Axonal excitability changes in children with spinal muscular atrophy treated with nusinersen

• Published in: The Journal of physiology Vol. 600; no. 1; pp. 95 - 109
• Main Authors: Kariyawasam, Didu S. T., D'Silva, Arlene M., Herbert, Karen, Howells, James, Carey, Kate, Kandula, Tejaswi, Farrar, Michelle A., Lin, Cindy (Shin‐Yi)
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.01.2022
• Subjects: Action potential; Action Potentials; Atrophy; axonal excitability; Axonogenesis; Axons; Child; Child, Preschool; Children; Excitability; Humans; Maturation; Motor neurons; Muscular Atrophy, Spinal - drug therapy; neurobiology; Neurodegeneration; Neurodevelopment; Neuromuscular diseases; nusinersen; Oligonucleotides; SMN protein; Spinal cord; Spinal muscular atrophy; Ventral roots; Wrist; neurobiology; axonal excitability; nusinersen; spinal muscular atrophy; neurodevelopment
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/JP282249

Spinal muscular atrophy (SMA) is associated with developmental disruption of motor axons in ventral roots of the spinal cord alongside motor axon degeneration. The pathogenesis of peripheral axonal change during development is pertinent to understand treatment response. Nerve excitability techniques, stimulating the median motor nerve at the wrist, were utilised to investigate axonal change during neurodevelopment in 24 children with SMA, compared with 71 age‐matched controls. Longitudinal axonal response to nusinersen treatment in 18 children was also investigated. Significant differences in axonal development were noted in the youngest children with SMA, signified by reduced compound muscle action potential (CMAP) (P = 0.030), higher axonal threshold (P = 0.016), rheobase (minimal current amplitude of infinite duration, required to generate an action potential) (P = 0.012) and greater changes in depolarising and hyperpolarising threshold electrotonus. Subexcitability increased in all children with SMA, compared to controls. With treatment, nerve excitability changes were observed prominently in young children, with increases in CMAP, reduction in axonal threshold, fanning‐in of threshold electrotonus, increase in resting current–threshold slope and reduction in subexcitability. Whilst motor axons continue to mature in SMA, developmental delays in passive and active membrane properties occur especially in early childhood. Concurrently, motor axons actively undergo degeneration. Nusinersen restores the developmental trajectory of motor axons reducing degeneration, especially in children with early treatment initiation. Our findings move the field forward in understanding the developmental aspect of childhood‐onset motor neurone diseases and changes in axonal function associated with disease modification. Key points Pathomechanisms in spinal muscular atrophy involve concurrent neurodevelopmental and neurodegenerative processes. The greatest delays in maturation of the passive and active properties of the peripheral motor axon are seen in early childhood. Nusinersen facilitates developmental recovery of the motor axon whilst also reducing neurodegeneration. Axonal dysfunction is reversed with SMN repletion particularly when intervention occurs early in development. figure legend In untreated spinal muscular atrophy, delays in the normal maturation processes of motor nerves, concurrent with neurodegeneration, are observed. Nusinersen promotes developmental recovery of the motor axon to some extent, with nerve excitability changes suggesting radial growth, myelination of the axon and localisation of potassium ion channels to the juxtaparanode, paralleling maturational changes seen in healthy children. Concomitant restoration of potassium conductance suggest a reduction in axonal degeneration with disease modifying therapy.