Retinal arterial but not venous tortuosity correlates with facioscapulohumeral muscular dystrophy severity Susannah Q. Longmuir, MD, a,b Katherine D. Mathews, MD, b,c Reid A. Longmuir, MD, a,e Vinayak Joshi, MS, d Richard J. Olson, MD, a,b and Michael D. Abra `moff, MD, PhD a,e BACKGROUND Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease beginning with facial and shoulder girdle weakness with variable progression. Exudative retinal detachment, retinal vessel irregularities on fluorescein angiography, and retinal vessel tortuosity have been found in association with FSHD. METHODS In this retrospective study, muscle affectedness severity was rated as mild, moderate, or severe by a neurologist masked to the retinal images. Three ophthalmologists masked to disease severity graded the degree of arterial and venous tortuosity on a scale of 1 to 4. An automated method estimated an index of tortuosity for arteries and veins from color fundus photographs. Spearman rank correlation coefficients were used to describe the relationship between retinal vessel tortuosity and disease severity. RESULTS Seven patients with an average age of 13 years (range, 7-36 years) were selected. Correlation between the subjective tortuosity for arteries, and the severity of FSHD was 0.78 (p 5 0.039). The correlation coefficient for venous tortuosity was 0.06 and was not significant (p 5 0.882). The correlation coefficient between the average algorithmic computer-generated tortuosity indices for arteries and FSHD severity was high (0.85, p 5 0.016), but for veins it was low and not significant (0.19, p 5 0.662). CONCLUSIONS The authors of previous reports have shown retinal vascular abnormalities did not correlate to FSHD disease severity. Our results suggest a correlation between the tortuosity of arteries and the severity of disease in FSHD patients. These results suggest the tortuosity of arteries can serve as a biomarker of severity of disease in these FSHD patients, either as determined by human experts or by an automated method. ( J AAPOS 2010;14:240-243) F acioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease that begins with facial and shoulder girdle weakness and has variable progression. FSHD has a highly variable clinical presentation, ranging from patients who have a more severe disease with onset in childhood through the usual presentation with weakness in young adulthood to minimally symptomatic patients in later adulthood. Retinal vasculopathy is an established component of the FSHD phenotype. Exudative retinal detachment, retinal vessel irregularities on fluorescein angiography, and retinal vessel tortuosity have been reported in association with FSHD. However, it has not been reported whether the ves- sel tortuosity was arterial, venous, or both. Abnormalities in retinal blood vessels in those affected by facioscapulohum- eral muscular dystrophy have been noted in 50% to 75% of patients. 1,2 In addition to the muscle weakness and retinal abnormalities, hearing loss, supraventricular arrhythmias, and, rarely, central nervous system manifestations also are noted to occur in patients with FSHD. There has been a strong link between sensorineural hearing loss and eye complications associated with FSHD. 1-5 Currently, we know that FSHD is caused by deletion of a 3.3 kb repeat at 4q35. Severity is broadly correlated with the number of residual 4q35 D4Z4 repeats; therefore, patients with fewer repeats have more severe disease. Pathophysiology is likely to involve altered regulation of transcription, possibly of more than one gene. Microarray analysis identified a cluster of genes with a role in vascular biology that was up-regulated in early FSHD muscles, leading to a hypothesis that vasculopathy may have a pri- mary role in FSHD pathogenesis. 6 This study is the first to use a novel, computer-driven analysis of arterial tortuosity in FSHD and to show this calculated index of Author affiliations: a Department of Ophthalmology; b Department of Pediatrics; c Department of Neurology, and d Department of Biomedical Engineering, University of Iowa Hospitals and Clinics; e VA Medical Center, Iowa City, Iowa Presented as a poster at the 35th Annual Meeting of the American Association for Pediatric Ophthalmology and Strabismus, San Francisco, CA, April 17-21, 2009. Submitted October 9, 2009. Revision accepted March 16, 2010. Reprint requests: Susannah Longmuir, MD, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52246 (email: Susannah-longmuir@uiowa.edu). Copyright Ó 2010 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2010/$36.00 1 0 doi:10.1016/j.jaapos.2010.03.006 240 Journal of AAPOS