G.P.52

GNE myopathy is an adult-onset distal myopathy caused by mutations in the GNE gene, which codes for a bifunctional enzyme important in sialic acid biosynthesis. GNE myopathy is characterized by gradually progressive weakness and atrophy that preferentially involves distal extremities. Muscle degeneration occurs, with accumulation of inclusion bodies and rimmed vacuoles in muscle fibers. Although GNE myopathy is known to preferential affect skeletal muscles, there had been a few reports demonstrating involvement of the cardiac muscles. Through our Natural History Study (NCT01417533), we found that cardiac involvement in GNE myopathy patients may have a higher occurrence than expected. In this study we established a systematic evaluation of the cardiac involvement in GNE myopathy by analyzing the mouse model Gne-/-hGNED176VTg. Histopathology showed the presence of rimmed vacuoles and disorganization of cardiac myofibrils. Lectin staining array corroborated the hyposialylation of O-linked glycoproteins. Echocardiogram revealed decreased ejection fraction and fractional shortening, and increased left ventricle mass, indicating a decrease of cardiac function. These data were also confirmed by functional MRI on the mouse model. Our findings provide evidence that cardiac muscles are involved in GNE myopathy. We propose that hyposialylation of cardiac muscles can lead to impaired cardiac muscle contractility, and may be improved with sialylation-increasing therapies. It is important for clinicians to be aware of the possible occurrence of cardiac disease in GNE myopathy for careful examination of the cardiac function in patients and proper management.