Abstract Details

Pathogenic mis-sense variants in the ACTA2 gene at Arg179 cause a severe syndrome, multisystem smooth muscle dysfunction syndrome (MSMDS), characterized by systemic smooth muscle cell dysfunction, hypotension, aortic aneurysms and cerebrovascular disease leading to death in the first 3 decades of life. The involvement of brain vasculature and its onset during childhood distinguishes ACTA2^R179H mutations and is characterized small and large vessel involvement leading recurrent ischemic strokes.

While congenital mydriasis has been consistently reported in most patients with ACTA2 Arg179 and allows for earlier diagnosis, other ocular and retinal anomalies have not been systematically characterized. If not, while assessing the brain vasculature commonly requiring sedation in children, retinal vessels which may recapitulate features of the disease are easily evaluated. 

To study retinal and vascular features of pediatric patients affected by ACTA2 arginine 179 pathogenic variants using optical coherence tomography (OCT), fundoscopic photography, and fluorescein angiography (FA). 

Retrospective cross-sectional analysis of 9 pediatric patients, ages 4-12, with known ACTA2 Arg179 variants, were evaluated at Massachusetts Eye and Ear Institute or Boston Children’s Hospital for a neuro-ophthalmology evaluation. 

Iris evaluation showed congenital mydriasis in all patients (n=9), loss of iris smooth muscle tone (n=6), and persistent wispy pupillary membrane fibers adherent to the anterior lens (n=4). On retinal evaluations we found 100% of subjects with tortuous vasculature consistently in fundoscopic photography, FA, OCT. All patients had associated white matter hyperintensities and dilated petrous with tapering of the terminal internal carotid arteries on brain MRIs. 

We report the largest cohort of MSMDS ACTA2 R179H with ocular and retinal phenotypic characterization. Congenital mydriasis can be identified at birth and could be added to the universal newborn eye screening to enable early diagnosis and preventive stroke care. Moreover, vessel tortuosity maybe used as non-invasive biomarker of cerebrovascular disease for monitoring disease progression and future therapies.