Oculomotor deficits in spinocerebellar ataxia type 3: Potential biomarkers of preclinical detection and disease progression

Wu, Chao; Chen, Dingbang; Li, Feng; Zhou, Xin; Zhang, Jiwei; You, Huajing; Liang, Xiaoyan; Pei, Zhong; Li, Xunhua

doi:10.1111/cns.12676

Cited by 41 publications

(40 citation statements)

References 30 publications

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“…These studies reported that brainstem oculomotor signs (67.9%) were the most common in their cohort of SCA3 patients (13, 14). However, brainstem oculomotor signs were less frequent (23.5%) in our SCA3 group, which was supported by another study in Chinese SCA3 patients (25). Previous studies have shown that oculomotor alterations could be detected in the preclinical stage of SCAs (26).…”

Section: Discussionsupporting

confidence: 89%

Extra-Cerebellar Signs and Non-motor Features in Chinese Patients With Spinocerebellar Ataxia Type 3

Yuan

Hou

et al. 2019

Front. Neurol.

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Objectives: Our study attempted to systematically explore the prevalence of extra-cerebellar signs and non-motor symptoms, such as anxiety, depression, fatigue, excessive daytime sleepiness (EDS) and sleep disturbances in a cohort of Chinese patients with spinocerebellar ataxia type 3 (SCA3), and further investigated the correlations between non-motor symptoms and clinical characteristics in SCA3 patients. Methods: This study included 68 molecular-proven SCA3 patients. Extra-cerebellar signs were evaluated with the Inventory of Non-Ataxia Symptoms (INAS). The INAS count indicated the number of non-ataxia signs in each patient. The severity of ataxia, fatigue, EDS, sleep quality, anxiety, and depression were assessed using the Scale for the assessment and rating of ataxia (SARA), Fatigue Severity Scale (FSS), Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), Hamilton Anxiety Rating Scale (HAMA), and the Hamilton Depression Rating Scale (HAMD) (24 items), respectively. Results: Extra-cerebellar signs were detected in 91.2% of all SCA3 patients and the mean total INAS count was 2.72 ± 1.88. Rigidity was the most frequent extra-cerebellar sign (47.1%, N = 32). Sensory symptoms (2.9%, N = 2) and chorea (5.9%, N = 4) were rare, and myoclonus (0%) was not found in this cohort. High frequencies of sleep disturbances (64.7%), fatigue (52.9%), depression (48.5%), and anxiety (42.6%) were detected in SCA3 patients. The Spearman correlation indicated that the HAMD score was associated with the CAG repeat length and HAMA score, while the PSQI score was correlated with the SARA and FSS score. In addition, multivariate linear regression analysis showed that the CAG repeat length, age of onset, sleep disturbances and depression were significant predictors of fatigue in SCA3 patients. Conclusions: Our study indicates that the vast majority of SCA3 patients display extra-cerebellar signs. Except for EDS, anxiety, depression, fatigue and impaired sleep quality are present in SCA3 patients. The CAG repeat length, age of onset, sleep disturbances and depression are predictors of fatigue in SCA3 patients.

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Section: Discussionsupporting

confidence: 89%

Extra-Cerebellar Signs and Non-motor Features in Chinese Patients With Spinocerebellar Ataxia Type 3

Yuan

Hou

et al. 2019

Front. Neurol.

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“…Oculomotor characteristics are recognized as distinguishing features among SCAs. Slow saccades is a key feature of SCA2 and could be detected in SCA3 but usually in late stage in our cohort (Wu et al, ). We found a mild reduced horizontal saccade velocity in both Patients 1 and 2, which could be the effect of the CAG expansions in ATXN2 , or just a coincidence of the phenotypic heterogeneity in SCA3 alternatively.…”

Section: Discussionmentioning

confidence: 55%

“…To measure the severity of ataxia, we used the Scale for the Assessment and Rating of Ataxia (SARA) that has been validated. Eye movements were recorded using video‐oculography following a central oculomotor battery that we described before (Wu et al, ). AAO was determined by a structured interview in which the patient and close family members were asked about the age of start of permanent and progressive gait instability.…”

Section: Methodsmentioning

confidence: 99%

Co‐occurrence of ATXN3 and ATXN2 repeat expansions in Chinese ataxia patients with slow saccades

Cai

You

et al. 2019

Molec Gen & Gen Med

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Background The presence of more than one polyQ‐related gene within a single individual is a rare incidence, which may provide the potential opportunity to study the combined effects of these spinocerebellar ataxia (SCA) genes. Methods We retrospectively analyzed genetic data from 112 SCA3 probands and found Patient 1 harbored expanded ATXN2 allele (33 repeats) and intermediate TBP allele (41 repeats), and Patient 2 with intermediate ATXN2 allele (32 repeats). Detailed clinical and oculomotor performances were investigated. The age at onset and oculomotor parameters of both patients were compared with matched pure SCA3 groups controlling either disease severity or CAG repeats. Results Most of the clinical phenotypes and oculomotor characteristics of these two patients were common to typical SCA3 patients. Compared to pure SCA3 groups controlling disease severity, mild reduced horizontal saccade velocity could be detected in both patients. However, mild expansions of the ATXN2 allele seemed to have no influence on the age at onset of Patient 1 but might have a mild impact on Patient 2. Conclusion Our study provides supporting evidence that mild expansions of ATXN2 may have modifying effects on SCA3 phenotype. Larger control series and longitudinal data are warranted to confirm our results.

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“…Oculomotor involvement is present at an early phase of SCA and is detectable even at premanifest stages as a higher rate of gaze-evoked nystagmus or other alterations, such as a square-wave jerk during central fixation, impaired vertical smooth pursuit, slow saccade, and a higher antisaccade error rate in SCA3 carriers than controls 13 , 38 , 39 . These alterations have been studied in detail in SCA2 patients, all of whom present specific oculomotor abnormalities (slow horizontal saccades up to saccade paresis) 40 .…”

Section: Biomarkersmentioning

confidence: 99%

Recent advances in understanding dominant spinocerebellar ataxias from clinical and genetic points of view

2018

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Spinocerebellar ataxias (SCAs) are rare types of cerebellar ataxia with a dominant mode of inheritance. To date, 47 SCA subtypes have been identified, and the number of genes implicated in SCAs is continually increasing. Polyglutamine (polyQ) expansion diseases ( ATXN1/SCA1, ATXN2/SCA2, ATXN3/SCA3, CACNA1A/SCA6, ATXN7/SCA7, TBP/SCA17, and ATN1/DRPLA) are the most common group of SCAs. No preventive or curative treatments are currently available, but various therapeutic approaches, including RNA-targeting treatments, such as antisense oligonucleotides (ASOs), are being developed. Clinical trials of ASOs in SCA patients are already planned. There is, therefore, a need to identify valid outcome measures for such studies. In this review, we describe recent advances towards identifying appropriate biomarkers, which are essential for monitoring disease progression and treatment efficacy. Neuroimaging biomarkers are the most powerful markers identified to date, making it possible to reduce sample sizes for clinical trials. Changes on brain MRI are already evident at the premanifest stage in SCA1 and SCA2 carriers and are correlated with CAG repeat size. Other potential biomarkers have also been developed, based on neurological examination, oculomotor study, cognitive assessment, and blood and cerebrospinal fluid analysis. Longitudinal studies based on multimodal approaches are required to establish the relationships between parameters and to validate the biomarkers identified.

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Oculomotor deficits in spinocerebellar ataxia type 3: Potential biomarkers of preclinical detection and disease progression

Cited by 41 publications

References 30 publications

Extra-Cerebellar Signs and Non-motor Features in Chinese Patients With Spinocerebellar Ataxia Type 3

Extra-Cerebellar Signs and Non-motor Features in Chinese Patients With Spinocerebellar Ataxia Type 3

Co‐occurrence of ATXN3 and ATXN2 repeat expansions in Chinese ataxia patients with slow saccades

Recent advances in understanding dominant spinocerebellar ataxias from clinical and genetic points of view

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