Impaired Eye Movements in Presymptomatic Spinocerebellar Ataxia Type 6

Department of Neuroscience, University of Minnesota, Minneapolis 55455, USA.
Archives of neurology (Impact Factor: 7.42). 05/2008; 65(4):530-6. DOI: 10.1001/archneur.65.4.530
Source: PubMed


Early detection of impaired neurological function in neurodegenerative diseases may aid in understanding disease pathogenesis and timing of therapeutic trials.
To identify early abnormalities of ocular motor function in individuals who have the spinocerebellar ataxia type 6 (SCA6) gene (CACNA1A) but no clinical symptoms.
Physiological techniques were used to record and analyze eye movements and postural sway.
Four presymptomatic and 5 ataxic patients with SCA6, genetically identified, and 10 healthy controls.
Presymptomatic individuals had normal postural sway but definite ocular motor abnormalities. Two had a low-amplitude horizontal gaze-evoked nystagmus, 1 of whom had a significantly decreased eye velocity for upward saccades and an abnormal frequency of square-wave jerks. Another had abnormal square-wave jerks and a fourth had a reduced gain for pursuit tracking. Not all of the presymptomatic patients had the same findings, but a multivariate analysis discriminated the presymptomatic patients, as a group, from healthy controls and the ataxic patients.
Among the earliest functional deficits in SCA6 are eye movement abnormalities, including impaired saccade velocity, saccade metrics, and pursuit gain. This suggests that early functional impairments are caused by cellular dysfunction and/or loss in the posterior cerebellar vermis and flocculus. These findings might help to determine the timing of a treatment and to define variables that could be used as outcome measures for the efficacy of therapeutic trials.

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    • "A large-scale study including 107 SCA6 patients (Jacobi et al. 2012) showed that the disruption of smooth-pursuit movements had the highest prevalence (92.5%) of the ocular motor deficits. Additionally, by using sensitive eye movement recording techniques (Christova et al. 2008), alterations in saccadic (velocity and metrics) as well as smooth-pursuit gain of eye movements in presymptomatic SCA6 subjects have been reported. Interestingly, both saccades and smooth-pursuit eye movements are known to place a high computational demand on the cerebellum, particularly the vermis (Konen et al. 2005). "
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    ABSTRACT: Spinocerebellar ataxia 6 (SCA6), an autosomal dominant degenerative disease, is characterized by diplopia, gait ataxia, and incoordination due to severe progressive degeneration of Purkinje cells in the vestibulo- and spinocerebellum. Ocular motor deficits are common, including difficulty fixating on moving objects, nystagmus and disruption of smooth pursuit movements. In presymptomatic SCA6, there are alterations in saccades and smooth-pursuit movements. We sought to assess functional and structural changes in cerebellar connectivity associated with a visual task, hypothesizing that gradual changes would parallel disease progression. We acquired functional magnetic resonance imaging and diffusion tensor imaging data during a passive smooth-pursuit task in 14 SCA6 patients, representing a range of disease duration and severity, and performed a cross-sectional comparison of cerebellar networks compared with healthy controls. We identified a shift in activation from vermis in presymptomatic individuals to lateral cerebellum in moderate-to-severe cases. Concomitantly, effective connectivity between regions of cerebral cortex and cerebellum was at its highest in moderate cases, and disappeared in severe cases. Finally, we noted structural differences in the cerebral and cerebellar peduncles. These unique results, spanning both functional and structural domains, highlight widespread changes in SCA6 and compensatory mechanisms associated with cerebellar physiology that could be utilized in developing new therapies. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail:
    Cerebral Cortex 07/2015; DOI:10.1093/cercor/bhv154 · 8.67 Impact Factor
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    • "Sizes of expanded repeat allele, age at onset, age, and disease duration have been described as factors that might influence clinical expression of the common SCAs [15-17]. Although neuropathology of the polyglutamine-associated SCAs is generally widespread over the cerebellum, brainstem and cerebral hemisphere in the advance stage of the diseases [18], observations of some non-ataxic signs such as slow saccade in presymptomatic carriers or at the early symptomatic stage suggest that other neurons apart from cerebellar neurons may also be similarly vulnerable to the pathological process caused by the polyglutamine-associated SCAs [19,20]. Slow saccade represents loss of excitatory burst neuronal function, whose neurons initiate the pulse sequence of saccadic eye movement [21]. "
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    ABSTRACT: Non-ataxic symptoms of spinocerebellar ataxias (SCAs) vary widely and often overlap with various types of SCAs. Duration and severity of the disease and genetic background may play a role in such phenotypic diversity. We conducted the study in order to study clinical characteristics of common SCAs in Thailand and the factors that may influence their phenotypes. 131 (49.43%) out of 265 Thai ataxia families with cerebellar degeneration had positive tests for SCA1, SCA2, Machado-Joseph disease (MJD) or SCA6. The study evaluated 83 available families including SCA1 (21 patients), SCA2 (15), MJD (39) and SCA6 (8). Comparisons of frequency of each non-ataxic sign among different SCA subtypes were analysed. Multivariate logistic regression analyses were undertaken to analyze parameters in association with disease severity and size of CAG repeat. Mean ages at onset were not different among patients with different SCAs (40.31 +/- 11.33 years, mean +/- SD). Surprisingly, SCA6 patients often had age at onset and phenotypes indistinguishable from SCA1, SCA2 and MJD. Frequencies of ophthalmoparesis, nystagmus, hyperreflexia and areflexia were significantly different among the common SCAs, whilst frequency of slow saccade was not. In contrast to Caucasian patients, parkinsonism, dystonia, dementia, and facial fasciculation were uncommon in Thai patients. Multivariate logistic regression analysis demonstrated that ophthalmoparesis (p < 0.001) and sensory impairment (p = 0.025) were associated with the severity of the disease. We described clinical characteristics of the 4 most common SCAs in Thailand accounting for almost 90% of familial spinocerebellar ataxias. There were some different observations compared to Caucasian patients including earlier age at onset of SCA6 and the paucity of extrapyramidal features, cognitive impairment and facial fasciculation. Severity of the disease, size of the pathological CAG repeat allele, genetic background and somatic heterogeneity of pathological alleles may influence clinical expressions of these common SCAs.
    BMC Neurology 04/2014; 14(1):75. DOI:10.1186/1471-2377-14-75 · 2.04 Impact Factor

  • 01/1995; DOI:10.1016/S0167-9449(06)80114-X
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