Characterization of Australian Labradoodle dystrophinopathy

摘要

In humans, dystrophin mutations cause the X-linked recessive disorder known as Duchenne muscular dystrophy (DMD). These mutations result in skeletal and cardiac muscle damage with mortality increasingly associated with cardiomyopathy. We have identified a novel dystrophin mutation in exon 21 in a line of Australian Labradoodles; affected dogs develop progressive clinical signs including poor weight gain and weight loss, gait abnormalities, exercise intolerance, skeletal muscle atrophy, macroglossa, ptyalism, dysphagia, kyphosis, and a plantigrade stance. Echocardiographic abnormalities include hyperechoic foci in the left ventricular papillary muscles, septal hypokinesis, and decreased left ventricular systolic and diastolic volume and internal diameter. Holter recordings found a Mobitz type II second-degree atrioventricular (AV) block in one affected dog. Analysis of phosphocreatine-to-ATP ratios (PCr/ATP) (obtained via cardiac magnetic resonance imaging and spectroscopy evaluation), found no statistically significant difference in the mean PCr/ATP between groups. Histopathologic skeletal muscle changes included fibrofatty infiltration, myocyte degeneration, necrosis, and regeneration, lymphohistiocytic inflammation, and mineralization; cardiac changes were limited to a focal area of mineralization adjacent to the sinoatrial node in the dog with a second-degree AV block. Due to rapidly progressive clinical signs, a severe phenotype, and potential for cardiac involvement, Australian Labradoodle dystrophinopathy may be a useful model to further study DMD pathogenesis.