# Microvascular pathology in the spinal cord of severe spinal muscular atrophy patients

## TL;DR

This study finds vascular and blood-spinal cord barrier issues in the spinal cords of infants with severe spinal muscular atrophy, suggesting a link between microvascular dysfunction and neurodegeneration.

## Contribution

The study identifies microvascular pathology and blood-spinal cord barrier dysfunction in human SMA patients, expanding understanding of non-neuronal disease mechanisms.

## Key findings

- Von Willebrand Factor levels were reduced in vascular endothelial cells in SMA patients.
- Endothelial cell damage was associated with BSCB leakage and microglial activation.
- Vascular defects were confirmed in post-mortem spinal cord samples from severe SMA infants.

## Abstract

Severe spinal muscular atrophy (SMA) is a life-limiting neurodegenerative disease of infancy and early childhood, caused by reduced expression of the ubiquitous survival motor neuron protein (SMN). While current therapies aim to increase SMN levels and preserve motor neurons, significant deficits remain in treated patients and non-neuronal manifestations of SMN deficiency are underexplored. Vascular abnormalities including intrinsic endothelial cell dysfunction, altered vessel morphology, and altered vascular distribution have been reported in preclinical SMA models. Here, we characterised vascular architecture and blood-spinal cord barrier (BSCB) morphology and integrity in post-mortem spinal cord samples from severe SMA patients compared with unaffected controls. Von Willebrand Factor (vWF), a marker of endothelial cell health, was reduced within individual vascular endothelial cells, and associated with ultrastructural endothelial cell oedema, vacuolisation and compromised endothelial integrity. Ultrastructural damage extended to other components of the BSCB as evidenced by extravascular leakage of fibrinogen into the neural parenchyma and microglial activation consistent with a neuroinflammatory environment. Together, these findings suggest that vascular defects with associated dysfunction of the BSCB are present in the spinal cord of infants with severe SMA. This work adds to a growing body of evidence linking microvascular dysfunction to neurodegeneration in human neurodegenerative diseases. Further studies are warranted to define the contribution of vascular dysfunction to SMA pathogenesis and to assess whether current therapies adequately address this aspect of the disease.

The online version contains supplementary material available at 10.1186/s40478-026-02232-y.