Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2

Pulst, Stefan M.; Nechiporuk, Alex; Nechiporuk, Tamilla; Gispert, Suzana; Chen, Xiao Ning; Lopes‐Cendes, Íscia; Pearlman, Susan; Starkman, Sidney; Orozco-Díaz, Guillermo; Lunkes, Astrid; deJong, Pieter J.; Rouleau, Guy A.; Auburger, Georg; Korenberg, Julie R.; Figueroa, Carla P.; Sahba, Soodabeh

doi:10.1038/ng1196-269

Cited by 1,001 publications

(700 citation statements)

References 33 publications

Supporting

Mentioning

679

Contrasting

Unclassified

Order By: Relevance

“…In the manifest stage, we could not detect any correlations of volumetric changes with genetics, disease duration or age of onset. As CAG repeat length is inversely correlated with age of onset,1, 16 this might indicate that genetic load plays a role in the early degenerative process, but may have no additional impact on volumetric changes in the manifest stage. In patients, we only observed a medium‐sized, albeit nonsignificant, association between SARA scores and reduced brainstem volumes.…”

Section: Discussionmentioning

confidence: 99%

Brain atrophy measures in preclinical and manifest spinocerebellar ataxia type 2

Reetz

Rodríguez‐Labrada²,

Dogan

et al. 2018

Ann Clin Transl Neurol

Self Cite

View full text Add to dashboard Cite

ObjectiveSpinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited neurodegenerative disease mainly affecting the cerebellum and brainstem. In this Cuban‐German research collaboration, we aimed to characterize atrophy patterns and associations with clinical measures in preclinical and manifest SCA2.MethodsIn this study, 16 nonmanifest SCA2 mutation carriers, 26 manifest patients with SCA2, and 18 healthy control subjects underwent magnetic resonance imaging, as well as genetic and clinical characterization including assessment of ataxia (Scale for the Assessment and Rating of Ataxia) and saccade velocity in Cuba were enrolled. Semiautomated quantitative volumetry of the cerebellum and brainstem, subdivided into the medulla oblongata, the pontine brainstem, and mesencephalon was performed. Additionally, the anteroposterior diameter of the pontine brainstem was measured.ResultsAnalysis of volumetric data revealed degeneration of the cerebellum and brainstem, in particular of pontine volumes and the anteroposterior diameter of the pons, in both manifest SCA2 patients and individuals at risk for SCA2 compared to controls. Comparing patients with nonataxic preclinical SCA2 mutation carriers, we found more pronounced reductions of the pontine brainstem and cerebellum in manifest SCA2. Volumetric data further showed associations with CAG repeat length and predicted age of onset in preclinical SCA2 individuals, and by trend with ataxia signs in patients. Although saccade velocity was associated with reduction in the pontine brainstem in preclinical and manifest SCA2, reduced ability to suppress interfering stimuli measured by the Stroop task was related to cerebellar volume loss in patients.InterpretationPreclinical SCA2 mutation carriers exhibit brain abnormalities, which could be targeted as surrogate parameters for disease progression and in future preventive trials.

show abstract

Section: Discussionmentioning

confidence: 99%

Brain atrophy measures in preclinical and manifest spinocerebellar ataxia type 2

Reetz

Rodríguez‐Labrada²,

Dogan

et al. 2018

Ann Clin Transl Neurol

Self Cite

View full text Add to dashboard Cite

show abstract

“…SCA2 is caused by a CAG repeat expansion in the ATXN2 gene 2, 3, 4. In most control individuals, the N‐terminal region of the gene harbors the repetitive trinucleotide sequence (CAG)8(CAA)1(CAG)4(CAA)1(CAG)8, encoding for consecutive glutamine residues.…”

Section: Geneticsmentioning

confidence: 99%

The Multiple Faces of Spinocerebellar Ataxia type 2

Antenora

Rinaldi

Roca

et al. 2017

Ann Clin Transl Neurol

View full text Add to dashboard Cite

Spinocerebellar ataxia type 2 (SCA2) is among the most common forms of autosomal dominant ataxias, accounting for 15% of the total families. Occurrence is higher in specific populations such as the Cuban and Southern Italian. The disease is caused by a CAG expansion in ATXN2 gene, leading to abnormal accumulation of the mutant protein, ataxin‐2, in intracellular inclusions. The clinical picture is mainly dominated by cerebellar ataxia, although a number of other neurological signs have been described, ranging from parkinsonism to motor neuron involvement, making the diagnosis frequently challenging for neurologists, particularly when information about the family history is not available. Although the functions of ataxin‐2 have not been completely elucidated, the protein is involved in mRNA processing and control of translation. Recently, it has also been shown that the size of the CAG repeat in normal alleles represents a risk factor for ALS, suggesting that ataxin‐2 plays a fundamental role in maintenance of neuronal homeostasis.

show abstract

“…Due to the genetic heterogeneity, patients with SCAs can develop impaired vision, dysarthria, pyramidal signs, ophthalmoplegia, extrapyramidal signs, loss of sensory function, dementia, or any combination of these abnormalities (Rossi et al., 2014; van Gaalen, Giunti, & van de Warrenburg, 2011). Among these, spinocerebellar ataxia type 2 (SCA2), one of the most frequent types, is definitely caused by an CAG repeat expansion in the ATXN2 gene (Pulst et al., 1996). Although the main clinical features of SCA2 are a series of cerebellar signs, including ataxic gait, dysarthria, and dysmetria, which highlight the involvement of cerebellum, some other symptoms such as slow saccades, cognitive impairments, peripheral neuropathy, and depression indicate the abnormalities are beyond the cerebellum (Pulst et al., 1996; Rodríguez‐Labrada et al., 2016; Schmitz‐Hübsch et al., 2011; van Gaalen et al., 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Among these, spinocerebellar ataxia type 2 (SCA2), one of the most frequent types, is definitely caused by an CAG repeat expansion in the ATXN2 gene (Pulst et al., 1996). Although the main clinical features of SCA2 are a series of cerebellar signs, including ataxic gait, dysarthria, and dysmetria, which highlight the involvement of cerebellum, some other symptoms such as slow saccades, cognitive impairments, peripheral neuropathy, and depression indicate the abnormalities are beyond the cerebellum (Pulst et al., 1996; Rodríguez‐Labrada et al., 2016; Schmitz‐Hübsch et al., 2011; van Gaalen et al., 2011). The morphological study is essential to detect affected areas of SCA2 while exploring associations between affected areas in the whole brain and clinical manifestations of SCA2 may help us more deeply understand its pathophysiological mechanism, which has remained unknown until now.…”

Section: Introductionmentioning

confidence: 99%

Voxel‐based meta‐analysis of gray and white matter volume abnormalities in spinocerebellar ataxia type 2

et al. 2018

View full text Add to dashboard Cite

ObjectiveTo identify the consistent findings from the whole‐brain voxel‐based morphometry (VBM) studies on spinocerebellar ataxia type 2 (SCA2).MethodsThe whole‐brain VBM studies comparing SCA2 patients and healthy controls (HCs) were systematically searched in PubMed, Embase databases from January 2000 to June 2017. The coordinates with significant differences in gray matter (GM) and white matter (WM) between SCA2 patients and HCs were extracted separately from each cluster. A meta‐analysis was performed using anisotropic effect size‐based signed differential mapping (AES‐SDM) software.ResultsA total of five studies with 65 SCA2 patients and 124 HCs were included in the GM meta‐analysis. Four of the five studies with 50 SCA2 patients and 109 HCs were included in the WM meta‐analysis. Significant and consistent GM volume reductions were detected in bilateral cerebellar hemispheres, cerebellar vermis, the right fusiform gyrus, the right parahippocampal gyrus, and the right lingual gyrus. The WM volume reductions were observed in bilateral cerebellar hemispheres, cerebellar vermis, middle cerebellar peduncles, pons, and bilateral cortico‐spinal projections. The findings of the study remained largely unchanged in jackknife sensitivity analysis.ConclusionsThe consistent findings from our meta‐analysis showed that GM volume reductions in SCA2 patients were not limited in cerebellum while significant WM volume reductions widely existed in cerebellum and pyramidal system. The findings provide morphological basis for further studies on SCA2.

show abstract

Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2

Cited by 1,001 publications

References 33 publications

Brain atrophy measures in preclinical and manifest spinocerebellar ataxia type 2

Brain atrophy measures in preclinical and manifest spinocerebellar ataxia type 2

The Multiple Faces of Spinocerebellar Ataxia type 2

Voxel‐based meta‐analysis of gray and white matter volume abnormalities in spinocerebellar ataxia type 2

Contact Info

Product

Resources

About