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|Title:||GAIT DISTURBANCES IN ATM -/- MICE, A MODEL OF ATAXIA-TELANGIECTASIA|
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|Authors/Affiliations:||3 Ajit Kale; 4 Cynthia J. Rothblum-Oviatt; 2 Michael Weil; 1 Ivo Amende; 5 Thomas Hampton*; |
1 Caritas St. Elizabeth’s Medical Center, Tufts University, Boston, MA, USA; 2 Colorado State University, Fort Collins, USA; 3 Mouse Specifics, Inc.Boston, MA, USA; 4 The A-T Children’s Project, Deerfield Beach, USA; ; 5 The CuraVita Corporation, Boston, MA, USA
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|Content:||Introduction: Ataxia-Telangiectasia (A-T) first becomes apparent when the affected child begins to walk, usually between 12 and 18 months of age. Children with A-T present with an unsteady gait, possibly due to cerebellar dysfunction. Mice lacking the Atm gene provide a model of the human disorder. Analysis of locomotion in this mouse model may be useful in evaluating drug efficacy for treating A-T. We, therefore, have commenced serial comprehensive gait analysis in young Atm-deficient (Atm -/-) mice to determine onset and severity of motor dysfunction. Here, we present some of our early observations.|
Methods: Gait parameters are determined by ventral plane videography in Atm -/- mice and Atm +/+ (WT) mice walking on a transparent treadmill belt at a speed of 24 cm/s. Because of genetic strain differences in latency and incidence of lymphomas in Atm -/- mice, we are studying male mice on 3 different background strains: C57BL/6J (B6), A/J, and 129S6/SvEvTac (129/S6).
Results: The gait analysis database of Atm -/- and WT mice is freely accessible from the “Ataxia-Telangiectasia Children's Project” (www.atcp.org/gait_analysis). To date, gait data are available from ~30 Atm -/- and ~30 WT mice - starting as early as ~6 weeks of age - on a weekly basis. To date, all mice have been able to walk on the moving treadmill belt. The data indicate similarities and differences between strains [~6 weeks old] in several gait metrics, including stride length [B6 = 5.6 ± 0.1 cm, A/J=5.6 ± 0.1 cm, 129/S6=5.3 ± 0.1 cm], hind paw placement angle [B6 = 10.7 ± 0.1 deg, A/J=17.9 ± 1.5 deg, 129/S6=9.1 ±2.1 deg], and stance width [B6 = 2.4 ±0.1 cm, A/J=2.5 ± 0.1 cm, 129/S6=2.4 ± 0.1 cm], metrics that may be of interest in ataxia. At ~6 weeks of age, Atm -/- mice of the 129/S6 background strain demonstrate significantly greater fore paw eversion during stance than WT 129/S6 [7.9 ± 1.1 deg vs. 2.9 ± 1.9 deg, P<0.05].
Conclusion: The aim of this project is to provide detailed postural and kinematic gait data that may be phenotypic of gait disturbances in Atm -/- mice, consistent with cerebellar dysfunction that is characteristic of A-T. Findings to date include characterization of gait in 3 commonly studied inbred strains and evidence of ataxia in Atm -/- mice. Quantitative gait analysis should facilitate the testing of potential therapies for correcting gait disturbances in Ataxia-Telangiectasia.
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