Blue Cone Monochromacy Caused by the C203R Missense Mutation or Large Deletion Mutations

Abstract

PURPOSE. To compare the phenotype of blue cone monochromacy (BCM) caused by large deletion mutations with those having the C203R missense mutation. METHODS. BCM patients with large deletion mutations (n ¼ 21; age range, 5-60 years), and with the C203R missense mutation (n ¼ 13; age range, 5-70 years), were studied with optical coherence tomography, visual acuity, and perimetric sensitivity in a retrospective observational case series. Perceptual estimates of spatial resolution driven by rods, Scones , and L/M-cones were obtained by the choice of chromatic gratings presented on varied adapting conditions with a modified microperimeter. RESULTS. Both genotypes had abnormal foveal photoreceptor structure early in life. Patients with the C203R mutation, however, had decades-longer persistence of foveal photoreceptor outer nuclear layer thickness and a slower rate of development of inner segment/outer segment defects than did patients with large deletion mutations. At late ages, both genotypes had comparably severe losses of central structure. At the rod-rich hot spot, there was no difference in structure between cohorts with age. Grating acuities in all BCM patients were driven by Scones and rods; the foveal structural differences were not reflected in a difference between cohorts in visual sensitivity and spatial resolution. CONCLUSIONS. A difference in structural phenotype due to the C203R mutation versus large deletion mutations in BCM was detected as a more prolonged persistence of foveal photoreceptor structure in patients with the missense mutation. This should be taken into account in planning natural history studies, selecting outcomes for clinical trials, and defining the time window for possible therapies.

Foveal Therapy in Blue Cone Monochromacy: Predictions of Visual Potential From Artificial Intelligence

“…The BCM patients had either disease-associated large deletion mutations or the C203R mutation ( Supplementary Tables S1 , S2 ). The two categories of genotypes were recently found to have different phenotypes in terms of persistence of foveal structure; patients with large deletions show on average more severe losses of central structure at earlier ages ( Sumaroka et al, 2018 ). The cohort of eight patients with large deletion mutations tended to be younger in age than those with the C203R mutation.…”

“…More recently, the question of genetic heterogeneity and possible phenotypic differences within BCM was addressed with studies of cohorts of patients with large deletions versus patients with missense mutation, specifically C203R. An unexpected observation was that foveal cone structure was more persistent in the cohort of patients with the C203R mutation and the difference in natural history of disease progression could be as much as two to three decades ( Sumaroka et al, 2018 ). Examination of further C203R patients in the sixth and seventh decades of life confirmed the original findings (Sumaroka, unpublished observation).…”

“…Data from three normal subjects (N1–3, ages 22–32) were also included in this “training set” to cover the full range of foveal photoreceptor layer parameters. BCM patients included two eight-patient cohorts with different genotypes: those with large deletion mutations and those with the C203R missense mutation in a singular resident OPN1LW or OPN1LW/MW hybrid gene or in all genes of the OPN1LW/OPN1MW gene cluster ( Sumaroka et al, 2018 ). All subjects underwent a complete eye examination as well as specialized tests of visual function and structure.…”

“…Cross-sections along the horizontal meridian through the fovea were obtained with OCT (RTVue-100; Optovue Inc., Fremont, CA, United States). The principles of the method and our recording and analysis techniques have been published (e.g., Sumaroka et al, 2016 , 2018 ). Three 15° wide B-scans composed of 4,091 A-scans or longitudinal reflectivity profiles (LRPs) were selected from each subject.…”

“…Among these IRDs is blue cone monochromacy (BCM), the X-linked congenital disorder with loss of red (L, long wavelength sensitive) and green (M, middle wavelength sensitive) cone photoreceptor function secondary to mutations in the OPN1LW/OPN1MW gene cluster on chromosome Xq28. There is evidence of retained L/M cones at and around the fovea in BCM, suggesting that this condition may be a candidate for intravitreal gene therapy ( Cideciyan et al, 2013 ; Carroll et al, 2014 ; Scoles et al, 2016 ; Sumaroka et al, 2018 ; Garafalo et al, 2019 ). Missing to date, however, have been studies that would determine the level of efficacy that could be expected from such therapy, i.e., what is the degree of improvement in foveal function that could occur in the individual BCM patient.…”