Neuronal death is enhanced and begins during foetal development in type I spinal muscular atrophy spinal cord

Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by mutations in the survival motor neurone gene (SMN). The degeneration and loss of the anterior horn cells is the major neuropathological finding in SMA, but the mechanism and timing of this abnormal motor neurone death remain unknown. A quantitative study was carried out comparing neuronal death in controls and SMA foetuses and neonates. Between 12 and 15 weeks of gestational age, a significant increase in nuclear DNA vulnerability, as revealed with the method of in situ end-labelling of nuclear DNA fragmentation, was detected in SMA foetuses and was reflected by a decrease in the number of neurones of the anterior horn. Neurones with nuclear DNA vulnerability are no longer detected at the end of the foetal period and the post-natal period. On the other hand, abnormal morphology of motor neurones, mainly early chromatolytic changes, was observed only after birth. Our findings indicate that in type I SMA, the absence or dysfunction of SMN is reflected by an enhanced neuronal death that is already detectable at 12 weeks, the earliest SMA foetal stage analysed. This is associated with a progressive loss of motor neurones towards the neonatal period. Given that a proportion of the remaining SMA motor neurones in the neonatal period appear with pathological findings not detected at earlier stages, it can be hypothesized that type I SMA results in differential age-dependent responses leading to cell death and motor neurone degeneration during development.