Acute cerebellar knockdown of Sgce reproduces salient features of myoclonus-dystonia (DYT11) in mice.

Myoclonus dystonia (DYT11) is a movement disorder caused by loss-of-function mutations in SGCE and characterized by involuntary jerking and dystonia that frequently improve after drinking alcohol. Existing transgenic mouse models of DYT11 exhibit only mild motor symptoms, possibly due to rodent-specific developmental compensation mechanisms, which have limited the study of neural mechanisms underlying DYT11. To circumvent potential compensation, we used short hairpin RNA (shRNA) to acutely knock down Sgce in the adult mouse and found that this approach produced dystonia and repetitive, myoclonic-like, jerking movements in mice that improved after administration of ethanol. Acute knockdown of Sgce in the cerebellum, but not the basal ganglia, produced motor symptoms, likely due to aberrant cerebellar activity. The acute knockdown model described here reproduces the salient features of DYT11 and provides a platform to study the mechanisms underlying symptoms of the disorder, and to explore potential therapeutic options.

Proportion of life lived with dystonia inversely correlates with response to pallidal deep brain stimulation in both primary and secondary childhood dystonia.

AIM: The aim of this study was to examine the impact of dystonia aetiology and duration, contracture, and age at deep brain stimulation (DBS) surgery on outcome in a cohort of children with medically refractory, disabling primary, secondary-static, or secondary-progressive dystonias, including neurodegeneration with brain iron accumulation (NBIA). METHOD: Dystonia severity was assessed using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor score at baseline and 6 and 12 months postoperatively in a cohort of 70 consecutive children undergoing DBS between June 2005 and July 2011. RESULTS: Two children (3%) received unilateral DBS for hemidystonia and were excluded and five (7%) developed infections requiring part-DBS removal within 6 months, leaving 63 children (90%) undergoing bilateral DBS for follow-up (34 males, 29 females; mean age at surgery for the whole group 10y 4mo, SD 4y 2mo, range 1-14y). Seventeen children were classified with primary dystonia: mean age 12 years 11 months, SD 4 years 6 months range 4 years 6 months to 17 years 3 months; 28 as having secondary-static dystonia: mean age 10 years 2 months, SD 4 years 9 months (range 3y 3mo-20y); five as having secondary-progressive dystonia: mean age 8 years 11 months, SD 3 years 9 months (range 5y 5mo-13y 1mo); and 13 as having NBIA dystonia: mean age 10 years 2 months, SD 3 years 11 months (range 1-14y). Children with primary dystonias demonstrated greater improvements in BFMDRS motor score than those in the other aetiological categories (Kruskal-Wallis test, p<0.001), which correlated negatively with dystonia duration and more strongly still against the ratio of dystonia duration normalized to age at surgery (DD/AS ratio) at 1 year (Spearman's rank correlation coefficient 0.4752 and -0.599 respectively). A similar significant negative correlation was found in the secondary-static dystonia group between outcome at 1 year and DD/AS ratio (-0.461). Poorer outcome in secondary dystonia coincided with the absence of a period of normal motor development in comparison with the primary dystonia group. A significant improvement in BFMDRS motor score was seen in the NBIA group at 6, but not 12 months (Wilcoxon signed rank test p=0.028, p=0.85 respectively). No reduction in efficacy was seen in children with a musculoskeletal deformity at the time of surgery. CONCLUSION: Response to pallidal DBS in the treatment of dystonia declines with the proportion of life lived with dystonia in primary and secondary dystonia. Other intrinsic factors reduce the median magnitude of reduction in secondary dystonia after DBS. DBS should be offered early, preferably within 5 years of onset, to maximize benefits and reduce the childhood experience of dystonia, including musculoskeletal deformity. Other multidimensional assessments are required to understand how DBS improves the lives of children with dystonia.