Bardet-Biedl syndrome-7 (BBS7) shows treatment potential and a cone-rod dystrophy phenotype that recapitulates the non-human primate model

ABSTRACT

Purpose: To provide a detailed ophthalmic phenotype of two male patients with Bardet-Biedl Syndrome (BBS) due to mutations in the BBS7 gene

Methods: Two brothers ages 26 (Patient 1, P1) and 23 (P2) underwent comprehensive ophthalmic evaluations over three years. Visual function was assessed with full-field electroretinograms (ffERGs), kinetic and chromatic perimetry, multimodal imaging with spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF) with short- (SW) and near-infrared (NIR) excitation lights and adaptive optics scanning light ophthalmoscopy (AOSLO).

Results: Both siblings had a history of obesity and postaxial polydactyly; P2 had diagnoses of type 1 Diabetes Mellitus, Addison’s disease, high-functioning autism-spectrum disorder and −12D myopia. Visual acuities were better than 20/30. Kinetic fields were moderately constricted. Cone-mediated ffERGs were undetectable, rod ERGs were ~80% of normal mean. Static perimetry showed severe central cone and rod dysfunction. Foveal to parafoveal hypoautofluorescence, most obvious on NIR-FAF, co-localized with outer segment shortening/loss and outer nuclear layer thinning by SD-OCT, and with reduced photoreceptors densities by AOSLO. A structural-functional dissociation was confirmed for cone- and rod-mediated parameters. Worsening of the above abnormalities was documented by SD-OCT and FAF in P2 at 3 years. Gene screening identified compound heterozygous mutations in BBS7 (p.Val266Glu: c.797 T > A of maternal origin; c.1781_1783delCAT, paternal) in both patients.

Conclusions: BBS7-associated retinal degeneration may present as a progressive cone-rod dystrophy pattern, reminiscent of both the murine and non-human primate models of the disease. Predominantly central retinal abnormalities in both cone and rod photoreceptors showed a structural-functional dissociation, an ideal scenario for gene augmentation treatments.

KEYWORDS:

• Bardet-Biedl
• BBS
• BBS7
• OCT
• cone dystrophy
• cone-rod dystrophy
• adaptive optics ophthalmoscopy
• retinitis pigmentosa
• RP

Acknowledgments

We thank the family who participated in this research. We also thank Alfredo Dubra and Min Chen. Dr. E.C. O’Neil is a recipient of the Diana Davis Spencer Clinical/Research Fellowship Award Program in Inherited Retinal Degenerations within FFB’s Alan Laties Career Development Program. Additional support is from grants from Hope for Vision, Macula Vision Research Foundation and The Pennsylvania Lions Sight Conservation and Research Foundation. Foundation Fighting Blindness (BR-CL-0619-0768-UPA), Research to Prevent Blindness Stein Innovation Award, and National Eye Institute, National Institute of Health (NEI, NIH) (P30 EY001583, R01 EY028601, R01 EY030227), and the F. M. Kirby Foundation; and the Paul and Evanina Mackall Foundation Trust.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Financial and competing interests

JIWM is an inventor on US Patent 8226236.

Additional information

Funding

This work was supported by the Hope For Vision; F. M. Kirby Foundation; and the Paul and Evanina Mackall Foundation Trust; The Pennsylvania Lions Sight Conservation and Research Foundation; Foundation Fighting Blindness; National Eye Institute, National Institute of Health [P30 EY001583, R01 EY028601, R01 EY030227]; Diana Davis Spencer Clinical/Research Fellowship Award Program in Inherited Retinal Degenerations within FFB’s Alan Laties Career Development Program; Research to Prevent Blindness Stein Innovation Award; Macula Vision Research Foundation.