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

Dominantly inherited, late-onset pure cerebellar ataxia is a group of genetically heterogeneous neurodegenerative disorders. Approximately half of these disorders in the Japanese population are caused by moderate expansion of a CAG repeat in the coding region of the CACNA1A gene on chromosome 19p13 (SCA6). However, neither the loci nor the specific mutations for the remaining disorders have been determined. We performed systematic linkage analysis in a three-generation Japanese family with a locus or mutation that differed from those of known spinocerebellar ataxias. The family members with a late onset (> or =39 years old) exhibited pure cerebellar ataxia, whereas those with an early onset (< or =27 years old) first showed intermittent axial myoclonus followed by ataxia. Other neurological signs were sparse, and neuroimaging studies revealed that atrophy was confined to the cerebellum. Multipoint analysis and haplotype reconstruction ultimately traced this novel spinocerebellar ataxia locus (SCA14) to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter (Zmax = 4.08, corrected for age-dependent penetrance).
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PMID:A novel locus for dominant cerebellar ataxia (SCA14) maps to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter. 1093 65

Mutations in the brain specific P/Q type Ca2+ channel alpha1 subunit gene, CACNA1A, have been identified in three clinically distinct disorders, viz. episodic ataxia type 2 (EA-2), familial hemiplegic migraine (FHM) and spinocerebellar ataxia 6 (SCA6). For individuals with EA-2, the mutations described thus far are presumed to result in a truncated protein product. Several different missense mutations have been identified in patients with FHM. At least two of these mutations have been identified on two different chromosome 19p13 haplotypes and thus represent recurrent mutations. In the present study, we have screened several individuals for mutations in all 47 exons in the CACNA1A gene by single-strand conformation analysis. We have characterised a novel missense mutation, G5260A, in exon 32 in a family segregating for EA-2. The consequence of this mutation is an amino acid substitution at a highly conserved position within the CACNA1A gene. This represents the first point mutation not resulting in a proposed truncated protein. Furthermore, this mutation has been detected in a family member with mild clinical signs including only migraine. Additionally, a second previously identified recurrent muta tion, C2272T, in exon 16 has been discovered in a patient with FHM.
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PMID:Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM. 1098 55

Familial hemiplegic migraine, episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 are allelic disorders of the CACNA1A gene (coding for the alpha(1A) subunit of P/Q calcium channels), usually associated with different types of mutations (missense, protein truncating, and expansion, respectively). However, the finding of expansion and missense mutations in patients with EA2 has blurred this genotype-phenotype correlation. We report the first functional analysis of a new missense mutation, associated with an EA2 phenotype-that is, T-->C transition of nt 4747 in exon 28, predicted to change a highly conserved phenylalanine residue to a serine at codon 1491, located in the putative transmembrane segment S6 of domain III. Patch-clamp recording in HEK 293 cells, coexpressing the mutagenized human alpha(1A-2) subunit, together with human beta(4) and alpha(2)delta subunits, showed that channel activity was completely abolished, although the mutated protein is expressed in the cell. These results indicate that a complete loss of P/Q channel function is the mechanism underlying EA2, whether due to truncating or to missense mutations.
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PMID:Complete loss of P/Q calcium channel activity caused by a CACNA1A missense mutation carried by patients with episodic ataxia type 2. 1117 22

We describe here familial dyskinesia and facial myokymia (FDFM), a novel autosomal dominant disorder characterized by adventitious movements that sometimes appear choreiform and that are associated with perioral and periorbital myokymia. We report a 5-generation family with 18 affected members (10 males and 8 females) with FDFM. The disorder has an early childhood or adolescent onset. The involuntary movements are paroxysmal at early ages, increase in frequency and severity, and may become constant in the third decade. Thereafter, there is no further deterioration, and there may even be improvement in old age. The adventitious movements are worsened by anxiety but not by voluntary movement, startle, caffeine, or alcohol. The disease is socially disabling, but there is no intellectual impairment or decrease in lifespan. A candidate gene and haplotype analysis was performed in 9 affected and 3 unaffected members from 3 generations of this family using primers for polymorphic loci closely flanking or within genes of interest. We excluded linkage to 11 regions containing genes associated with chorea and myokymia: 1) the Huntington disease gene on chromosome 4p; 2) the paroxysmal dystonic choreoathetosis gene at 2q34; 3) the dentatorubral-pallidoluysian atrophy gene at 12p13; 4) the choreoathetosis/spasticity disease locus on 1p that lies in a region containing a cluster of potassium (K+) channel genes; 5) the episodic ataxia type 1 (EA1) locus on 12p that contains the KCNA1 gene and two other voltage-gated K+ channel genes, KCNA5 and KCNA6; 6) the chorea-acanthocytosis locus on 9q21; 7) the Huntington-like syndrome on 20p; 8) the paroxysmal kinesigenic dyskinesia locus on 16p11.2-q11.2; 9) the benign hereditary chorea locus on 14q; 10) the SCA type 5 locus on chromosome 11; and 11) the chromosome 19 region that contains several ion channels and the CACNA1A gene, a brain-specific P/Q-type calcium channel gene associated with ataxia and hemiplegic migraine. Our results provide further evidence of genetic heterogeneity in autosomal dominant movement disorders and suggest that a novel gene underlies this new condition.
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PMID:Familial dyskinesia and facial myokymia (FDFM): a novel movement disorder. 1131 Jun 26

We describe a peculiar form of late onset paroxysmal cerebellar ataxia including clinical features similar to episodic ataxia type 2 (EA2) but unresponsive to acetazolamide. Four unrelated patients were clinically investigated. Neuropathological examination was performed in one patient and molecular analysis in all four. All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis in three patients. In addition, the length of the CAG repeat was determined in all four patients. The four patients were in their 60s at the onset of the disease, which was characterized by cerebellar ataxia attacks lasting from a few minutes to 1-2 h and occurring mainly in the morning. In the interictal period a nystagmus was present together with a slowly progressive cerebellar ataxia over the years. The neuropathological examination disclosed a dramatic loss of Purkinje cells mainly in the vermis. Moreover, certain cerebellar granular neurons had a strong cytoplasmic staining at immunopathological examination with an anti-tau protein serum. Search for truncating mutations or CAG repeat expansion in CACNA1A was negative. This late-onset paroxysmal cerebellar ataxia with neuropathological lesions restricted to Purkinje cells and with negative results both for truncating mutations and CAG expansion in the CACNA1A gene represents a new entity. Further studies are needed to delineate the underlying process.
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PMID:Sporadic late onset paroxysmal cerebellar ataxia in four unrelated patients: a new disease? 1262 85

The vestibulo-ocular reflexes stabilize retinal images during head movements. While there is a wealth of information about the interaction between the cerebellum and vestibulo-ocular reflexes mediated by the semicircular canals, little is known about the role of the cerebellum in the generation of the otolith-mediated linear vestibulo-ocular reflex (LVOR). By means of transient linear acceleration of the whole body along the interaural axis, we examined the LVOR in six patients with hereditary cerebellar ataxia due to mutations of the calcium channel gene CACNA1A, five with spinocerebellar ataxia type 6 (SCA6) and one with episodic ataxia type 2 (EA-2). Six age-matched normal subjects served as controls. Using a peak acceleration of 0.5 g in combination with recording by the binocular scleral magnetic search coil method, it was possible to study the latency and sensitivity of the LVOR in the first 150 ms after motion onset. The normal LVOR showed a significant dependence on viewing distance and covaried with vergence angle, and could be enhanced by the presence of a visible target. In contrast, the LVOR of ataxic patients had normal latency but significantly decreased sensitivity that was not enhanced with visible or nearer targets despite normal vergence. Substituting for the normal smooth LVOR slow phase, ataxic patients employed catch-up saccades 150-250 ms after motion onset. These findings suggest a critical role of the cerebellum in the modulation of otolith-ocular signals that is independent of motor vergence.
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PMID:Otolith function in cerebellar ataxia due to mutations in the calcium channel gene CACNA1A. 1170 95

Spinocerebellar ataxia type 6 (SCA6) is due to small expansions of a CAG repeat at the 3' end of the CACNA1A gene, coding for the alpha(1A) subunit of voltage-gated calcium channels type P/Q, expressed in the cerebellar Purkinje and granule cells. It is one of three allelic disorders, the other two being episodic ataxia type 2 (EA2), due mostly to protein truncating mutations, and familial hemiplegic migraine, associated with missense mutations. The latter disorders, due to point mutations altering the P/Q channel activity, clearly belong to the group of channelopathies. For SCA6, due to CAGn expansions, a toxic gain of function might, instead, be envisaged homologous to that of glutamine repeat disorders. A comparison between SCA6 and EA2 phenotypes performed on available literature data, shows that the clinical features of the two disorders are widely overlapping and that the differences could be accounted for with the older age of patients in the SCA6 group. A similar phenotype in the two disorders could imply the same pathogenic process. Functional analyses on cells expressing the protein with an expanded polyglutamine stretch have shown, in fact, an altered channel activity. In conclusion, available data seem to suggest that SCA6 is more likely belonging to channelopathies than to polyglutamine disorders.
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PMID:Spinocerebellar ataxia type 6: channelopathy or glutamine repeat disorder? 1171 55

This review focuses on the different molecular genetic findings in migraine. Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura, which is inherited as an autosomal dominant. Half the cases of FHM are caused by point mutations in the CACNA1A gene on the short arm of chromosome 19 (19p). The gene encodes a calcium ion channel. Other mutation types cause episodic ataxia 2 (EA-2). Expansions of the CAG repeat in the 3' end bring about spinocerebellar ataxia 6 (SCA 6). Some families with FHM link to loci on the long arm of chromosome 1 (1q). The genes have not yet been identified. Some families neither link to 1q nor to 19p. Population-based family and twin studies have shown that migraine both with and without aura have a multifactorial inheritance. The CACNA1A gene may be of importance for ordinary forms of migraine in a few families. Mutations in genes on the X chromosome, dopamine receptor genes, and the ACE gene appear to be involved in migraine in a few families, whereas genes for nitric oxide synthase, serotonin receptors, and mitochondrial DNA do not seem to be involved. The positive associations have not been reproduced in other studies and therefore they should be interpreted with care. It is to be hoped that in the next few years much more will be known about the molecular genetic mechanisms of migraine with and without aura. FHM is an ion channel disorder, and many factors suggest that migraine is also an ion channel disorder, which is consistent with the paroxysmal nature of the illness.
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PMID:[Molecular genetic findings in migraine]. 1172 84

Spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and familial hemiplegic migraine (FHM) have been known as allelic disorders, which are caused by the alteration of the alpha1A voltage-dependent calcium channel subunit. Expansions of the CAG repeat in the CACNA1A gene on the short arm of the chromosome 19 induce SCA6, and point mutations in the same gene are responsible for EA2 and FHM. In recent studies, both SCA6 and EA2 have been concurrently found in families with 26 CAG repeats without previously reported point mutations either in coding sequences or in intron-exon junctions. We describe a Korean family with CAG26 repeats in the CACNA1A gene. Some of the affected family members had progressive ataxia typical of SCA6 whereas others had episodic vertigo responsive to acetazolamide typical of EA2. Our family support that SCA6 and EA2 are allelic disorders with a high phenotypic variability.
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PMID:Spinocerebellar ataxia type 6 and episodic ataxia type 2 in a Korean family. 1174 69

Episodic ataxia type 2 is a prototypical episodic vertigo and ataxia syndrome that is caused by mutations in the calcium channel gene CACNA1A. Recent discoveries regarding the molecular mechanisms that underlie this syndrome provide a model for understanding the more common familial episodic vertigo syndromes, particularly those associated with migraine. Vertigo due to cerebrovascular disease can be of peripheral or central origin, and can mimic more benign peripheral vestibular disorders. Small infarcts in the cerebellum and lateral medulla can present with vertigo without other localizing symptoms.
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PMID:Episodic vertigo: central nervous system causes. 1179 46


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