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)

Familial hemiplegic migraine (FHM) is an autosomal dominant variety of migraine with aura. We previously mapped an FHM gene on the short arm of chromosome 19. Mutations in this gene, recently shown to be the alpha1 subunit of a P/Q-type voltage-dependent calcium channel, CACNL1A4, are involved in approximately 50% of unselected FHM families and in all families where migraine attacks are associated with permanent cerebellar ataxia. As a first step toward the identification of other FHM genes, we conducted a genetic linkage analysis in one large French pedigree and showed significant linkage to two microsatellite markers D1S2635 (Zmax: 3.33 at theta = 0.05) and D1S2705 (Zmax: 3.64 at theta = 0.05), establishing the existence of a second locus for FHM (FHM2) on chromosome 1q21-q23. Analysis of six additional FHM families favored linkage to this locus in two of them; linkage was excluded in the last four families, indicating further heterogeneity. Chromosome 1-linked families differ from the ones linked to chromosome 19, because penetrance in those families is much lower, and in some of their members, epileptic seizures occur during severe migraine attacks.
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PMID:Mapping of a second locus for familial hemiplegic migraine to 1q21-q23 and evidence of further heterogeneity. 940 81

Familial hemiplegic migraine (FHM) is an autosomal dominant subtype of migraine with hemiparesis during the aura. In over 50% of cases the causative gene is CACNA1A (FHM1), which in some cases produces a phenotype with cerebellar signs, including ataxia and nystagmus. Recently, mutations in ATP1A2 on chromosome 1q23 encoding a Na+/K+ -ATPase subunit were identified in four families (FHM2). We now describe an FHM2 pedigree with a fifth ATP1A2 mutation coding for a G301R substitution. The phenotype was particularly severe and included hemiplegic migraine, seizure, prolonged coma, elevated temperature, sensory deficit, and transient or permanent cerebellar signs, such as ataxia, nystagmus, and dysarthria. A mild crossed cerebellar diaschisis during an attack further supported the clinical evidence of a cerebellar deficit. This is the first report suggesting cerebellar involvement in FHM2. A possible role for CACNA1A in producing the phenotype in this family was excluded by linkage studies to the FHM1 locus. The study of this family suggests that the absence of cerebellar signs may not be a reliable indicator to clinically differentiate FHM2 from FHM1.
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PMID:A G301R Na+/K+ -ATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs. 1545 25

Recent advances in the studies of the genetic liability to migraine include the discovery of two genes responsible for familial hemiplegic migraine (FHM) and the analysis of several sites of linkage or genetic association for the so-called typical migraines, e. g., migraine with (MA) and without aura (MO). The 2 genes implicated in the genetics of FHM are CACNA1A for FHM1 and ATP1A2 for FHM2. It is still unclear how dysfunction in these genes may trigger attacks of migraine with hemiplegic features and, in at least part of the families with FHM, also paroxysmal or progressive ataxia and epileptic seizures. It appears that mutations in CACNA1A responsible for FHM1 alter calcium influx and calcium currents in neurons, possible factors of spreading depression like events. On the other hand, abnormal regulation of intracellular calcium concentrations could alter neurotransmitter release and other cellular functions. In the case of ATP1A2 mutations, haplo-insufficiency of the gene has been hypothesised to result in abnormal potassium level regulation because of faulty Na/K exchange with subsequent depolarisation and increased liability to spreading depression, or/and in abnormal calcium levels because of the concomitant activation of the Na/Ca exchanger, with a mechanism therefore comparable to that at work in FHM1. Much more work is clearly necessary to elucidate these pathophysiological mechanisms; advances in genetics however may represent important steps in the clarification of the physiopathology of the migraine attack.
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PMID:The physiopathology of migraine: the contribution of genetics. 1554 78

Alternating hemiplegia of childhood (AHC) is a severe brain disorder, mainly characterised by episodes of hemiplegia, progressive mental retardation, and other severe paroxysmal and permanent neurological symptoms. Clinically and genetically, there is some overlap with sporadic (SHM) and familial (FHM) hemiplegic migraine, a severe monogenic subtype of migraine. Although no mutations were detected in the FHM1 CACNA1A and FHM2 ATP1A2 genes in sporadic AHC patients, a mutation was found in the FHM2 ATP1A2 gene in a family with AHC. Recently, a missense mutation was found in the SLC1A3 gene that encodes the glutamate transporter EAAT1, in a patient with alternating hemiplegia, episodic ataxia, seizures, and headache. Because of the remarkable clinical similarities and the potential role of glutamate in AHC, we analysed six sporadic patients with AHC for mutations in the SLC1A3 gene. No mutations were found. The SLC1A3 EAAT1 glutamate transporter gene does not seem to be involved in the pathogenesis of AHC.
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PMID:Alternating hemiplegia of childhood: no mutations in the glutamate transporter EAAT1. 1723 10

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

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

Migraine headaches are a common comorbidity in Rolandic epilepsy (RE) and familial aggregation of migraine in RE families suggests a genetic basis not mediated by seizures. We performed a genome-wide linkage analysis of the migraine phenotype in 38 families with RE to localize potential genetic contribution, with a follow-up in an additional 21 families at linked loci. We used two-point and multipoint LOD (logarithm of the odds) score methods for linkage, maximized over genetic models. We found evidence of linkage to migraine at chromosome 17q12-22 [multipoint HLOD (heterogeneity LOD) 4.40, recessive, 99% penetrance], replicated in the second dataset (HLOD 2.61), and suggestive evidence at 1q23.1-23.2, centering over the FHM2 locus (two-point LOD 3.00 and MP HLOD 2.52). Sanger sequencing in 14 migraine-affected individuals found no coding mutations in the FHM2 gene ATP1A2. There was no evidence of pleiotropy for migraine and either reading or speech disorder, or the electroencephalographic endophenotype of RE when the affected definition was redefined as those with migraine or the comorbid phenotype, and pedigrees were reanalyzed for linkage. In summary, we report a novel migraine susceptibility locus at 17q12-22, and a second locus that may contribute to migraine in the general population at 1q23.1-23.2. Comorbid migraine in RE appears genetically influenced, but we did not obtain evidence that the identified susceptibility loci are consistent with pleiotropic effects on other comorbidities in RE. Loci identified here should be fine-mapped in individuals from RE families with migraine, and prioritized for analysis in other types of epilepsy-associated migraine.
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PMID:Evidence for linkage of migraine in Rolandic epilepsy to known 1q23 FHM2 and novel 17q22 genetic loci. 2428 83