Assessing cone photoreceptor structure in patients with mutations in the OPN1LW/OPN1MW gene array

Abstract

Purpose : Blue cone monochromacy (BCM) is a cone dysfunction syndrome associated with mutations in the OPN1LW /OPN1MW gene array. Although the condition typically manifests with poor visual acuity, nystagmus, photophobia, and color vision defects, the severity of the phenotype is highly variable. Here we examined the genotype, clinical phenotype and cone structure in subjects with a clinical diagnosis of BCM.

Methods : Eleven males (aged 10 to 51 years) with suspected BCM were recruited and had their OPN1LW/OPN1MW gene arrays characterized. In 10 subjects, thickness and integrity of the retinal layers was evaluated using optical coherence tomography (OCT). Confocal and split-detection images of the cone mosaic were acquired using adaptive optics scanning light ophthalmoscopy (AOSLO). Imaging took place either at the Medical College of Wisconsin or at Moorfields Eye Hospital, London. Cone density was measured at foveal and parafoveal regions of interest using semi-automated cone-counting software in 9 subjects. Color vision was screened using the AO-HRR; 5 subjects also completed the Rayleigh match and 4 of those completed the Color Assessment and Diagnosis test.

Results : Genotypes varied and included deletions of the locus control region, point mutations and OPN1LW/OPN1MW interchange variants; as the latter can yield minor amounts of correctly spliced transcript, a BCM diagnosis is questionable in such cases. While all subjects had severe red-green color vision defects, some subjects demonstrated residual discrimination along the tritan axis. OCT revealed reduced retinal thickness (31 - 77% of normal), and reflectivity in confocal AOSLO was diminished for all subjects. Foveal inner-segment (IS) integrity was highly variable (661 - 35,041 cones/mm²) with large differences in cone packing geometry observed between subjects.

Conclusions : While the number of waveguiding cones was reduced, we found evidence of remnant cone IS structure in all subjects, albeit to a variable degree. In contrast to previous observations in patients with BCM, some subjects had a contiguous IS arrangement at the fovea. These data suggest that many BCM patients may be viable candidates for gene therapy efforts to restore cone function.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

 

AOSLO reveals highly variable cone packing and reflectivity. While confocal images (left) show reduced waveguiding, there is evidence for remnant IS structure in split-detection images (right).