Clinical and genetic study of autosomal recessive cerebellar ataxia type 1

Dupré, Nicolas; Gros‐Louis, François; Chrestian, Nicolas; Verreault, Steve; Brunet, Denis; Verteuil, Danielle de; Brais, Bernard; Bouchard, Jean‐Pierre; Rouleau, Guy A.

doi:10.1002/ana.21143

Cited by 81 publications

(37 citation statements)

References 13 publications

(19 reference statements)

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“…Contrary to the latter findings, our results suggest that pure, severe and diffuse cerebellar atrophy is associated with significant and specific cognitive changes. As described in earlier reports, ARCA-1 is a new recessive pure cerebellar ataxia that is caused by mutations in SYNE1 [21,22]. It shows relative homogeneity of the phenotype, despite being caused by more than seven different mutations.…”

Section: Discussionmentioning

confidence: 70%

“…All affected family members have a similar phenotype, which consists of a late-onset (mid-thirties) pure cerebellar ataxia with slow progression. This new disease entity has been named autosomal recessive cerebellar ataxia type 1 (ARCA-1) or recessive ataxia of Beauce [21,22] and is caused by mutations in the SYNE1 gene. ARCA-1 represents a unique model to explore the role of the cerebellum in cognition because all patients show diffuse severe cerebellar atrophy without involvement of other areas of the central or peripheral nervous system.…”

Section: Introductionmentioning

confidence: 99%

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Cognitive Impairment in ARCA-1, a Newly Discovered Pure Cerebellar Ataxia Syndrome

et al. 2010

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Cerebellar contribution to non-motor functions has been supported by several animal, human and functional neuroimaging studies. Which cognitive skills and to what extent the cerebrocerebellar loops contribute remain unclear, however. Among other reasons, this may be explained by the fact that authors have studied patients with extracerebellar lesions. The goal of this study was to explore the role of the cerebellum in cognition and affect in patients with autosomal recessive cerebellar ataxia type 1 (ARCA-1), a newly described inherited cerebellar disease characterised by middle-age onset of ataxia as well as pure, severe and diffuse cerebellar atrophy. To this end, the performance of 21 ARCA-1 patients was compared to that of 21 normal controls paired for age and education on a 3-h battery of attention, executive, visuospatial and memory skills. Results indicated similar IQ, naming and declarative memory abilities between groups. ARCA-1 patients showed significant deficits in attention (attention span, speed of information processing, sustained attention), verbal working memory and visuospatial/visuoconstructional skills (3-D drawings, copy of a complex figure). Functional brain imaging in a subset of patients showed diffuse severe cerebellar hypometabolism associated with a small area of right parietal hypometabolism. None of the patients presented a significant affective syndrome. Correlational analyses suggested that cognitive deficits could not be explained by the severity of motor deficits, duration of disease or mood. Altogether, this study confirms that pure cerebellar damage as seen in ARCA-1 is associated with significant cognitive impairments but not with psychiatric comorbidity. These deficits are correlated with an overall moderate impact on patient's autonomy. Our data favour an indirect participation of the dorsolateral prefrontal and posterior parietal cortical areas to the cerebrocerebellar circuit.

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Section: Discussionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Cognitive Impairment in ARCA-1, a Newly Discovered Pure Cerebellar Ataxia Syndrome

et al. 2010

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“…Dupre et al [27] have identified a patient population with a pure cerebellar ataxia that has diffuse atrophy throughout the cerebellum with no additional abnormalities in the central or peripheral nervous systems. This form of ataxia has been termed autosomal recessive cerebellar ataxia type 1 (ARCA-1, or recessive ataxia of Beauce), which is caused by mutations in the SYNE-1 gene.…”

Section: Introductionmentioning

confidence: 99%

“…This form of ataxia has been termed autosomal recessive cerebellar ataxia type 1 (ARCA-1, or recessive ataxia of Beauce), which is caused by mutations in the SYNE-1 gene. This is an inherited cerebellar ataxia with an onset at middle age progressing slowly and leading to a moderate level of disability [27,28]. In order to better understand the cerebellar contributions to locomotor coordination, the cerebellar ataxia participants recruited in this study were all identified as having ARCA-1 with confirmed mutations in the SYNE-1 gene.…”

Section: Introductionmentioning

confidence: 99%

Increased Obstacle Clearance in People with ARCA-1 Results in Part from Voluntary Coordination Changes Between the Thigh and Shank Segments

2011

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Obstacle clearance can be a hazardous locomotor task if not coordinated with the utmost accuracy. The current study explored changes in leading limb segment coordination during obstacle clearance in a population with cerebellar ataxia using the planar law of intersegmental coordination. Eight participants with ARCA-1, caused by mutations in the SYNE-1 gene, and eight healthy adults stepped over obstacles. Healthy adults walked at natural speeds, as well as a velocity similar to the participants with cerebellar ataxia, resulting in three groups [healthy (H), matched velocity (MV) and cerebellar ataxia (CA)]. Elevation angles of the foot, shank and thigh in the sagittal plane were calculated. A principal component analysis was applied to limb segment trajectories, and a Fourier harmonic series was further used to determine temporal phase differences between adjacent segments. Although obstacle clearance was greater in the CA group, the planar nature of the 3D covariance plot of segment elevation angles, the covariance loop width and orientation did not differ between the CA, H and MV groups, suggesting that the planar patterns between elevation angles may not be heavily influenced by the cerebellum. Further analysis led to the observation of a nonlinear relationship between covariance loop width and thigh-shank fundamental harmonic phase difference, and a decrease in covariance loop width was observed when the fundamental harmonic phase difference between the thigh and shank segments is >90°. This study supports previous work that a greater safety margin is used in people with cerebellar ataxia when stepping over obstacles, but reveals a mechanism of segmental coordination to facilitate this increase in toe clearance. Further work is required to determine whether ataxia severity has an effect on the observed coordination variables.

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“…However, the majority of the sporadic adult-onset ataxias begin considerably later [ 22 ], so it is questionable if ARCA1 accounts for many of the sporadic ataxia cases. The seven point mutations described so far do not differ in clinical presentation [ 23 ]. All affect proper splicing, which results in truncation of the large protein of greater than 1000 kD that is expressed in multiple tissues, with predominant expression in cerebellar neurons.…”

Section: New Loci/new Genesmentioning

confidence: 97%

An update on inherited ataxias

Schmitz‐Hübsch

Klockgether

2008

Curr Neurol Neurosci Rep

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This article provides an overview of recent advances in the field of inherited ataxias. In the past few years, new causative mutations that broaden the diagnostic spectrum of ataxias have been described. In addition, important advances have unveiled the molecular pathology of these disorders, resulting in a classification based on the pathogenetic pathways rather than clinical or genetic features. As concepts of treatment principles emerge, debate continues as to whether such concepts might be applicable to more than one genetically defined disorder or whether each ataxia disorder requires its own unique therapeutic approach. New clinical assessment instruments have been developed that will facilitate future interventional trials. A recent phase 2 clinical trial suggested a positive effect of high-dose idebenone in Friedreich's ataxia, raising hopes that a treatment option will soon be available for this disorder.

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Clinical and genetic study of autosomal recessive cerebellar ataxia type 1

Cited by 81 publications

References 13 publications

Cognitive Impairment in ARCA-1, a Newly Discovered Pure Cerebellar Ataxia Syndrome

Cognitive Impairment in ARCA-1, a Newly Discovered Pure Cerebellar Ataxia Syndrome

Increased Obstacle Clearance in People with ARCA-1 Results in Part from Voluntary Coordination Changes Between the Thigh and Shank Segments

An update on inherited ataxias

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