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Gait analysis in a Mecp2 knockout mouse model of Rett syndrome reveals early-onset and progressive motor deficits.

Gadalla KK, Ross PD, Riddell JS, Bailey ME, Cobb SR - PLoS ONE (2014)

Bottom Line: Rett syndrome (RTT) is a genetic disorder characterized by a range of features including cognitive impairment, gait abnormalities and a reduction in purposeful hand skills.As hand stereotypies and gait abnormalities constitute major diagnostic criteria in RTT, it is clear that motor and gait-related phenotypes will be of importance in assessing preclinical therapeutic outcomes.These data suggest that gait measures may be used as a robust and early marker of MeCP2-dysfunction in future preclinical therapeutic studies.

View Article: PubMed Central - PubMed

Affiliation: Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; Pharmacology Department, Faculty of Medicine, Tanta University, Egypt.

ABSTRACT
Rett syndrome (RTT) is a genetic disorder characterized by a range of features including cognitive impairment, gait abnormalities and a reduction in purposeful hand skills. Mice harbouring knockout mutations in the Mecp2 gene display many RTT-like characteristics and are central to efforts to find novel therapies for the disorder. As hand stereotypies and gait abnormalities constitute major diagnostic criteria in RTT, it is clear that motor and gait-related phenotypes will be of importance in assessing preclinical therapeutic outcomes. We therefore aimed to assess gait properties over the prodromal phase in a functional knockout mouse model of RTT. In male Mecp2 knockout mice, we observed alterations in stride, coordination and balance parameters at 4 weeks of age, before the onset of other overt phenotypic changes as revealed by observational scoring. These data suggest that gait measures may be used as a robust and early marker of MeCP2-dysfunction in future preclinical therapeutic studies.

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Automated gait analysis reveals early signs of motor defects in Mecp2stop/y mice.(A) Plot showing aggregate phenotype severity score (mean +/− SEM) in male wild-type (WT, black diamond symbols) and Mecp2stop/y (grey circles) mice. Mecp2stop/y mice show a gradual phenotype score progression that is significantly different from WT (WT n = 7; Mecp2stop/y n = 8 at 3–7 weeks, n = 7 at week 8, n = 5 at week 9 and n = 4 at week 10); decreasing numbers of Mecp2stop/y mice are explained by early death of some mutant mice. (B–F) Plots showing stride length, overlap distance, stance width, step angle and gait symmetry (mean +/− SEM) measured in WT and Mecp2stop/y mice at 4, 8 and 10 weeks (WT n = 7 at 4 weeks and 5 at 8 & 10 weeks; Mecp2stop/y n = 6 at 4 weeks, n = 5 at weeks 8 & 10. The treadmill speed was 25 cm/s. *p<0.05 **p<0.01 ***p<0.001, Mann Whitney pairwise comparisons (A) and 2-way repeated measures ANOVA with Tukey post hoc pairwise comparisons (B–F).
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pone-0112889-g002: Automated gait analysis reveals early signs of motor defects in Mecp2stop/y mice.(A) Plot showing aggregate phenotype severity score (mean +/− SEM) in male wild-type (WT, black diamond symbols) and Mecp2stop/y (grey circles) mice. Mecp2stop/y mice show a gradual phenotype score progression that is significantly different from WT (WT n = 7; Mecp2stop/y n = 8 at 3–7 weeks, n = 7 at week 8, n = 5 at week 9 and n = 4 at week 10); decreasing numbers of Mecp2stop/y mice are explained by early death of some mutant mice. (B–F) Plots showing stride length, overlap distance, stance width, step angle and gait symmetry (mean +/− SEM) measured in WT and Mecp2stop/y mice at 4, 8 and 10 weeks (WT n = 7 at 4 weeks and 5 at 8 & 10 weeks; Mecp2stop/y n = 6 at 4 weeks, n = 5 at weeks 8 & 10. The treadmill speed was 25 cm/s. *p<0.05 **p<0.01 ***p<0.001, Mann Whitney pairwise comparisons (A) and 2-way repeated measures ANOVA with Tukey post hoc pairwise comparisons (B–F).

Mentions: The mutant phenotype trajectory was assessed by weekly observational scoring from week three onwards. From five weeks of age Mecp2stop/y animals showed a progressively more severe phenotype (figure 2A) that was significantly different from that for WT animals, which scored zero for the duration of the study (p<0.002 from 5 weeks onwards, Mann Whitney pairwise comparisons; we set p<0.01 as our alpha value for significance to control for multiple testing). Mecp2stop/y mice have reduced survival [8], [13] and consequently the study was restricted to 10 weeks.


Gait analysis in a Mecp2 knockout mouse model of Rett syndrome reveals early-onset and progressive motor deficits.

Gadalla KK, Ross PD, Riddell JS, Bailey ME, Cobb SR - PLoS ONE (2014)

Automated gait analysis reveals early signs of motor defects in Mecp2stop/y mice.(A) Plot showing aggregate phenotype severity score (mean +/− SEM) in male wild-type (WT, black diamond symbols) and Mecp2stop/y (grey circles) mice. Mecp2stop/y mice show a gradual phenotype score progression that is significantly different from WT (WT n = 7; Mecp2stop/y n = 8 at 3–7 weeks, n = 7 at week 8, n = 5 at week 9 and n = 4 at week 10); decreasing numbers of Mecp2stop/y mice are explained by early death of some mutant mice. (B–F) Plots showing stride length, overlap distance, stance width, step angle and gait symmetry (mean +/− SEM) measured in WT and Mecp2stop/y mice at 4, 8 and 10 weeks (WT n = 7 at 4 weeks and 5 at 8 & 10 weeks; Mecp2stop/y n = 6 at 4 weeks, n = 5 at weeks 8 & 10. The treadmill speed was 25 cm/s. *p<0.05 **p<0.01 ***p<0.001, Mann Whitney pairwise comparisons (A) and 2-way repeated measures ANOVA with Tukey post hoc pairwise comparisons (B–F).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4231076&req=5

pone-0112889-g002: Automated gait analysis reveals early signs of motor defects in Mecp2stop/y mice.(A) Plot showing aggregate phenotype severity score (mean +/− SEM) in male wild-type (WT, black diamond symbols) and Mecp2stop/y (grey circles) mice. Mecp2stop/y mice show a gradual phenotype score progression that is significantly different from WT (WT n = 7; Mecp2stop/y n = 8 at 3–7 weeks, n = 7 at week 8, n = 5 at week 9 and n = 4 at week 10); decreasing numbers of Mecp2stop/y mice are explained by early death of some mutant mice. (B–F) Plots showing stride length, overlap distance, stance width, step angle and gait symmetry (mean +/− SEM) measured in WT and Mecp2stop/y mice at 4, 8 and 10 weeks (WT n = 7 at 4 weeks and 5 at 8 & 10 weeks; Mecp2stop/y n = 6 at 4 weeks, n = 5 at weeks 8 & 10. The treadmill speed was 25 cm/s. *p<0.05 **p<0.01 ***p<0.001, Mann Whitney pairwise comparisons (A) and 2-way repeated measures ANOVA with Tukey post hoc pairwise comparisons (B–F).
Mentions: The mutant phenotype trajectory was assessed by weekly observational scoring from week three onwards. From five weeks of age Mecp2stop/y animals showed a progressively more severe phenotype (figure 2A) that was significantly different from that for WT animals, which scored zero for the duration of the study (p<0.002 from 5 weeks onwards, Mann Whitney pairwise comparisons; we set p<0.01 as our alpha value for significance to control for multiple testing). Mecp2stop/y mice have reduced survival [8], [13] and consequently the study was restricted to 10 weeks.

Bottom Line: Rett syndrome (RTT) is a genetic disorder characterized by a range of features including cognitive impairment, gait abnormalities and a reduction in purposeful hand skills.As hand stereotypies and gait abnormalities constitute major diagnostic criteria in RTT, it is clear that motor and gait-related phenotypes will be of importance in assessing preclinical therapeutic outcomes.These data suggest that gait measures may be used as a robust and early marker of MeCP2-dysfunction in future preclinical therapeutic studies.

View Article: PubMed Central - PubMed

Affiliation: Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; Pharmacology Department, Faculty of Medicine, Tanta University, Egypt.

ABSTRACT
Rett syndrome (RTT) is a genetic disorder characterized by a range of features including cognitive impairment, gait abnormalities and a reduction in purposeful hand skills. Mice harbouring knockout mutations in the Mecp2 gene display many RTT-like characteristics and are central to efforts to find novel therapies for the disorder. As hand stereotypies and gait abnormalities constitute major diagnostic criteria in RTT, it is clear that motor and gait-related phenotypes will be of importance in assessing preclinical therapeutic outcomes. We therefore aimed to assess gait properties over the prodromal phase in a functional knockout mouse model of RTT. In male Mecp2 knockout mice, we observed alterations in stride, coordination and balance parameters at 4 weeks of age, before the onset of other overt phenotypic changes as revealed by observational scoring. These data suggest that gait measures may be used as a robust and early marker of MeCP2-dysfunction in future preclinical therapeutic studies.

Show MeSH
Related in: MedlinePlus