Spinal muscular atrophy (SMA) is a neuromuscular disease affecting around 1 in 10,000 people and is characterized by neurodegeneration, loss of muscle mass, muscular weakness, and in some cases, respiration and oral functional deficits, including dysphagia. SMA develops due to the loss of the SMN1 gene and insufficient levels of SMN protein. Spinal muscular atrophy with respiratory distress (SMARD) is a similar neuromuscular disease caused by mutations in the IGHMBP2 gene. SMARD1 patients have many similar symptoms compared to SMA patients (muscle atrophy), however, SMARD1 is specifically characterized by respiratory distress.
SMA and SMARD1 patients suffer from respiratory and swallowing deficits, although likely due to distinct mechanisms compared between the two diseases. To better understand the pathways involved in these important hallmarks of disease, we sought to elucidate the specific respiratory pathways in SMARD and SMA model mice, (FVB-Ighmbp2nmd/nmd (FVB-nmd); and Smn-/- SMN2+/+ SMNΔ7+/+ (SMNΔ7) respectively. Untreated FVB-nmd mice show severe respiratory deficits in plethysmography however their neuromuscular junction occupancy in respiratory and swallowing muscles is intact. In the untreated SMNΔ7 mice, there was declining respiratory health over their lifespan and reduced neuromuscular junction occupancy in most respiratory muscles excluding the diaphragm. Analysis of skeletal muscles associated with respiration and swallowing will be presented as well as histological analysis of lung tissue from untreated and gene therapy treated SMARD1 and SMA model mice. Overall, we hope to identify specific pathways that contribute to disease progression with respect to respiration and swallowing defects.