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)

The relatively high percentages of patients with epilepsy, in whom seizures are uncontrolled in spite of optimal antiepileptic drug use, lead to continuous struggles to improve the treatment of epilepsy. The advances in defining the genetic basis of epilepsy can potentially lead to better understanding of the disorder as well as to more effective treatment. An example is the finding of SCN1A gene mutations in association with a large spectrum of neurological diseases, from generalized epilepsy with febrile seizures plus (GEFS +) to severe myoclonic epilepsy of infancy and to vaccine-induced encephalopathy and Rasmussen encephalitis, Panayiotopoulos syndrome and familial hemiplegic migraine. In parallel, throughout the world, imaging modalities of very high technology are being used to define the epileptogenic focus. A description from The Hospital for Sick Children in Toronto, of a topographic movie of high frequency oscillations on the brain surface, which allows visualization of the dynamic ictal changes, is remarkable. The ketogenic diet is a significant treatment option. The John Freeman Epilepsy Center in Johns Hopkins Hospital leads the way in using the diet in very young infants, including West syndrome. The vagus nerve stimulation is being used as another relatively safe and effective treatment, while epilepsy surgery continues to be applied. Better matching of patients to each modality can be expected with increased success in seizure control.
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PMID:[Epilepsy in Israel--2008]. 1835 70

Hemiplegic migraine (HM) is a rare variety of migraine with aura characterized by the presence of a motor weakness during the aura. Hemiplegic migraine has two main forms according to the familial history: patients with at least one first- or second-degree relative who has aura including motor weakness have familial hemiplegic migraine (FHM); patients without such familial history have sporadic hemiplegic migraine (SHM). The prevalence of HM is one in 10,000 with FHM and SHM being equally frequent. Typical HM attacks include a motor weakness that is always associated with other aura symptoms, the most frequent being sensory, visual and speech disorders. In addition, basilar-type symptoms occur in up to 70% of the patients. Severe attacks may occur in FHM as well as in SHM with prolonged hemiplegia, confusion, coma, fever and seizures. The clinical spectrum also includes permanent cerebellar signs (nystagmus, ataxia, dysarthria) and less frequently various types of seizures and intellectual deficiency. FHM is the only variety of the autosomal dominant migraine and all three know genes encode ion-transporters. A genetic diagnosis is now possible by screening the three known genes involved in FHM (CACNA1A, ATP1A2 and SCNA1). Prognosis is usually good. Treatment is similar to approaches used in other varieties of migraine with aura, excepted for triptans that are contraindicated in MHF/MHS. Based on new pathophysiological insight, preventive treatments by various antiepileptic agents seem promising.
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PMID:[Familial and sporadic hemiplegic migraine]. 1840 71

We studied four members of a family suffering from typical attacks of familial hemiplegic migraine (FHM) caused by a new mutation, R548C, of ATP1A2 gene in exon 12. One individual had also childhood absence epilepsy and generalized tonic-clonic seizures (GTCS). GTCS were followed by a severe attack of hemiplegic migraine at four times. Sodium valproate enabled control of both the epileptic seizures and the most severe FHM attacks. This association of FHM and epileptic seizures and their control with the same treatment suggest similar pathophysiological mechanisms.
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PMID:Severe attacks of familial hemiplegic migraine, childhood epilepsy and ATP1A2 mutation. 1849 90

The calcium channel CACNA1A gene encodes the pore-forming, voltage-sensitive subunit of the voltage-dependent calcium Ca(v)2.1 type channel. Mutations in this gene have been linked to several human disorders, including familial hemiplegic migraine, episodic ataxia 2 and spinocerebellar ataxia type 6. The mouse homologue, Cacna1a, is associated with the tottering, Cacna1a(tg), mutant series. Here we describe two new missense mutant alleles, Cacna1a(tg-4J) and Cacna1a(Tg-5J). The Cacna1a(tg-4J) mutation is a valine to alanine mutation at amino acid 581, in segment S5 of domain II. The recessive Cacna1a(tg-4J) mutant exhibited the ataxia, paroxysmal dyskinesia and absence seizures reminiscent of the original tottering mouse. The Cacna1a(tg-4J) mutant also showed altered activation and inactivation kinetics of the Ca(v)2.1 channel, not previously reported for other tottering alleles. The semi-dominant Cacna1a(Tg-5J) mutation changed a conserved arginine residue to glutamine at amino acid 1252 within segment S4 of domain III. The heterozygous mouse was ataxic and homozygotes rarely survived. The Cacna1a(Tg-5J) mutation caused a shift in both voltage activation and inactivation to lower voltages, showing that this arginine residue is critical for sensing Ca(v)2.1 voltage changes. These two tottering mouse models illustrate how novel allelic variants can contribute to functional studies of the Ca(v)2.1 calcium channel.
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PMID:Two novel alleles of tottering with distinct Ca(v)2.1 calcium channel neuropathologies. 1859 46

Familial hemiplegic migraine (FHM) is a severe dominant form of migraine with aura associated with transient hemiparesis. Several other neurological signs and symptoms can be associated with FHM such as cerebellar abnormalities, cerebral edema and coma after minor head trauma, epileptic seizures and mental retardation. The sporadic form of hemiplegic migraine named SHM, presents with identical clinical symptoms. Here we report a case of a young hemiplegic migraine patient, 11 years old, who had the first hemiplegic attack at the age of 10 years. This patient has a clinical history of epileptic seizures in the childhood successfully controlled with drug therapy. No familiarity for any type of migraine or seizures can be observed within the paternal or maternal line. The patient who can therefore be considered a sporadic case, carries a novel de novo nonsense mutation p.Tyr1009X in the ATP1A2 gene (FHM2), leading to a truncated alpha-2 subunit of the Na+/K+-ATPase pump thus lacking the last 11 amino acids. The novel mutation identified confirms the role of FHM2 gene in forms of hemiplegic migraine associated with epilepsy with both familial and sporadic occurrence, and expands the spectrum of mutations related to these forms of the disease.
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PMID:A novel de novo nonsense mutation in ATP1A2 associated with sporadic hemiplegic migraine and epileptic seizures. 1864 8

Mutations in CACNA1A were previously described in familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar ataxia type 6. We report on an 11-year-old girl with episodes of seizures, ataxia, headache, a decreased level of consciousness, and motor regression, with a background of mental retardation and mild cerebellar atrophy. Sequence analysis of the CACNA1A gene revealed a de novo Ile712Val sequence variant, which was not reported previously.
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PMID:Stepwise developmental regression associated with novel CACNA1A mutation. 1894 May 63

Voltage-gated sodium channels are critical for membrane excitability. Mutations in the genes coding for these proteins cause diseases related to altered excitability of cardiac or skeletal muscle and neurons. Mutations in the central nervous system-specific voltage-gated sodium channel alpha1 subunit gene (SCN1A) lead not only to seizure syndromes but also to familial hemiplegic migraine. The epilepsies range from benign febrile seizures to the catastrophic epileptic encephalopathy of Dravet syndrome (severe myoclonic epilepsy of infancy). Recently developed animal models of SCN1A mutants recapitulate the human disease. These models exemplify the potential inherent in translational research to debunk preconceived ideas regarding pathogenesis by showing the cellular substrate of Dravet syndrome to be interneurons rather than excitatory cells. This illustrates the key role that basic science plays in the development of targeted novel therapies and, ultimately, in the prevention of devastating genetic disorders.
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PMID:Translational research in epilepsy genetics: sodium channels in man to interneuronopathy in mouse. 1913 96

The calcium ion is one of the most versatile, ancient, and universal of biological signaling molecules, known to regulate physiological systems at every level from membrane potential and ion transporters to kinases and transcription factors. Disruptions of intracellular calcium homeostasis underlie a host of emerging diseases, the calciumopathies. Cytosolic calcium signals originate either as extracellular calcium enters through plasma membrane ion channels or from the release of an intracellular store in the endoplasmic reticulum (ER) via inositol triphosphate receptor and ryanodine receptor channels. Therefore, to a large extent, calciumopathies represent a subset of the channelopathies, but include regulatory pathways and the mitochondria, the major intracellular calcium repository that dynamically participates with the ER stores in calcium signaling, thereby integrating cellular energy metabolism into these pathways, a process of emerging importance in the analysis of the neurodegenerative and neuropsychiatric diseases. Many of the calciumopathies are common complex polygenic diseases, but leads to their understanding come most prominently from rare monogenic channelopathy paradigms. Monogenic forms of common neuronal disease phenotypes-such as seizures, ataxia, and migraine-produce a constitutionally hyperexcitable tissue that is susceptible to periodic decompensations. The gene families and genetic lesions underlying familial hemiplegic migraine, FHM1/CACNA1A, FHM2/ATP1A2, and FHM3/SCN1A, and monogenic mitochondrial migraine syndromes, provide a robust platform from which genes, such as CACNA1C, which encodes the calcium channel mutated in Timothy syndrome, can be evaluated for their role in autism and bipolar disease.
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PMID:Genetic calcium signaling abnormalities in the central nervous system: seizures, migraine, and autism. 1915 21

Different SCN1A mutations are known to cause a variety of phenotypes, such as generalized epilepsy with febrile seizures plus (GEFS+), Dravet syndrome and familial hemiplegic migraine (FHM). In Dravet syndrome, most mutations are de novo and familial cases are rare. In this study, Dravet syndrome is observed in two maternal half sisters. They have healthy fathers and their common mother has never experienced seizures, but has a lifelong history of migraine. Direct sequencing of DNA extracted from blood revealed a heterozygous SCN1A nonsense mutation c.3985C>T in the sisters, but not in the mother. The mutation induces a premature stop codon and probably leads to a non-functional protein. Further examination of the mother's DNA showed that she has a mosaicism of the mutation. This report of parental SCN1A nonsense mutation mosaicism in familial Dravet syndrome suggests that mosaicism might be more common than previously suspected and emphasizes the importance of taking mosaicism into account in genetic counselling of Dravet syndrome and SCN1A mutations. Furthermore, whether the migraine of the mother could be influenced by her SCN1A mutation mosaicism is not known, but increased awareness of migraine in future studies of SCN1A related epilepsies could clarify this intriguing link between migraine and epilepsy.
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PMID:Parental SCN1A mutation mosaicism in familial Dravet syndrome. 1967 51

The CACNA1A gene encodes the poreforming, voltage-sensitive subunit of the voltage-dependent Ca(v)2.1 calcium channel. Mutations in this gene have been linked to several human disorders, including familial hemiplegic migraine type 1, episodic ataxia type 2, and spinocerebellar ataxia type 6. In mice, mutations of the homolog Cacna1a cause recessively inherited phenotypes in tottering, rolling Nagoya, rocker, and leaner mice. Here we describe two knockdown mice with 28.4+/-3.4% and 13.8+/-3.3% of the wild-type Ca(v)2.1 quantity. 28.4+/-3.4% level mutants displayed ataxia, absence-like seizures and progressive cerebellar atrophy, although they had a normal life span. Mutants with 13.8+/-3.3% level exhibited ataxia severer than the 28.4+/-3.4% level mutants, absence-like seizures and additionally paroxysmal dyskinesia, and died premature around 3 weeks of age. These results indicate that knock down of Ca(v)2.1 quantity to 13.8+/-3.3% of the wild-type level are sufficient to induce the all neurological disorders observed in natural occurring Cacna1a mutants. These knockdown animals with Ca(v)2.1 calcium channels intact can contribute to functional studies of the molecule in the disease.
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PMID:Knockdown of Cav2.1 calcium channels is sufficient to induce neurological disorders observed in natural occurring Cacna1a mutants in mice. 1985 54


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