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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disorder caused by abnormal expansions of a trinucleotide CAG repeat in exon 47 of the CACNA1A gene, which encodes the alpha1A subunit of the P/Q-type voltage-gated calcium channel. The CAG repeat expansion is translated into an elongated polyglutamine tract in the carboxyl terminus of the alpha1A subunit. The alpha1A subunit is the main pore-forming subunit of the P/Q-type calcium channel. Patients with SCA6 suffer from a severe form of progressive ataxia and cerebellar dysfunction. Design of treatments for this disorder will depend on better definition of the mechanism of disease. As a disease arising from a mutation in an ion channel gene, SCA6 may behave as an ion channelopathy, and may respond to attempts to modulate or correct ion channel function. Alternatively, as a disease in which the mutant protein contains an expanded polyglutamine tract, SCA6 may respond to the targets of drug therapies developed for Huntington's disease and other polyglutamine disorders. In this review we will compare SCA6 to other polyglutamine diseases and channelopathies, and we will highlight recent advances in our understanding of alpha1A subunits and SCA6 pathology. We also propose a mechanism for how two seemingly divergent hypotheses can be combined into a cohesive model for disease progression.
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PMID:Molecular pathogenesis of spinocerebellar ataxia type 6. 1739 39

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

In infancy, the autosomal dominant inherited ataxias are severe neurological diseases, due to inherited mutations of ion channels. The main forms are: episodic ataxia type 1 (EA1), episodic ataxia type 2 (EA2), spinocerebellar ataxia type 6 (SCA6). EA1 is due to a mutation in KCNA1, the gene encoding human Kv1.1 on chromosome 12p13, which contributes as a subunit to the formation of potassium channels in motor nerve terminals and in many central nervous system neurones. To date, there are fifteen different mutations, which affect potassium channel's properties and lead to phenotypic variability and to different responses to therapy. EA2 can result from mutations in the CACNA1A gene, encoding calcium channels on chromosome 19p13.1 and widely distributed throughout the central nervous system. To date, associated with EA2, in the CACNA1A gene thirty different mutations have been described, resulting in altered or truncated protein products and, as a consequence, in nonfunctional calcium channels. There is phenotypic variability, also inside the same family, without correlation genotype-phenotype. SCA6 is a progressive neurodegenerative disease due to mutations of the CACNA1A gene. CACNA1A is responsible for both EA2 and SCA6. Nevertheless, the pathogenesis of the two diseases is different: SCA6 is associated with small expansion of a CAGn repeat, while EA2 is due to point mutations. Clinically, SCA6 is characterized by a slowly progressive development and by an inverse correlation between the number of repeats and the severity of the disease.
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PMID:[Spinocerebellar ataxias in infancy: pathogenesis of potassium and calcium channels' diseases, clinical features and therapeutical approach]. 1740 65

Primary episodic ataxias are autosomal dominant channelopathies that manifest as attacks of imbalance and incoordination. Mutations in two genes, KCNA1 and CACNA1A, cause the best characterized and account for the majority of identified cases of episodic ataxia. We summarize current knowledge of clinical and genetic diagnosis, genotype-phenotype correlations, pathophysiology and treatment of episodic ataxia syndromes. We focus on unresolved issues including phenotypic and genetic heterogeneity, lessons from animal models and technological advancement, rationale and feasibility of various treatment strategies, and shared mechanisms underlying episodic ataxia and other far more prevalent paroxysmal conditions such as epilepsy and migraine.
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PMID:Primary episodic ataxias: diagnosis, pathogenesis and treatment. 1757 81

Spinocerebellar ataxias (SCAs) are a group of clinically and genetically heterogeneous neurological diseases. The expansion of unstable microsatellite repeats has been identified as the underlying pathogenic cause of 10 subtypes of autosomal dominant SCAs. The aetiology of sporadic SCA is unknown. The aim of this study was to investigate the effect of large normal repeats in patients presenting with sporadic or familial ataxia compared to a control population. The size of the expansion was determined using a fluorescent PCR approach in 10 common SCA genes: SCA-1 (ATXN1), SCA-2 (ATXN2), SCA-3 (ATXN3), SCA-6 (CACNA1A), SCA-7 (ATXN7), SCA-8 (ATXN8OS), SCA-10 (ATXN10), SCA-12 (PPP2R2B), SCA-17 (TBP) and DRPLA (ATN1), in 165 ataxia patients and 307 controls of Welsh origin. There was no difference between cases and controls in the distribution of the large normal alleles, or in the distribution of the combined CAG repeats. The normal allele distribution in the Welsh population was largely similar to that of other Caucasian populations. Our study failed to demonstrate an effect of large normal repeats on the susceptibility to develop ataxia.
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PMID:Case control analysis of repeat expansion size in ataxia. 1796 20

Spinocerebellar ataxia type 6 (SCA6) is a common cause of dominantly inherited ataxia due to an expansion of the CAG repeat in the CACNA1A gene. Affected individuals from the same population share a common haplotype, raising the possibility that most SCA6 cases have descended from a small number of common founders across the globe. To test this hypothesis, we carried out haplotype analysis on SCA6 families from Europe, South America and the Far East, including an established de novo SCA6 expansion. A core CACNA1A disease haplotype was found in affected individuals across the globe. This was also present in the unaffected father of the de novo case, suggesting that the shared chromosome predisposes to the CAG repeat expansion at the SCA6 locus. The SCA6 expansion lies within a CpG island, which could act as a cis-acting element predisposing to repeat expansion as for other CAG/CTG repeat diseases. Polymorphic variation in this region may explain the high-risk haplotype found in SCA6 families.
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PMID:Pathogenic expansions of the SCA6 locus are associated with a common CACNA1A haplotype across the globe: founder effect or predisposing chromosome? 1828 29

Episodic ataxia type 2(EA-2) is a rare, autosomal dominant disorder characterised by recurrent episodes of ataxia and dysarthria,due to mutations in the CACNA1A gene on chromosome 19 encoding voltage-dependent Ca2+ channels. The aim of the present study was to explore whether axonal membrane properties, assessed using nerve excitability techniques, were abnormal in patients with EA-2 . Nerve excitability techniques were applied to the median nerve of three individuals from three generations of a single family, all of whom had typical features of EA-2. This family was found to have a novel mutation at codon 1451 of the Ca2+ channel alpha 1A subunit. Nerve excitability testing demonstrated significant abnormalities,with all patients outside the normal 95 % confidence limits in having a high rheobase and reduced early hyperpolarizing threshold electrotonus. On average there were also significant reductions in refractoriness,late sub excitability and early depolarizing threshold electrotonus. Mathematical modelling indicated that a similar pattern of abnormalities may result from a reduced voltage dependence of slow K+ channels (KCNQ channels). There are significant and distinctive changes in peripheral nerve excitability in EA-2 patients,which are presumably induced indirectly. These findings raise the possibility that excitability testing may prove a convenient screening test for patients with this suspected channelopathy.
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PMID:Axonal function in a family with episodic ataxia type 2 due to a novel mutation. 1833 96

A 71-year-old woman presented with recurrent episodes of headache accompanied by hemihypoesthesia, fever, aphasia, reduced consciousness and worsening of pre-existing ataxia. Brain imaging revealed atrophy of the cerebellum. The white cell count in the cerebrospinal fluid was slightly increased. The patient had a family history of migraine and cerebellar ataxia. DNA testing revealed a missense mutation in the CACNA1A gene, confirming the diagnosis of familial hemiplegic migraine. Familial hemiplegic migraine is a rare subtype of migraine with aura. It follows an autosomal dominant pattern of inheritance. Patients with familial hemiplegic migraine exhibit a wide spectrum of symptoms, which can hinder the diagnosis. If a patient presents with recurrent coma or encephalitis with or without cerebellar ataxia, familial hemiplegic migraine should be included in the differential diagnosis.
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PMID:[Familial hemiplegic migraine resulting in recurrent coma]. 1838 Mar 88

Of the 18 missense mutations in the CACNA1A gene, which are associated with familial hemiplegic migraine type 1 (FHM1), only mutations S218L, R583Q and T666M were identified in more than two independent families. Including the four novel families presented here, of which two represent de novo cases, the R1347Q mutation has now been identified in six families. A genotype-phenotype comparison of R1347Q mutation carriers revealed a wide clinical spectrum ranging from (trauma triggered) hemiplegic migraine with and without ataxia, loss of consciousness and epilepsy. R1347Q is the third most frequent mutation in hemiplegic migraine patients and should therefore be screened with priority for confirmation of clinical diagnosis. This study clearly demonstrates that the availability of multiple families better reflects the full clinical spectrum associated with FHM1 mutations.
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PMID:CACNA1A R1347Q: a frequent recurrent mutation in hemiplegic migraine. 1840 34

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


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