Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018681 (headache)
 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial hemiplegic migraine (FHM) is a rare autosomal dominant disorder characterized by episodes of transient hemiparesis followed by headache. Two chromosomal loci are associated to FHM: FHM1 on chromosome 19 and FHM2 on chromosome 1q21-23. Mutations of the alpha-1A subunit of the voltage gated calcium channel (CACNA1A) are responsible for FHM1. FHM2 critical region spans 28 cM, hence hampering the identification of the responsible gene. Here, we report the FHM2 locus refining by linkage analysis on two large Italian families affected by pure FHM. The new critical region covers a small area of 0.9Mb in 1q23 and renders feasible a positional candidate approach. By mutation analysis, we excluded the calsequestrin and two potassium channel genes mapping within the narrowed FHM2 locus.
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PMID:Familial hemiplegic migraine type 2 is linked to 0.9Mb region on chromosome 1q23. 1260 5

In anaesthetized rats, extracellular recordings were made from neurones of the spinal trigeminal nucleus, involved in the processing of nociceptive input from the dura. Blockers of voltage-gated calcium channels (VGCCs) were administered topically to the exposed brainstem. Blockade of N-type (CaV2.2) channels reduced spontaneous activity and responses of the neurones to cold and chemical stimuli applied to the dura, suggesting that N-type channels regulate excitatory synaptic activation. Blockade of L-type (CaV1) channels enhanced spontaneous discharges of the neurones. Blockade of P/Q-type (CaV2.1) channels slightly decreased responses to chemical and cold stimuli but markedly increased spontaneous activity, an effect which was absent during concomitant application of GABA to the brainstem. The data suggest that P/Q-type VGCCs regulate a tonic synaptic inhibitory control of the brainstem neurones. The risk of migraine by genetic modifications of P/Q-type channels may thus be sought in disturbed inhibition in the network that processes nociceptive dura input.
Cephalalgia 2004 Apr
PMID:Effects of N-, P/Q- and L-type calcium channel blockers on nociceptive neurones of the trigeminal nucleus with input from the dura. 1503 May 33

A growing interest in genetic research in migraine has resulted in the identification of several chromosomal regions that are involved in migraine. However, the identification of mutations in the genes for familial hemiplegic migraine (FHM) forms the only true molecular genetic knowledge of migraine thus far. The increased number of mutations in the FHM1 (CACNA1A) and the FHM2 (ATP1A2) genes allow studying the relationship between genetic findings in both genes and the clinical features in patients. A wide spectrum of symptoms is seen in patients. Additional cerebellar ataxia and (childhood) epilepsy can occur in FHM1 and FHM2. Functional studies show a dysfunction in ion transport as the key factor in the pathophysiology of (familial hemiplegic) migraine that predict an increased susceptibility to cortical spreading depression--the underlying mechanism of migraine aura.
Curr Pain Headache Rep 2005 Jun
PMID:Migraine genetics: an update. 1590 61

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

Migraine is a common, disabling, complex brain disorder, presenting in attacks that may have up to 3 phases: a prodromal phase, the aura phase, and the headache phase. The pathogenesis of the aura and headache phases is reasonably well understood, but the mechanism by which migraine attacks are triggered is unknown. Most likely, migraineurs have a genetically determined reduced threshold for migraine triggers. Identifying "threshold genes" and deciphering their function will help to unravel the triggering mechanisms for migraine attacks. Familial hemiplegic migraine is a rare monogenic subtype of migraine with aura. Three genes have been identified for familial hemiplegic migraine. Recently, knock-in mice carrying human pathogenic FHM1 mutations were generated, which show behavioral, electrophysiological, and neurobiological characteristics in line with prevailing views of migraine physiological processes. Genetic migraine models will be useful in unraveling the triggering mechanisms for migraine attacks and in identifying novel migraine prophylactic targets and therapies.
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PMID:Genetic models of migraine. 1750 63

Migraine is an episodic headache disorder affecting as many as 10% of people worldwide. Familial hemiplegic migraine (FHM) is an autosomal dominant subtype of severe migraine accompanied by visual disturbances known as aura. Migrainous aura is caused by cortical spreading depression (CSD) - a slowly advancing wave of tissue depolarization in the cortex. More than half of FHM cases are caused by mutations in the CACNA1A gene, which encodes a neuronal Cav2.1 Ca2+ channel, resulting in increased Ca2+ flow into dendrites and excessive release of the excitatory neurotransmitter glutamate. In this issue of the JCI, Eikermann-Haerter et al. show that transgenic mice with FHM-associated mutations in Cacna1a have increased susceptibility to CSD compared with wild-type animals, likely due to augmentation of excitatory neurotransmission (see the related article beginning on page 99). Additional as-yet-undefined channel mutations may similarly render the migraine brain more susceptible to the initiation of CSD, with implications not only for the genesis of migraine but also for the hypoxic injury that accompanies its worst manifestation, complicated migraine.
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PMID:Deciphering migraine. 1910 50

Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura that is characterized by motor weakness during attacks. FHM1 is associated with mutations in the CACNA1A gene located on chromosome 19. We report a severe, prolonged HM attack in a young pregnant patient who had the S218L FHM1. This CACNA1A mutation has been associated with HM, delayed cerebral oedema and coma following minor head trauma. The case history we report suggests a specific, severe phenotype and the co-occurrence of HM and epilepsy related to the S218L FHM1 mutation.
Cephalalgia 2009 Dec
PMID:The FHM1 mutation S218L: a severe clinical phenotype? A case report and review of the literature. 1943 26

A 34-year-old man was admitted with his unsteady gait, difficulty in speech and a paroxysmal severe headache accompanied with sensori-motor disturbance of the right extremities and aphasic symptom. His family history was unremarkable. His unsteadiness has progressed very slowly from childhood. He noted to be inarticulate at the age of 18 years. At the age of 33 years, he suddenly had an attack of severe throbbing headache, which was mainly left parietal, with nausea and photophobia. During the headache, his right extremities were paralyzed and he became aphasic. He had lost a partial memory of the event All these symptoms had gone within 24 hours. Thereafter, the same headache occurred about once a month. Neurological examination revealed a mild truncal ataxia and ataxic dysarthria. Electroencephalography (EEG) showed intermittent delta waves restricted over the left fronto-temporal region. Brain MRI showed a moderate atrophy of superior cerebellar vermis and anterior cerebellar lobe. The diagnosis of sporadic hemiplegic migraine (SHM) with cerebellar ataxia was made. Our case was very similar to familial hemiplegic migraine (FHM) 1, of which some families are accompanied with transient amnesia, cerebellar ataxia and EEG abnormality. Although we did not detect any mutations in CACNA1A gene previously reported in FHM1, our case might share same pathogenesis with FHM1.
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PMID:[Case of sporadic hemiplegic migraine with cerebellar ataxia]. 1959 4

A female patient presented with horizontal gaze nystagmus, mild cerebellar ataxia, recurrent headache and hemiplegia since childhood with cerebellar atrophy on magnetic resonance imaging. Genetic analysis revealed a CACNA1A gene mutation, leading to a diagnosis of familial hemiplegic migraine (FHM1). FHM is very rare, but should be considered as a differential diagnosis for childhood cerebellar symptoms and/or cerebellar atrophy. To avoid missing FHM1, a detailed clinical history including headache or hemiplegia is essential. Oral acetazolamide during the aura phase, comprising mild headache and abnormal leg sensation, relieved these symptoms in this patient, suggesting that acetazolamide could represent a first line of treatment.
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PMID:Genetic diagnosis and acetazolamide treatment of familial hemiplegic migraine. 2054 93

Several episodic neurological diseases, including familial hemiplegic migraine (FHM) and different types of epilepsy, are caused by mutations in ion channels, and hence classified as channelopathies. The classification of FHM as a channelopathy has introduced a new perspective in headache research and has strengthened the idea of migraine as a disorder of neural excitability. Here we review recent studies of the functional consequences of mutations in the CACNA1A and SCNA1A genes (encoding the pore-forming subunit of Ca(V)2.1 and Na(V)1.1 channels) and the ATPA1A2 gene (encoding the alpha(2) subunit of the Na(+)/K(+) pump), responsible for FHM1, FHM3, and FHM2, respectively. These studies show that: (1) FHM1 mutations produce gain-of-function of the Ca(V)2.1 channel and, as a consequence, increased glutamate release at cortical synapses and facilitation of induction and propagation of cortical spreading depression (CSD); (2) FHM2 mutations produce loss-of-function of the alpha(2) Na(+)/K(+)-ATPase; and (3) the FHM3 mutation accelerates recovery from fast inactivation of Na(V)1.5 channels. These findings are consistent with the hypothesis that FHM mutations share the ability to render the brain more susceptible to CSD, by causing excessive synaptic glutamate release (FHM1) or decreased removal of K(+) and glutamate from the synaptic cleft (FHM2) or excessive extracellular K(+) (FHM3).
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PMID:Biological science of headache channels. 2081 11


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