-term course involves ongoing, brief nocturnal convulsions and a characteristic deterioration in gait.
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PMID:Diagnosis and long-term course of Dravet syndrome. 2270 20

Rett syndrome (RTT) is a neurodevelopment disorder associated with intellectual disabilities and caused by loss-of-function mutations in the gene encoding the transcriptional regulator Methyl-CpG-binding Protein-2 (MeCP2). Neuronal dysfunction and changes in cortical excitability occur in RTT individuals and Mecp2-deficient mice, including hippocampal network hyperactivity and higher frequency of spontaneous multiunit spikes in the CA3 cell body layer. Here, we describe impaired synaptic inhibition and an excitation/inhibition (E/I) imbalance in area CA3 of acute slices from symptomatic Mecp2 knockout male mice (referred to as Mecp2(-/y) ). The amplitude of TTX-resistant miniature inhibitory postsynaptic currents (mIPSC) was smaller in CA3 pyramidal neurons of Mecp2(-/y) slices than in wildtype controls, while the amplitude of miniature excitatory postsynaptic currents (mEPSC) was significantly larger in Mecp2(-/y) neurons. Consistently, quantitative confocal immunohistochemistry revealed significantly lower intensity of the alpha-1 subunit of GABAA Rs in the CA3 cell body layer of Mecp2(-/y) mice, while GluA1 puncta intensities were significantly higher in the CA3 dendritic layers of Mecp2(-/y) mice. In addition, the input/output (I/O) relationship of evoked IPSCs had a shallower slope in CA3 pyramidal neurons Mecp2(-/y) neurons. Consistent with the absence of neuronal degeneration in RTT and MeCP2-based mouse models, the density of parvalbumin- and somatostatin-expressing interneurons in area CA3 was not affected in Mecp2(-/y) mice. Furthermore, the intrinsic membrane properties of several interneuron subtypes in area CA3 were not affected by Mecp2 loss. However, mEPSCs are smaller and less frequent in CA3 fast-spiking basket cells of Mecp2(-/y) mice, suggesting an impaired glutamatergic drive in this interneuron population. These results demonstrate that a loss-of-function mutation in Mecp2 causes impaired E/I balance onto CA3 pyramidal neurons, leading to a hyperactive hippocampal network, likely contributing to limbic seizures in Mecp2(-/y) mice and RTT individuals.
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PMID:Excitation/inhibition imbalance and impaired synaptic inhibition in hippocampal area CA3 of Mecp2 knockout mice. 2520 30

Severe myoclonic epilepsy in infancy (Dravet's syndrome) is a very rare form of epilepsy. Mutations of SCN1A gene encoding voltage-gated sodium channel alpha-1 subunit are major causes of the autosomal dominant disorder. Most cases are associated with a de novo point mutation, but some patients have copy number variations. The protein encoded by the SCN1A gene plays a role in the generation and propagation of action potentials. Loss of function caused by the majority of gene mutations leads to hyperexcitability of the neuronal network that finally results in the formation of the epileptic seizures. Molecular genetic test for copy number variations of SCN1A gene is available in the department of the authors since 2013 besides sequencing analysis of the whole gene. This article presents the case of a 7-year-old patient with two years of recorded patient history outside of the author's department. Molecular genetic test, which detected a de novo SCN1A gene deletion in heterozygous form, revealed SCN1A gene associated monogenic epileptic syndrome being in the genetic background of therapy-resistant seizures.
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PMID:[De novo SCN1A gene deletion in therapy-resistant Dravet syndrome]. 2661 43

Dravet syndrome (DS), also known as severe myoclonic epilepsy of infancy (SMEI), is one of the rare early childhood intractable epileptic encephalopathies associated with pleomorphic seizure activity, cognitive decline, motor, and behavioral abnormalities. The convulsive seizure is the most common type seen in DS. After the first episode of seizure-like activity, behavioral disorders and cognitive decline are progressive and long-lasting. The most common etiology identified in patients with DS is a de-novo genetic mutation alpha-1 subunit of voltage-gated calcium channel gene (SCN1A). DS is diagnosed clinically and if unclear, genetic testing is recommended. DS treatment options include anti-epileptic drugs and cannabinoids; ketogenic diet therapy and surgical options such as the deep brain and vagal nerve stimulation. Due to drug-refractory epilepsy in DS, many more therapies are being investigated to increase the longevity of patients.
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PMID:Dravet Syndrome: An Overview. 3149 36