The pathophysiology of spinal muscular atrophy

This thesis examines the disease course and pathophysiology of motor dysfunction in spinal muscular atrophy (SMA) using clinical, epidemiological, neurophysiological and genetic studies. Natural history studies confirmed the unique clinical course, atypical for a neurodegenerative disease, in which progression appeared most rapid initially and then plateaued. Significant associations between age of onset with survival and motor function were demonstrated, while long-standing motor function was not correlated with disease duration. These findings suggested early motor neuron degeneration with phenotype related to quantitative differences, followed by relative stability of remaining motor neurons. Axonal excitability studies were undertaken in adolescent and adult SMA patients to further investigate pathophysiological processes. These studies revealed changes in axonal K+ and Na+ conductances and passive membrane properties, the latter linked to clinical severity. Together these findings suggested a mixed pathology comprising features of axonal degeneration and regeneration. These studies possess clinical significance, having identified novel potential therapeutic targets and markers of severity. In order to examine the pathophysiology of SMA throughout the disease course, paediatric axonal excitability studies were instigated, establishing a platform for future studies. Healthy control studies revealed coherent age dependent changes in excitability properties, reflecting maturation of axonal size, myelination and membrane conductances. Studies in a paediatric disease control subject established that distinct pathophysiological processes may underlie neurodegeneration in SMA. To further assess cortical motor neuron function and potential adaptive processes, transcranial magnetic stimulation techniques were utilized in SMA patients. These studies identified preservation of cortical motor neuron function and potential adaptation to spinal motoneuron degeneration, with significant expansion of cortical motor neuron output. In conclusion studies undertaken in this thesis have established unique pathophysiological processes that develop throughout the motor axis in SMA. These include concurrent peripheral neurodegeneration and regeneration, with central neuroplasticity and provide insight into the unique clinical course. Importantly these studies may influence future treatment strategies and enable further pathophysiological investigations among various paediatric neuropathies at disease outset.

Grantor dc:publisher

UNSW, Sydney

Year dc:date

2012

Author dc:creator

• Farrar, Michelle Anne

• Pathophysiology
• Spinal Muscular Atrophy
• Motor neuron
• Neurodegeneration

Statement dc:rights

• open access
• CC BY-NC-ND 3.0
• free_to_read

Licence

• https://purl.org/coar/access_right/c_abf2
• https://creativecommons.org/licenses/by-nc-nd/3.0/au/

Language dc:language

EN

Identifier

https://doi.org/10.26190/unsworks/15587

OAI identifier oai:identifier

oai:unsworks.library.unsw.edu.au:1959.4/52032