Spinocerebellar ataxia type 6.
01 Jun 2005-Vol. 11, Iss: 3, pp 207-209
TL;DR: A 39-year-old woman with spinocerebellar ataxia type 6 appears to be the first case reported in Hong Kong, and genetic tests revealed an expanded allele of 24 CAG repeats at the spinocephalus type 6 locus.
Abstract: We report a 39-year-old woman with spinocerebellar ataxia type 6. She presented with ataxia and a 3-year history of progressive ataxia and recurrent falls. There was no relevant family history. Genetic tests revealed an expanded allele of 24 CAG repeats at the spinocerebellar ataxia type 6 locus. This appears to be the first case reported in Hong Kong. As genetic testing becomes more widely available and clinical awareness increases, more such patients are expected to be diagnosed.
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TL;DR: The designation of the loci, SCA for spinocerebellar ataxia, indicates the involvement of at least two systems: the spinal cord and the cerebellum.
Abstract: Summary Cerebellar ataxias with autosomal dominant transmission are rare, but identification of the associated genes has provided insight into the mechanisms that could underlie other forms of genetic or non-genetic ataxias. In many instances, the phenotype is not restricted to cerebellar dysfunction but includes complex multisystemic neurological deficits. The designation of the loci, SCA for spinocerebellar ataxia, indicates the involvement of at least two systems: the spinal cord and the cerebellum. 11 of 18 known genes are caused by repeat expansions in the corresponding proteins, sharing the same mutational mechanism. All other SCAs are caused by either conventional mutations or large rearrangements in genes with different functions, including glutamate signalling (SCA5/ SPTBN2 ) and calcium signalling (SCA15/16/ ITPR1 ), channel function (SCA13/ KCNC3 , SCA14/ PRKCG , SCA27/ FGF14 ), tau regulation (SCA11/ TTBK2 ), and mitochondrial activity (SCA28/ AFG3L2 ) or RNA alteration (SCA31/ BEAN-TK2 ). The diversity of underlying mechanisms that give rise to the dominant cerebellar ataxias need to be taken into account to identify therapeutic targets.
566 citations
TL;DR: The molecular properties of calcium channels are reviewed, their multiple roles in synaptic plasticity are considered, and their potential involvement in this wide range of neuropsychiatric diseases is discussed.
320 citations
Cites background from "Spinocerebellar ataxia type 6."
...1 channels encode a long glutamine repeat sequence (Kordasiewicz et al., 2006; Rajakulendran et al., 2010; Solodkin and Gomez, 2012; Zhuchenko et al., 1997)....
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University of Florida1, University of Utah2, University of California, Los Angeles3, University of Chicago4, Emory University5, Harvard University6, Johns Hopkins University7, University of South Florida8, University of Michigan9, University of Minnesota10, Columbia University11, University of California, San Francisco12, National Institutes of Health13
TL;DR: It is concluded that progression rates of these SCAs were comparable between US and Europe cohorts, suggesting the feasibility of international collaborative clinical studies.
Abstract: Background: All spinocerebellar ataxias (SCAs) are rare diseases. SCA1, 2, 3 and 6 are the four most common SCAs, all caused by expanded polyglutamine-coding CAG repeats. Their pathomechanisms are becoming increasingly clear and well-designed clinical trials will be needed. Methods: To characterize the clinical manifestations of spinocerebellar ataxia (SCA) 1, 2, 3 and 6 and their natural histories in the United States (US), we conducted a prospective multicenter study utilized a protocol identical to the European consortium study, using the Scale for the Assessment and Rating of Ataxia (SARA) score as the primary outcome, with follow-ups every 6 months up to 2 years. Results: We enrolled 345 patients (60 SCA1, 75 SCA2, 138 SCA3 and 72 SCA6) at 12 US centers. SCA6 patients had a significantly later onset, and SCA2 patients showed greater upper-body ataxia than patients with the remaining SCAs. The annual increase of SARA score was greater in SCA1 patients (mean ± SE: 1.61 ± 0.41) than in SCA2 (0.71 ± 0.31), SCA3 (0.65 ± 0.24) and SCA6 (0.87 ± 0.28) patients (p = 0.049). The functional stage also worsened faster in SCA1 than in SCA2, 3 and 6 (p = 0.002). Conclusions: The proportions of different SCA patients in US differ from those in the European consortium study, but as in the European patients, SCA1 progress faster than those with SCA2, 3 and 6. Later onset in SCA6 and greater upper body ataxia in SCA2 were noted. We conclude that progression rates of these SCAs were comparable between US and Europe cohorts, suggesting the feasibility of international collaborative clinical studies.
99 citations
Cites background from "Spinocerebellar ataxia type 6."
...Although these SCAs are all rare, with an estimated prevalence of less than 4/100,000 for each SCA [4-8], SCA1, 2, 3 and 6 are the most common among all SCAs....
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TL;DR: Chronic administration of the FDA-approved drug 4-aminopyridine (4-AP), which targets potassium channels, alleviated motor coordination deficits and restored cerebellar Purkinje cell firing precision to wildtype (WT) levels in SCA684Q/84Q mice both in acute slices and in vivo.
Abstract: Spinocerebellar ataxia type 6 (SCA6) is a devastating midlife-onset autosomal dominant motor control disease with no known treatment. Using a hyper-expanded polyglutamine (84Q) knock-in mouse, we found that cerebellar Purkinje cell firing precision was degraded in heterozygous (SCA684Q/+) mice at 19 months when motor deficits are observed. Similar alterations in firing precision and motor control were observed at disease onset at 7 months in homozygous (SCA684Q/84Q) mice, as well as a reduction in firing rate. We further found that chronic administration of the FDA-approved drug 4-aminopyridine (4-AP), which targets potassium channels, alleviated motor coordination deficits and restored cerebellar Purkinje cell firing precision to wildtype (WT) levels in SCA684Q/84Q mice both in acute slices and in vivo. These results provide a novel therapeutic approach for treating ataxic symptoms associated with SCA6.
72 citations
Cites background from "Spinocerebellar ataxia type 6."
...Mouse models fall broadly into two classes: (1) knock-in models with hyper-expanded polyQ repeats6,7, or (2) models with overexpression of pathological C-terminus fragments of the α 1A subunit of the P/Q channel8,9....
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TL;DR: There appears to be an inescapable obligatory dependence on sensory-prediction error-based learning-even when this system is impaired in patients with cerebellar disease.
Abstract: Systematic perturbations in motor adaptation tasks are primarily countered by learning from sensory-prediction errors, with secondary contributions from other learning processes. Despite the availability of these additional processes, particularly the use of explicit re-aiming to counteract observed target errors, patients with cerebellar degeneration are surprisingly unable to compensate for their sensory-prediction error deficits by spontaneously switching to another learning mechanism. We hypothesized that if the nature of the task was changed-by allowing vision of the hand, which eliminates sensory-prediction errors-patients could be induced to preferentially adopt aiming strategies to solve visuomotor rotations. To test this, we first developed a novel visuomotor rotation paradigm that provides participants with vision of their hand in addition to the cursor, effectively setting the sensory-prediction error signal to zero. We demonstrated in younger healthy control subjects that this promotes a switch to strategic re-aiming based on target errors. We then showed that with vision of the hand, patients with cerebellar degeneration could also switch to an aiming strategy in response to visuomotor rotations, performing similarly to age-matched participants (older controls). Moreover, patients could retrieve their learned aiming solution after vision of the hand was removed (although they could not improve beyond what they retrieved), and retain it for at least 1 year. Both patients and older controls, however, exhibited impaired overall adaptation performance compared to younger healthy controls (age 18-33 years), likely due to age-related reductions in spatial and working memory. Patients also failed to generalize, i.e. they were unable to adopt analogous aiming strategies in response to novel rotations. Hence, there appears to be an inescapable obligatory dependence on sensory-prediction error-based learning-even when this system is impaired in patients with cerebellar disease. The persistence of sensory-prediction error-based learning effectively suppresses a switch to target error-based learning, which perhaps explains the unexpectedly poor performance by patients with cerebellar degeneration in visuomotor adaptation tasks.
45 citations
References
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TL;DR: There is a direct correlation between the size of the (CAG)n repeat expansion and the age–of–onset of SCA1, with larger alleles occurring in juvenile cases.
Abstract: Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant disorder characterized by neurodegeneration of the cerebellum, spinal cord and brainstem. A 1.2-Megabase stretch of DNA from the short arm of chromosome 6 containing the SCA1 locus was isolated in a yeast artificial chromosome contig and subcloned into cosmids. A highly polymorphic CAG repeat was identified in this region and was found to be unstable and expanded in individuals with SCA1. There is a direct correlation between the size of the (CAG)n repeat expansion and the age-of-onset of SCA1, with larger alleles occurring in juvenile cases. We also show that the repeat is present in a 10 kilobase mRNA transcript. SCA1 is therefore the fifth genetic disorder to display a mutational mechanism involving an unstable trinucleotide repeat.
1,586 citations
"Spinocerebellar ataxia type 6." refers background in this paper
...The genes for SCA1 and SCA6 were identified in 1993 and 1997 respectively.(1,5) The author’s hospital introduced genetic testing for the disorders in March 2001....
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TL;DR: It is concluded that a small polyglutamine expansion in the human α1A calcium channel is most likely the cause of a newly classified autosomal dominant spinocerebellar ataxia, SCA6.
Abstract: A polymorphic CAG repeat was identified in the human α1A voltage-dependent calcium channel subunit. To test the hypothesis that expansion of this CAG repeat could be the cause of an inherited progressive ataxia, we genotyped a large number of unrelated controls and ataxia patients. Eight unrelated patients with late onset ataxia had alleles with larger repeat numbers (21‐27) compared to the number of repeats (4‐16) in 475 non‐ataxia individuals. Analysis of the repeat length in families of the affected individuals revealed that the expansion segregated with the phenotype in every patient. We identified six isoforms of the human α1A calcium channel subunit. The CAG repeat is within the open reading frame and is predicted to encode glutamine in three of the isoforms. We conclude that a small polyglutamine expansion in the human α1A calcium channel is most likely the cause of a newly classified autosomal dominant spinocerebellar ataxia, SCA6.
1,558 citations
TL;DR: The results show that EA2 and SCA6 are the same disorder with a high phenotypic variability, at least partly related to the number of repeats, and suggest that the small CAG expansions may not be as stable as previously reported.
Abstract: Point mutations of the CACNA1A gene coding for the alpha 1A voltage-dependent calcium channel subunit are responsible for familial hemiplegic migraine (FHM) and episodic ataxia type 2 (EA2). In addition, expansions of the CAG repeat motif at the 3' end of the gene, smaller than those responsible for dynamic mutation disorders, were found in patients with a progressive spinocerebellar ataxia, named SCA6. In the present work, the analysis of two new families with small CAG expansions of the CACNA1A gene is presented. In one family, with a clinical diagnosis of EA2, a CAG23 repeat allele segregated in patients showing different interictal symptoms, ranging from nystagmus only to severe progressive cerebellar ataxia. No additional mutations in coding and intron-exon junction sequences in disequilibrium with the CAG expansion were found. In the second family, initially classified as autosomal dominant cerebellar ataxia of unknown type, an inter-generational allele size change showed that a CAG20 allele was associated with an EA2 phenotype and a CAG25 allele with progressive cerebellar ataxia. These results show that EA2 and SCA6 are the same disorder with a high phenotypic variability, at least partly related to the number of repeats, and suggest that the small expansions may not be as stable as previously reported. A refinement of the coding and intron-exon junction sequences of the CACNA1A gene is also provided.
275 citations
"Spinocerebellar ataxia type 6." refers background in this paper
...Age of onset varies from 19 to 72 years of age, but is usually between 43 and 52 years of age.(17,18) There are no diagnostic features specific for SCA6....
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...High cortical function is usually intact and life span is not affected.(17,18) Age of onset varies from 19 to 72 years of age, but is usually between 43 and 52 years of age....
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TL;DR: Clinical and quantitative measurement of extraocular movements demonstrated a characteristic pattern of ocular motor and vestibular abnormalities, including horizontal and vertical nystagmus and an abnormal vestibulo‐ocular reflex, which identifies a distinct phenotype associated with this newly recognized form of dominant SCA.
Abstract: Spinocerebellar ataxia type 6 (SCA6) was recently identified as a form of autosomal dominant cerebellar ataxia associated with small expansions of the trinucleotide repeat (CAG)n in the gene CACNL1A4 on chromosome 19p13, which encodes the α1 subunit of a P/Q-type voltage-gated calcium channel. We describe clinical, genetic, neuroimaging, neuropathological, and quantitative oculomotor studies in four kindreds with SCA6. We found strong genetic linkage of the disease to the CACNL1A4 locus and strong association with the expanded (CAG)n alleles in two large ataxia kindreds. The expanded alleles were all of a single size (repeat number) within the two large kindreds, numbering 22 and 23 repeat units. It is noteworthy that the age of onset of ataxia ranged from 24 to 63 years among all affected individuals, despite the uniform repeat number. Radiographically and pathologically, there was selective atrophy of the cerebellum and extensive loss of Purkinje cells in the cerebellar cortex. In addition, clinical and quantitative measurement of extraocular movements demonstrated a characteristic pattern of ocular motor and vestibular abnormalities, including horizontal and vertical nystagmus and an abnormal vestibulo-ocular reflex. These studies identify a distinct phenotype associated with this newly recognized form of dominant SCA.
268 citations
"Spinocerebellar ataxia type 6." refers background in this paper
...CAG expansion in SCA6 may have a direct pathogenic effect on the function of α1A-calcium channels.(1,17,21)...
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...Age of onset varies from 19 to 72 years of age, but is usually between 43 and 52 years of age.(17,18) There are no diagnostic features specific for SCA6....
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...High cortical function is usually intact and life span is not affected.(17,18) Age of onset varies from 19 to 72 years of age, but is usually between 43 and 52 years of age....
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...De-novo gene mutation may occur but the incidence is unknown.(13,17,19,21)...
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TL;DR: It is shown that, under appropriate conditions, binding and unbinding reactions of single protons and deuterium ions to a single site on the L-type calcium channel can be resolved and the protonation and deprotonation rates quantified, which considerably exceeds previous estimates obtained in simpler systems.
Abstract: Protons participate in most biologically important reactions, as substrates, products, cofactors and modulators, and proton transport is an essential step in energy transduction The dynamics of protonation reactions have been studied extensively in solution and in model systems involving lipid-water interfaces, but have never been resolved at the timescale of the elementary molecular event Here we show that, under appropriate conditions, binding and unbinding reactions of single protons and deuterium ions to a single site on the L-type calcium channel can be resolved and the protonation and deprotonation rates quantified The protonation rate constant considerably exceeds previous estimates obtained in simpler systems The functional consequences of channel protonation is a threefold reduction of the channel conductance, independent of the applied voltage The data are consistent with the presence of a single protonatable group with pK in the physiological pH range, close to the external mouth of the channel The two conductance levels of the open channel might be explained by greatly differing local potentials associated with the protonated and deprotonated state of the group
189 citations