Gait characteristics in a canine model of X-linked myotubular myopathy

Abstract

X-linked myotubular myopathy (XLMTM) is a fatal pediatric disease where affected boys display profound weakness of the skeletal muscles. Possible therapies are under development but robust outcome measures in animal models are required for effective translation to human patients. We established a naturally-occuring canine model, where XLMTM dogs display clinical symptoms similar to those observed in humans. The aim of this study was to determine potential endpoints for the assessment of future treatments in this model. Video-based gait analysis was selected, as it is a well-established method of assessing limb function in neuromuscular disease and measures have been correlated to patient quality of life. XLMTM dogs (N=3) and their true littermate wild type controls (N=3) were assessed at 4–5 time points, beginning at 10 weeks and continuing through 17 weeks. Motion capture and an instrumented carpet were used separately to evaluate spatiotemporal and kinematic changes over time. XLMTM dogs walk more slowly and with shorter stride lengths than wild type dogs, and these differences became greater over time. However, there was no clear difference in angular measures between affected and unaffected dogs. These data demonstrate that spatiotemporal parameters capture functional changes in gait in an XLMTM canine model and support their utility in future therapeutic trials.

Long‐term effects of systemic gene therapy in a canine model of myotubular myopathy

“…Gait analysis with the instrumented carpet provided measures of gait speed, stride length, stride time, step length, step time, and stance time. These parameters were evaluated as outcome measures likely to display changes over time due to disease progression or subsequent recovery as a result of treatment …”

“…Video motion capture data were simultaneously recorded in the middle 2.4 meters of the instrumented carpet in front of a dark cloth backdrop at 8, 12, and 16 weeks of age. As previously described, retro‐reflective tape was placed on the greater trochanter of the femur, a point equidistant between the lateral epicondyle of the femur and the fibular head, the lateral malleolus of the distal tibia, and the distolateral aspect of the fifth metatarsus. A spotlight was used during video capture for maximal marker brightness.…”

“…We previously found that a direct intramuscular injection of AAV serotype 8 (AAV8) carrying a normal copy of the canine MTM1 gene to the cranial tibialis muscle of MTM1 ‐mutant dogs restored strength of the injected limb muscle to near‐normal, but contiguous noninjected limb muscles remained weakened without a commensurate improvement in overall walking gait . Compared with normal dogs, XLMTM dogs averaged a 46% reduction in gait speed and a 68% decrease in stride length near the end of their lifespan at 18 weeks …”

Gene therapy in monogenic congenital myopathies

“…However, distribution may be limited, even within the injected muscle 65 . For example, XLMTM dogs treated by AAV8- MTM1 injection into the cranial tibialis of the hindlimb show improvements in the strength, size and histopathology of the treated limb 2 but show a continued progression of the disease including muscle weakness, impaired ambulation and early death 2,66 . This limited distribution is therefore disadvantageous when the disease affects multiple systems or the entire body, as is often the case with congenital myopathies.…”

Kinetic and kinematic follow‐up gait analysis in Doberman Pinschers with cervical spondylomyelopathy treated medically and surgically

“…Specifically, gait analysis has been used for evaluation of orthopedic diseases including cranial cruciate ligament disease, hip dysplasia, and treatment outcomes after surgical repair of these conditions . Gait analysis also has been used in the evaluation of neurologic diseases in animal models, including dogs, horses, and rodents . More recently, these techniques were applied in evaluating dogs with CSM …”