Microvasculopathy in spinal muscular atrophy is driven by a reversible autonomous endothelial cell defect

J Clin Invest, 2022 · DOI: https://doi.org/10.1172/JCI153430 · Published: November 1, 2022

Cardiovascular Science Neurology Genetics

Simple Explanation

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by degeneration of spinal cord motor neurons. This study reveals a retinal vascular defect in SMA patients, which is also found in SMA transgenic mice. This defect is due to problems with the growth and development of blood vessels. The study also found an imbalance between damage and repair of blood vessels in patients, with increased markers of injury and decreased markers of repair. The vascular issues are linked to the severity of the disease. Further, experiments showed that SMN deficiency directly impairs the ability of endothelial cells to form vessels. Overall, the research indicates that microvasculopathy, a disease of small blood vessels, is a key feature of SMA. The findings provide insights into microvascular complications in SMA and highlight the role of SMN in the vascular system.

Study Duration

Not specified

Participants

11 SMA patients and 23 healthy control children

Evidence Level

Not specified

Key Findings

1
SMA patients exhibit retinal vascular defects, characterized by a less dense and less complex primary retinal vasculature compared to age-matched controls.
2
Systemic administration of antisense therapy at birth, which increases SMN protein expression, can normalize the microvascular defect in SMA mice.
3
Cultured human endothelial cells with induced SMN deficiency display defects in vascular tube formation and endothelial cell migration, indicating a cell-autonomous defect.

Research Summary

This study identifies microvascular defects in SMA patients, transgenic SMA mice, and cellular models with SMN deficiency. It reveals a widespread microvascular pathology that is amenable to systemically delivered SMN-restoring therapy, and describes gross and cellular biomarkers of vascular pathology. The eye and neural retina are a window on the brain, and an area of growing interest in neurodegenerative diseases, including motor neuron disease. The authors detected a retinal vascular phenotype in children with SMA by analyzing ultra-widefield ophthalmoscopy images. The study indicates that microvasculopathy is a widespread phenomenon in patients and mice affected by SMA, driven by an endothelial cell–autonomous defect in angiogenesis. This likely accelerates disease progression by further compromising organs already affected by SMN deficiency.

Practical Implications

Therapeutic Strategies

Therapeutic strategies for SMA should include the correction of SMN deficiency in the periphery, including the vascular system.

Monitoring Retinal Toxicity

Further analysis of the vasculature of retinal images may provide more valuable information in patients receiving risdiplam.

Patient Evaluation

It is important to evaluate the baseline vascular status of patients before commencing AAV-mediated treatment, as this might help to identify potentially susceptible individuals to thrombotic microangiopathy.

Study Limitations

1
Retinal imaging could not be performed in type 1 SMA infants due to the positioning compliance needed.
2
There are limitations to FD computation using the method of automatic vessel detection or segmentation.
3
The long-term biological implications of lower FD in the retina are unknown.

Your Feedback

Was this summary helpful?

Back to Cardiovascular Science