Cardiac defects contribute to the pathology of spinal muscular atrophy models

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive disorder, which is the leading genetic cause of infantile death. SMA is the most common inherited motor neuron disease and occurs in approximately 1:6000 live births. The gene responsible for SMA is called Survival Motor Neuron-1 (SMN1). Interestingly, a human-specific copy gene is present on the same region of chromosome 5q, called SMN2. Motor neurons are the primary tissue affected in SMA. Although it is clear that SMA is a neurodegenerative disease, there are clinical reports that suggest that other tissues contribute to the overall phenotype, especially in the most severe forms of the disease. In severe SMA cases, a growing number of congenital heart defects have been identified upon autopsy. The most common defect is a developmental defect referred to as hypoplastic left heart. The purpose of this report is to determine whether cardiac tissue is altered in SMA models and whether this could contribute to SMA pathogenesis. Here we identified early-stage developmental defects in a severe model of SMA. Additionally, pathological responses including fibrosis and oxidative stress markers were observed shortly after birth in a less severe model of disease. Similarly, functional differences were detected between wild-type and early-stage SMA animals. Collectively, this work demonstrates the importance of cardiac development and function in these severe models of SMA.

Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585

“…Cardiomyopathic changes can be rooted or result in rhythm disturbances, which (eg, bradycardia) have been extensively described and seem to be a consistent feature in SMA mice. 42,43,64 In humans, cardiac involvement has been described in the form of congenital malformations (predominantly SMA type I) and case reports of cardiomyopathy (predominantly SMA type III). 41,44,[65][66][67] The question remains whether our observations are due to autonomous nerve involvement or muscle development or affection.…”

“…Cardiac histology suggested interventricular septum (IVS) thinning ( Figure 4B) in accordance with previous observations for the D7 mouse model and the severe SMA mouse model containing two SMN2 copies. 43 Respective differences were present at P5, a time point before any motor phenotype was observed (Figure 2b). Pulmonary lesions in SMA animals were characterized by variable degrees of emphysema with ruptured alveolar septa and enlarged alveolar spaces compared with heterozygous animals (Figures 4Ac and g).…”

“…The remaining 50% are healthy SMA carriers (Smn þ / À ; SMN2 tg/0 ) and used as controls. 30 Recent reports suggest that abnormal heart development in mice and human [41][42][43][44] as well as defects in skeletal muscle 45 and skeletal muscle vasculature 46 of mice are part of the phenotype and that SMA may be not a pure motoneuron disease. In addition, decreased levels of hepatic insulin-like growth factor binding protein acid labile subunit 18 possibly account for some of the dwarfism observed consistently across different SMA mouse models.…”

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

“…Investigation of cell death revealed very little change in the Taiwanese model 9. Vasculature abnormalities were reported in other organs and could have been the initial trigger 12, 13. Immunostaining of blood vessels markers revealed very little change in the spleens of Taiwanese and Smn ∆7 mice 9, 10.…”

Emerging therapies and challenges in spinal muscular atrophy

“…These include functional and structural cardiac defects,66 abnormal development of the gastrointestinal tract, liver, and spleen,64, 67, 68 and irregular bone remodeling and skeletal pathology 69. These findings suggest that successful treatment of SMA may require systemic targeting of a range of affected tissues.…”