Blue Cone Monochromacy: Visual Function and Efficacy Outcome Measures for Clinical Trials

Abstract

BackgroundBlue Cone Monochromacy (BCM) is an X-linked retinopathy caused by mutations in the OPN1LW / OPN1MW gene cluster, encoding long (L)- and middle (M)-wavelength sensitive cone opsins. Recent evidence shows sufficient structural integrity of cone photoreceptors in BCM to warrant consideration of a gene therapy approach to the disease. In the present study, the vision in BCM is examined, specifically seeking clinically-feasible outcomes for a future clinical trial.MethodsBCM patients (n = 25, ages 5–72) were studied with kinetic and static chromatic perimetry, full-field sensitivity testing, and eye movement recordings. Vision at the fovea and parafovea was probed with chromatic microperimetry.ResultsKinetic fields with a Goldmann size V target were generally full. Short-wavelength (S-) sensitive cone function was normal or near normal in most patients. Light-adapted perimetry results on conventional background lights were abnormally reduced; 600-nm stimuli were seen by rods whereas white stimuli were seen by both rods and S-cones. Under dark-adapted conditions, 500-nm stimuli were seen by rods in both BCM and normals. Spectral sensitivity functions in the superior retina showed retained rod and S-cone functions in BCM under dark-adapted and light-adapted conditions. In the fovea, normal subjects showed L/M-cone mediation using a 650-nm stimulus under dark-adapted conditions, whereas BCM patients had reduced sensitivity driven by rod vision. Full-field red stimuli on bright blue backgrounds were seen by L/M-cones in normal subjects whereas BCM patients had abnormally reduced and rod-mediated sensitivities. Fixation location could vary from fovea to parafovea. Chromatic microperimetry demonstrated a large loss of sensitivity to red stimuli presented on a cyan adapting background at the anatomical fovea and surrounding parafovea.ConclusionsBCM rods continue to signal vision under conditions normally associated with daylight vision. Localized and retina-wide outcome measures were examined to evaluate possible improvement of L/M-cone-based vision in a clinical trial.

Spatially Resolved Spectral Sensitivities as a Potential Read-out Parameter in Clinical Gene Therapeutic Trials

“…A similar set-up for SST testing was used by others to test spectral sensitivities in ACHM due to CNGA3 mutations and in BCM patients with the particular aim to characterize retinal function at defined retinal loci (14° in the superior field) and at the foveal centre in order to develop a read-out parameter for later gene therapeutic trials [11][12][13] . They showed that BCM patients have differing thresholds depending on the location tested, such as measurable rod and S cone function in the superior field, while in the fovea only rod function was detectable [13] .…”

“…They showed that BCM patients have differing thresholds depending on the location tested, such as measurable rod and S cone function in the superior field, while in the fovea only rod function was detectable [13] . Likewise, ACHM patients due to CNGA3 mutations reveal an absence of cone function in the superior field and a curve resembling the one for rods under photopic conditions.…”

“…Detailed information has been gathered in several studies for ACHM (CNGA3 -/-) [11] or BCM patients [12,13] .…”

High‐resolution microarray analysis unravels complex Xq28 aberrations in patients and carriers affected by X‐linked blue cone monochromacy

“…Black squares represent affected males with blue cone monochromacy (BCM). Retinal findings of these three subjects were reported previously and are summarized in the Appendix S1. Slashes through symbols indicate deceased individuals; the arrows designate the probands P1, P2, and P3 in Families 1, 2, and 3, respectively.…”

“…Three unrelated men (P1–P3; Fig. ) with a clinical diagnosis of BCM were referred for testing by X‐HR microarray. Informed consents were obtained using the UTHSC IRB protocols.…”