TY  - JOUR
AU  - Goddard, Melissa A.
AU  - Mack, David L.
AU  - Czerniecki, Stefan M.
AU  - Kelly, Valerie E.
AU  - Snyder, Jessica M.
AU  - Grange, Robert W.
AU  - Lawlor, Michael W.
AU  - Smith, Barbara K.
AU  - Beggs, Alan H.
AU  - Childers, Martin K.
PY  - 2015
TI  - Muscle pathology, limb strength, walking gait, respiratory function and neurological impairment establish disease progression in the p.N155K canine model of X-linked myotubular myopathy
JF  - Annals of Translational Medicine; Vol 3, No 18 (October 30, 2015): Annals of Translational Medicine (Focus on “Melanoma”)
Y2  - 2015
KW  - 
N2  - Background: Loss-of-function mutations in the myotubularin (MTM1) gene cause X-linked myotubular myopathy (XLMTM), a fatal, inherited pediatric disease that affects the entire skeletal musculature. Labrador retriever dogs carrying an MTM1 missense mutation exhibit strongly reduced synthesis of myotubularin, the founder member of a lipid phosphatase required for normal skeletal muscle function. The resulting canine phenotype resembles that of human patients with comparably severe mutations, and survival does not normally exceed 4 months.  Methods: We studied MTM1 mutant dogs (n=7) and their age-matched control littermates (n=6) between the ages of 10 and 25 weeks. Investigators blinded to the animal identities sequentially measured limb muscle pathology, fore- and hind limb strength, walking gait, respiratory function and neurological impairment.  Results: MTM1-mutant puppies display centrally-nucleated myofibers of reduced size and disrupted sarcotubular architecture progressing until the end of life, an average of 17 weeks. In-life measures of fore- and hind limb strength establish the rate at which XLMTM muscles weaken, and their corresponding decrease in gait velocity and stride length. Pulmonary function tests in affected dogs reveal a right-shifted relationship between peak inspiratory flow (PIF) and inspiratory time (TI); neurological assessments indicate that affected puppies as young as 10 weeks show early signs of neurological impairment (neurological severity score, NSS =8.6±0.9) with progressive decline (NSS =5.6±1.7 at 17 weeks-of-age).  Conclusions: Our findings document the rate of disease progression in a large animal model of XLMTM and lay a foundation for preclinical studies.
UR  - https://atm.amegroups.org/article/view/8106