Neuronal Deficit in Severe Infantile SMA Broader Than Previously Thought, Study Finds

Patients with severe infantile spinal muscular atrophy (SMA) have significant loss of and damage to thoracic ventral horn neurons at the end of life, a new analysis has found.

The report, which was published in the journal Neuropathology and Applied Neurobiology, suggests a wider range of cells are affected in SMA than once thought.¹

New research sheds light on the impact of neuronal deficits in SMA | image credit: HendraGalus - stock.adobe.com

“Degeneration and specific loss of alpha motor neurons, central chromatolysis of remaining motor neurons and mis-migrated motor neurons are described as ‘characteristic’ of SMA pathology,” wrote corresponding author Hazel Allardyce, PhD, of the University of Aberdeen, and colleagues. “However, this dogmatic view of SMA is based on scant original data, small patient cohorts and inadequate quantitative techniques.”

More recent studies have shown SMA pathology manifests in astrocytes, microglia, oligodendrocytes, and blood vessels, among other areas, they explained.

One reason for the limited view of the disease’s pathology has to do with quantification methods. Allardyce and colleagues said only 1 previous study has used stereology—the gold standard in quantifying motor neuron loss. That study, they said, found 73% of loss of spinal motor neurons, though it did not specify the spinal level.²

A better understanding of the degree of loss is necessary, the investigators said, since current therapies can only rescue surviving neurons.

Allardyce and colleagues said thoracic spinal motor neurons warrant attention because they are affected early in the disease and serve as an “ideal” region to reassess spinal cord pathology in SMA.

In an effort to better characterize spinal cord pathology in severe infantile SMA, the investigators used detailed histological analysis, stereology, and transmission electron microscopy to conduct a post-mortem analysis of the spinal cord pathology of the disease. Among other goals, they sought to characterize the morphology of ventral horn, lateral horn, and Clarke’s column neuron populations.

The 7 patients included in the study ranged in age from 7 days to 11 months at the time of their deaths. All but 1 of the patients in the cohort possessed 2 copies of spinal motor neuron 2 (SMN2). The remaining patient’s copy number was unknown.

The authors found that all of the patients had substantial ventral horn neuron loss, regardless of the length of their postnatal survival. Most (65% on average) of the ventral horn neurons that survived were abnormal, the authors said.

“The remaining ventral horn neurons were small with abnormal, occasionally chromatolytic morphology, indicating cellular damage,” they wrote.

Additionally, Clarke’s column sensory-associated neurons showed evidence of cellular injury, though lateral horn neurons were preserved. The investigators found that these changes were linked with aberrant gray and white matter structures, which in turn was reflected in stunted postnatal spinal cord growth.

Reflecting on their findings, Allardyce and colleagues said most of what is known about SMA pathology is based on a small number of samples and inadequate methodologies.

“[L]ong-accepted dogmas of SMA disease pathology, including selective loss of alpha motor neurons, are based upon weak evidence and should be challenged,” they wrote.

The authors said previous research into SMA has failed to capture the breadth of the impacts of low levels of the SMN protein in people with SMA. They said their research demands a broader viewpoint.

“These data provide a new normal upon which to base future research to further appreciate significant pathologies beyond the loss of alpha motor neurons in the spinal cord, evaluate the success of current therapies, and aid in the design of novel ones,” they concluded.

References:

1. Allardyce H, Lawrence BD, Crawford TO, Sumner CJ, Parson SH. A reassessment of spinal cord pathology in severe infantile spinal muscular atrophy: reassessment of spinal cord pathology. Neuropathol Appl Neurobiol. 2024;50(5):e13013. doi:10.1111/nan.13013
2. Simic G, Seso-Simic D, Lucassen PJ, et al. Ultrastructural analysis and TUNEL demonstrate motor neuron apoptosis in Werdnig-Hoffmann disease. J Neuropathol Exp Neurol. 2000;59(5):398-407. doi:10.1093/jnen/59.5.398