New insights into the pathogenesis of spinal muscular atrophy

To clarify the pathomechanism of spinal muscular atrophy (SMA) with mutations in the gene for survival motor neuron (SMN) protein, postmortem neuropathological analyses were performed on spinal cords obtained at autopsy from 2 fetuses with SMA, 5 infants and a low teenager with SMA type 1, and a higher teenager with SMA type 2; the diagnosis of all of them was confirmed clinically and genetically. Histopathologically, it was noted that lower motor neurons (LMNs) in the SMA cases showed immature profiles characterized by fine Nissl bodies restricted to the periphery of small round somata with a few cell processes in the fetal period, and showed small-sized profiles in the postnatal period. LMNs began to reduce in size and number in the fetal period, ballooned neurons (BNs) appeared postnatally, and the remaining LMNs including BNs diminished with age. BNs were filled with phosphorylated neurofilament protein, and morphologically similar to but smaller than typical chromatolytic neurons as axonal reaction. The population of survived LMNs was relatively preserved in an SMA type 2 case, who lived to 17-year-old, as compared to SMA type 1 cases. Immunohistochemical analysis demonstrated expression of Bcl-2, Bax, activated caspase-3 and SMN in the LMNs prominent in the fetal cases. There was no significant difference in staining for these substances between the control and SMA cases. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay revealed no significant signal in the control and SMA cases. Given that downregulation of SMN leads to a failure in neurite outgrowth and neuromuscular contact of LMNs, the present results suggest the involvement of a fetal developmental maturation error as well as a postnatal retrograde dying-back degeneration of LMNs in SMN-mutated SMA.