Analysis of Cardiac Defects in the Context of Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive disorder and a leading genetic cause of infantile death. SMA is caused by reduced levels of the Survival Motor Neuron (SMN) protein, resulting in the loss of functional motor neurons. A growing number of congenital heart defects have been identified in infants with the most severe form of SMA (accounts for more than 60% of SMA cases). Recently, we have uncovered cardiac defects occurring at embryonic stage in a severe SMA mouse model and shortly after birth in a less severe model, demonstrating that cardiac defects precede motor neuron degeneration. We investigated the relationship between the level of SMN deficiency and the extent of cardiac structural/functional abnormalities in three SMA animal models ranging in severity. Our results indicate that the intensity and timing of the cardiac abnormalities directly correlate with the severity of the SMA phenotype. We have also examined the impact of gene replacement therapy in repairing cardiac deficiencies. Structural and functional ( cine ‐MRI) analysis revealed that the heart of the treated SMA mice, albeit more improved than untreated mice, still exhibit morphological and functional defects. Treated mice demonstrate complete rescue of motor function which suggests that the onset of heart defects are earlier than the motor neuron defects and therefore, cannot be completely restored with post‐birth treatment.