Dystonia in spinocerebellar ataxia type 6

Sethi, Kapil D.; Jankovic, Joseph

doi:10.1002/mds.1252

Cited by 57 publications

(35 citation statements)

References 16 publications

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“…Given the diversity of dystonias, it would be surprising if both cases are not rampant. Nonetheless there are clear examples of dystonia in patients that appear to be causally related to cerebellar dysfunction, particularly when dystonia manifests as a symptom in cerebellar-centric disorders such as spinocerebellar or episodic ataxias (Bang et al, 2003; Kawarai et al, 2016; Mariotti et al, 2007; Muglan et al, 2016; Nakagaki et al, 2002; Sethi and Jankovic, 2002). In some cases, lesioning or stimulation of the cerebellum has been documented to improve the symptoms, corroborating the notion that in some patients, dystonia can arise from cerebellar dysfunction (Koch et al, 2014; Panov et al, 2013; Teixeira et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

A role for cerebellum in the hereditary dystonia DYT1

Fremont

Tewari

Angueyra

et al. 2017

eLife

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DYT1 is a debilitating movement disorder caused by loss-of-function mutations in torsinA. How these mutations cause dystonia remains unknown. Mouse models which have embryonically targeted torsinA have failed to recapitulate the dystonia seen in patients, possibly due to differential developmental compensation between rodents and humans. To address this issue, torsinA was acutely knocked down in select brain regions of adult mice using shRNAs. TorsinA knockdown in the cerebellum, but not in the basal ganglia, was sufficient to induce dystonia. In agreement with a potential developmental compensation for loss of torsinA in rodents, torsinA knockdown in the immature cerebellum failed to produce dystonia. Abnormal motor symptoms in knockdown animals were associated with irregular cerebellar output caused by changes in the intrinsic activity of both Purkinje cells and neurons of the deep cerebellar nuclei. These data identify the cerebellum as the main site of dysfunction in DYT1, and offer new therapeutic targets.DOI: http://dx.doi.org/10.7554/eLife.22775.001

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Section: Discussionmentioning

confidence: 99%

A role for cerebellum in the hereditary dystonia DYT1

Fremont

Tewari

Angueyra

et al. 2017

eLife

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“…Because the cerebellum has a fractured somatotopic representation (Manni and Petrosini 2004; Apps and Garwicz 2005), neuronal loss in one region may result in ataxia in some body parts whereas neuronal dysfunction in another cerebellar region may cause dystonia in other body parts. This may explain why patients with degenerative cerebellar ataxias may also have dystonia (Sethi and Jankovic 2002; Kuoppamaki, Giunti et al 2003; Wilder-Smith, Tan et al 2003; Hagenah, Zuhlke et al 2004; Le Ber, Clot et al 2006; van Gaalen, Giunti et al 2011; Jhunjhunwala, Netravathi et al 2013). …”

Section: Discussionmentioning

confidence: 99%

“…The majority of cerebellar degenerative syndromes are also associated with ataxia. However, in several of these, ataxia may be combined with dystonia, or the dystonia may be the presenting or dominant motor abnormality (Sethi and Jankovic 2002; Kuoppamaki, Giunti et al 2003; Wilder-Smith, Tan et al 2003; Hagenah, Zuhlke et al 2004; Le Ber, Clot et al 2006; van Gaalen, Giunti et al 2011; Jhunjhunwala, Netravathi et al 2013). The reasons that cerebellar defects may sometimes cause ataxia or dystonia are unknown, but may be related to the type of lesion.…”

Section: Introductionmentioning

confidence: 99%

Dystonia and cerebellar degeneration in the leaner mouse mutant

2015

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Cerebellar degeneration is traditionally associated with ataxia. Yet, there are examples of both ataxia and dystonia occurring in individuals with cerebellar degeneration. There is also substantial evidence suggesting that cerebellar dysfunction alone may cause dystonia. The types of cerebellar defects that may cause ataxia, dystonia, or both have not been delineated. In the current study, we explored the relationship between cerebellar degeneration and dystonia using the leaner mouse mutant. Leaner mice have severe dystonia that is associated with dysfunctional and degenerating cerebellar Purkinje cells. Whereas the density of Purkinje cells was not significantly reduced in 4 week-old leaner mice, approximately 50% of the neurons were lost by 34 weeks of age. On the other hand, the dystonia and associated functional disability became significantly less severe during this same interval. In other words, dystonia improved as Purkinje cells were lost, suggesting that dysfunctional Purkinje cells, rather than Purkinje cell loss, contribute to the dystonia. These results provide evidence that distorted cerebellar function may cause dystonia and support the concept that different types of cerebellar defects can have different functional consequences.

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“…As dystonic features such as CD, hemidystonia and writer's cramp have been reported in several different SCA mutations, our findings suggest that a dysfunctional basal ganglia circuitry in addition to dysfunctional pontocerebellar pathways may be important in CD in hereditary ataxias. [18][19][20] Authors' affiliations …”

Section: Discussionmentioning

confidence: 99%