World-leading research from the University of Aberdeen has made a significant breakthrough in understanding a form of childhood motor neuron disease.
Professor Simon Parson, Chair in Anatomy at the University of Aberdeen, and colleagues at Edinburgh, Oxford and University College London, have, for the first time, shown that insufficient blood supply likely contributes to motor neuron loss in the childhood disease, spinal muscular atrophy.
In a paper published in Annals of Neurology, Professor Parson describes how his research suggests that expanding the focus beyond the nervous system to include the vascular system is important for developing effective treatments for the disease.
Spinal muscular atrophy (SMA), often described as a childhood form of motor neuron disease, is the most common inherited cause of infant death in the world and affects one in 6000 live births. Also, known as floppy baby syndrome, SMA is usually diagnosed when infants fail to reach developmental milestones such as sitting unaided. In the most severe cases life expectancy does not exceed three years with the cause of death usually being respiratory failure.
Professor Parson said: “SMA presents itself like a motor neuron disease so research and treatment has been focussed mainly around protecting motor nerve cells.
“But, we have shown that in SMA, the blood vessels that course through every structure in the body are also severely affected. Importantly, this results in reduced delivery of oxygen to the body, including the motor nerve cells which die in SMA.
“This new information provides us with an entirely new avenue for research and the development of potential therapies for this devastating disease.”
Simon Parson was formerly of Edinburgh University where some of this work was carried out. He is part of the Euan MacDonald Centre for Motor Neurone Disease (Edinburgh), a Scotland-wide centre for the study of motor neurone diseases.
Work was also carried out with colleagues at the University of Oxford, while patient biopsies came from The Institute of Child Health at University College London.
Funding: Funding for this research came from the SMA Trust, The Euan MacDonald Centre for Motor Neurone Disease Research, Muscular Dystrophy UK, Motor Neurone Disease Association, National Institute for Health Research, Great Ormond Street HospitalBiomedical Research Centre, the Medical Research Council, Great Ormond Street Hospital Charity and the MRC Centre for Neuromuscular Diseases. BioBank London (CNMD_BBL) is gratefully acknowledged.
Source: University of Aberdeen
Image Source: The image is adapted from the University of Aberdeen press release
Original Research: Abstract for “Vascular defects and spinal cord hypoxia in spinal muscular atrophy” by E Somers, RD Lees, K Hoban, JN Sleigh, H Zhou, F Muntoni, K Talbot, TH Gillingwater and SH Parson in Annals of Neurology. Published online October 27 2015 doi:10.1002/ana.24549
Abstract
Vascular defects and spinal cord hypoxia in spinal muscular atrophy
Objective
Spinal Muscular Atrophy (SMA) is a major inherited cause of infant death worldwide. It results from mutations in a single, ubiquitously expressed gene (SMN1), with loss of lower motor neurons being the primary pathological signature. Systemic defects have also been reported in SMA patients and animal models. We investigated whether defects associated with the vasculature contribute to motor neuron pathology in SMA.
Methods
Development and integrity of the capillary bed was examined in skeletal muscle and spinal cord of SMA mice, and muscle biopsies from SMA patients and controls, using quantitative morphometric approaches on immunohistochemically-labelled tissue. Pimonidazole hydrochloride-based assays were used to identify functional hypoxia.
Results
The capillary bed in muscle and spinal cord was normal in pre-symptomatic SMA mice (post-natal day 1), but failed to match subsequent post-natal development in control littermates. At mid- and late-symptomatic time-points the extent of the vascular architecture observed in two distinct mouse models of SMA was ∼50% of that observed in control animals. Skeletal muscle biopsies from human patients confirmed the presence of developmentally similar, significant vascular depletion in severe SMA. Hypovascularity in SMA mouse spinal cord was accompanied by significant functional hypoxia and defects in the blood-spinal cord barrier.
Interpretation
Our results indicate that vascular defects are a major feature of severe forms of SMA, present in both mouse models and patients, resulting in functional hypoxia of motor neurons. Thus, abnormal vascular development and resulting hypoxia may contribute to the pathogenesis of SMA.
“Vascular defects and spinal cord hypoxia in spinal muscular atrophy” by E Somers, RD Lees, K Hoban, JN Sleigh, H Zhou, F Muntoni, K Talbot, TH Gillingwater and SH Parson in Annals of Neurology. Published online October 27 2015 doi:10.1002/ana.24549
