Cardiac pathology is emerging as a prominent systemic feature of spinal muscular atrophy (SMA), but little is known about the underlying molecular pathways. Using quantitative proteomics analysis, we demonstrate widespread molecular defects in heart tissue from the Taiwanese mouse model of severe SMA. We identify increased levels of lamin A/C as a robust molecular phenotype in the heart of SMA mice and show that lamin A/C dysregulation is also apparent in SMA patient fibroblast cells and other tissues from SMA mice. Lamin A/C expression was regulated in vitro by knockdown of the E1 ubiquitination factor ubiquitin-like modifier activating enzyme 1, a key downstream mediator of SMN-dependent disease pathways, converging on β-catenin signaling. Increased levels of lamin A are known to increase the rigidity of nuclei, inevitably disrupting contractile activity in cardiomyocytes. The increased lamin A/C levels in the hearts of SMA mice therefore provide a likely mechanism explaining morphological and functional cardiac defects, leading to blood pooling. Therapeutic strategies directed at lamin A/C may therefore offer a new approach to target cardiac pathology in SMA.

Spinal Muscular Atrophy (SMA) occurs as a result of cell-ubiquitous depletion of the essential SMN protein. Characteristic disease pathology is driven by a particular vulnerability of the ventral motor neurons of the spinal cord to decreased SMN. Perhaps not surprisingly, many other organ systems are also impacted by SMN depletion. The normal kidney expresses very high levels of SMN protein, equivalent to those found in the nervous system and liver, and levels are dramatically lowered by ~ 90–95% in mouse models of SMA. Taken together these data suggest that renal pathology may be present in SMA. We have addressed this using an established mouse model of severe SMA. Nephron number, as assessed by gold standard stereological techniques, was significantly reduced. In addition, morphological assessment showed decreased renal vasculature, particularly of the glomerular capillary knot, dysregulation of nephrin and collagen IV, and ultrastructural changes in the trilaminar filtration layers of the nephron. To explore the molecular drivers underpinning this process, we correlated these findings with quantitative PCR measurements and protein analyses of Glial Cell-Line Derived Neurotrophic Factor (GDNF), a crucial factor in ureteric bud branching and subsequent nephron development. GDNF levels were significantly reduced at early stages of disease in SMA mice. Collectively, these findings reveal significant renal pathology in a mouse model of severe SMA, further reinforcing the need to develop and administer systemic therapies for this neuromuscular disease.

The prevalence and complexity of cardiovascular disease (CVD) in the West of Scotland are high with the aortic arch and abdominal aorta, particularly at increased risk of cardiovascular pathology. Stent deployment can be key in preventing further cardiovascular events, however, current stent design does not account for complex advanced CVD in these areas. This cadaveric study aimed to provide anatomical measurements requested by manufacturers to improve stent design and deployment in this target population. Nine cadavers (six females and three males; age range = 82.7 ± 10.4 years) from the West of Scotland were dissected to expose the aortic arch and abdominal aorta. Digital callipers and protractors were used to collect data on vessel diameters (including taper), branch spacing, angles and presence of collaterals. CVD was present in all cadavers and ranged from mild plaque presence to aortic dissections. One possessed a bovine aortic arch variation. Supra‐aortic vessels were approximately equally spaced, but the left common carotid had the most acute branching angle. Angulation of the arch from the coronal plane positively correlated with a deviation of the left subclavian artery (LSA) from the sternal midline (Spearman's coefficient r = 0.82, p = 0.01) which may impact surgical access. The origin of the vertebral artery on the LSA was also highly variable. The diameter of the descending aorta decreased along its length from the aortic hiatus to superior mesenteric by 21 ± 10% indicating a high degree of taper. The artery of Adamkiewicz was present in 33% and additional renal collaterals were present in 22%. 66% had tortuous vessels in the abdominal region. These results highlight the need for more data to aid the refinement of stent‐graft design and deployment methods to ensure successful surgical intervention in this population.