Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

  • Dr Michelle Farrar, Sydney Children's Hospital, Prince of Wales Medical Research Instituteand University of New South Wales, Australia
  • Dr Steve Vucic, Prince of Wales Medical Research Institute, Australia
  • Dr Heather Johnston, Sydney Children's Hospital, Australia
  • Professor Matthew Kiernan, University of New South Wales and Prince of Wales Medical Research Institute, Australia

Objective: To gain further insights into corticomotorneuronal and lower motor neuron function and thereby disease pathogenesis in spinal muscular atrophy(SMA), the present study utilised novel threshold tracking transcranial magnetic stimulation(TMS) techniques combined with peripheral nerve excitability studies to investigate SMA patients.
Methods: Cortical and peripheral nerve excitability studies were undertaken in 13 SMA patients with homozygous deletions in the SMN1 gene(mean age=20.2 years, range:15-31 years) and 62 normal controls. Comparison was also made with a disease control group, comprising 103 amyotrophic lateral sclerosis(ALS) patients. Motor-evoked potentials and compound muscle action potentials(CMAPs) were recorded from the right abductor pollicis brevis. Neurophysiological parameters were correlated with clinical measures of disease severity.
Results: In contrast to patients with ALS, short interval intracortical inhibition (SICI:SMA=8.0+/-1.9%;controls=10.3+/-0.7%, P=0.3;ALS=2.6+/-1.9%,P=0.009) and the cortical silent period duration(CSP:SMA=199.8+/-8.2ms;control=210.2+/-3.1ms,P=0.2;ALS=181.3+/-4.3ms,P<0.05) were preserved. Measures of peripheral disease burden, namely the CMAP(SMA=5.4+/-0.7mV;controls=10.2+/-0.4 mV,P<0.00001;ALS =5.6+/-0.3mV,P=0.4) and neurophysiological index(NI:SMA=0.5+/-0.1;controls=2.5+/-0.1,P<0.0001;ALS=0.7+/-0.1,P=0.2) were significantly reduced. The strength-duration time constant(ΤSD), a peripheral marker of axonal hyperexcitability, was not increased, in contrast to ALS(SMA:0.45+/-0.02ms,controls=0.43+/-0.09,P=0.2,ALS=0.50+/-0.03ms,). CMAPs and the neurophysological index correlated with the total MRC score(R=0.64,R=0.57) and the ALSFRS (R=0.77,R=0.78) in SMA patients.
Conclusions: Simultaneous assessment of central and peripheral motor pathways has established the degeneration of the lower motor neuron axis despite the preservation of corticomotorneurons in SMA, in contrast to ALS. Furthermore, the normal ΤSD in chronic SMA patients may support the hypothesis that the rate of neurodegeneration slows to reach a plateau over time, promoting survival in less severe or chronic forms of SMA.