Spectrum of neuropathophysiology in spinal muscular atrophy type I

J Neuropathol Exp Neurol. 2015 Jan;74(1):15-24. doi: 10.1097/NEN.0000000000000144.


Neuropathologic findings within the central and peripheral nervous systems in patients with spinal muscular atrophy type I (SMA-I) were examined in relation to genetic, clinical, and electrophysiologic features. Five infants representing the full clinical spectrum of SMA-I were examined clinically for compound motor action potential amplitude and SMN2 gene copy number; morphologic analyses of postmortem central nervous system, neuromuscular junction, and muscle tissue samples were performed and SMN protein was assessed in muscle samples. The 2 clinically most severely affected patients had a single copy of the SMN2 gene; in addition to anterior horn cells, dorsal root ganglia, and thalamus, neuronal degeneration in them was widespread in the cerebral cortex, basal ganglia, pigmented nuclei, brainstem, and cerebellum. Two typical SMA-I patients and a milder case each had 2 copies of the SMN2 gene and more restricted neuropathologic abnormalities. Maturation of acetylcholine receptor subunits was delayed and the neuromuscular junctions were abnormally formed in the SMA-I patients. Thus, the neuropathologic findings in human SMA-I are similar to many findings in animal models; factors other than SMN2 copy number modify disease severity. We present a pathophysiologic model for SMA-I as a protein deficiency disease affecting a neuronal network with variable clinical thresholds. Because new treatment strategies improve survival of infants with SMA-I, a better understanding of these factors will guide future treatments.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Central Nervous System / pathology*
  • Child
  • Ganglia, Spinal / pathology
  • Humans
  • Infant
  • Infant, Newborn
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology*
  • Mutation / genetics
  • Neuromuscular Junction / metabolism
  • Neuromuscular Junction / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Peripheral Nerves / pathology*
  • Receptors, Nicotinic / metabolism
  • Spinal Cord / pathology
  • Spinal Muscular Atrophies of Childhood / genetics
  • Spinal Muscular Atrophies of Childhood / pathology*
  • Spinal Muscular Atrophies of Childhood / physiopathology*
  • Survival of Motor Neuron 2 Protein / genetics
  • Survival of Motor Neuron 2 Protein / metabolism
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism


  • CHRNG protein, human
  • Receptors, Nicotinic
  • Survival of Motor Neuron 2 Protein
  • alpha7 Nicotinic Acetylcholine Receptor