Resumen de Desarrollo neuromuscular en la atrofia muscular espinal
Rebeca Martínez Hernández
BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by degeneration and loss of spinal cord motor neurons leading to denervation and muscular atrophy. It is caused by defects in the Survival Motor Neuron 1 gene (SMN1) and it is classified by age of onset and motor milestones into three main types which strongly correlate with the copy number of its homologous gene, SMN2. SMN2 expresses markedly less full?length protein than SMN1, provoking disease manifestations. The essential neuropathological feature in SMA is motor neuron death. Previous studies in SMA foetal samples showed early pathological changes in spinal cord suggesting that the disease is a developmental disorder. Studies in mouse SMA models support that neuromuscular junctions (NMJs) may play a significant role in the disease, although this implication has not yet been addressed in humans. AIMS AND METHODOLOGIES: To better understand the mechanisms of SMA disease, a comprehensive histologic, immunohistochemical and ultrastructural analysis of the muscle and neuromuscular junctions in prenatal and postnatal SMA samples was carried out. To further correlate neuropathological findings with early developmental manifestations of the disease, foetal motility between 11?14 gestational weeks was recorded and analyzed by 2D ultrasound in pregnancies predicted to develop SMA. RESULTS: At 12 weeks, most SMA myotubes were smaller than controls, indicating a delay in muscle maturation. At this stage, the presence of early acetylcholine receptor (AChR) clusters in developing SMA muscles suggested that pre?patterned and nerve?independent AChR clustering would not be affected by the disease. However, as development proceeded in the following weeks, early degeneration of nerve terminals was present associated with a dispersion of AChRs and abnormal preterminal accumulation of vesicles. These findings pointed towards a defect in maintenance of the initial innervation in developmental SMA muscle. Furthermore, postnatal muscle of type I SMA patients showed persistence of the foetal subunit of acetylcholine receptors, suggesting a continuous delay in maturation of neuromuscular junctions. Therefore, if nerve terminals are unable to efficiently maintain functional NMJs, a dying?back process leading to motor neuron degeneration and loss may appear, with the consequent increase in programmed cell death. Despite all these early neuropathological findings, we did not observe qualitative differences in foetal movements between unaffected and SMA prenatal cases. The synaptic defects in SMA at this stage of development, therefore, might be compensated by several mechanisms. During perinatal and postnatal periods compensation would no longer be present, resulting in the drastic SMA pathology and clinical manifestations. CONCLUSIONS: These developmental studies open new possibilities to improve our knowledge of presymptomatic SMA stages. Early therapeutic strategies should be investigated to reverse the process of denervation, maintain activity of the NMJ, and improve maturity of the motor endplates.
