Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 subtype of migraine with hemiparesis during attacks. We scanned 10 families with FHM without mutations in the CACNA1A (FHM1) and ATP1A2 (FHM2) genes. We identified the novel p.L1649Q mutation (c.4946T>A) in Na(v)1.1 sodium channel gene SCN1A (FHM3) in a North American kindred with FHM without associated ataxia or epilepsy. Functional analysis of the mutation, introduced in the highly homologous human SCN5A, revealed markedly slowed inactivation and a two-fold faster recovery from fast inactivation predicting enhanced neuronal excitation. Our findings establish the role of neuronal Na(v)1.1 sodium channels in FHM and reinforce the involvement of ion channel dysfunction in the pathogenesis of this episodic brain disorder.
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PMID:The novel p.L1649Q mutation in the SCN1A epilepsy gene is associated with familial hemiplegic migraine: genetic and functional studies. Mutation in brief #957. Online. 1739 47

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