Reading Performance in Blue Cone Monochromacy: Defining an Outcome Measure for a Clinical Trial

Purpose Blue cone monochromacy (BCM), a congenital X-linked retinal disease caused by mutations in the OPN1LW/OPN1MW gene cluster, is under consideration for intravitreal gene therapy. Difficulties with near vision tasks experienced by these patients prompted this study of reading performance as a potential outcome measure for a future clinical trial. Methods Clinically and molecularly diagnosed patients with BCM (n = 17; ages 15–63 years) and subjects with normal vision (n = 22; ages 18–72 years) were examined with the MNREAD acuity chart for both uniocular and binocular conditions. Parameters derived from the measurements in patients were compared with normal data and also within the group of patients. Intersession, interocular and between-subject variabilities were determined. The frequent complaint of light sensitivity in BCM was examined by comparing results from black text on a white background (regular polarity) versus white on black (reverse polarity) conditions. Results MNREAD curves of print size versus reading speed were right-shifted compared with normal in all patients with BCM. All parameters in patients with BCM indicated abnormal reading performance. Intersession variability was slightly higher in BCM than in normal, but comparable with results previously reported for other patients with maculopathies. There was a high degree of disease symmetry in reading performance in this BCM cohort. Reverse polarity showed better reading parameters than regular polarity in 82% of the patients. Conclusions MNREAD measures of reading performance in patients with BCM would be a worthy and robust secondary outcome in a clinical trial protocol, given its dual purpose of quantifying macular vision and addressing an important quality of life issue. Translational Relevance Assessment of an outcome for a clinical trial.

[1]  V. Sothilingam,et al.  Safety and Vision Outcomes of Subretinal Gene Therapy Targeting Cone Photoreceptors in Achromatopsia , 2020, JAMA ophthalmology.

[2]  Susana T. L. Chung.  Reading in the presence of macular disease: a mini‐review , 2020, Ophthalmic & physiological optics : the journal of the British College of Ophthalmic Opticians.

[3]  T. Wisløff,et al.  Psychometric properties of the National Eye Institute Visual Function Questionnaire (NEI-VFQ 25) in a Norwegian population of patients with neovascular age-related macular degeneration compared to a control population , 2019, Health and Quality of Life Outcomes.

[4]  A. Tafreshi,et al.  Ophthalmic Diagnostic Imaging: Retina , 2019, High Resolution Imaging in Microscopy and Ophthalmology.

[5]  G. Querques,et al.  Emerging therapies in the management of macular edema: a review , 2019, F1000Research.

[6]  C. Luu,et al.  Microperimetry for geographic atrophy secondary to age-related macular degeneration. , 2019, Survey of ophthalmology.

[7]  A. Elsner,et al.  Adaptive optics imaging of the human retina , 2019, Progress in Retinal and Eye Research.

[8]  A. J. Roman,et al.  Blue Cone Monochromacy Caused by the C203R Missense Mutation or Large Deletion Mutations. , 2018, Investigative ophthalmology & visual science.

[9]  V. Sothilingam,et al.  Development of Methodology and Study Protocol: Safety and Efficacy of a Single Subretinal Injection of rAAV.hCNGA3 in Patients with CNGA3-Linked Achromatopsia Investigated in an Exploratory Dose-Escalation Trial. , 2018, Human gene therapy. Clinical development.

[10]  Emily J Patterson,et al.  Residual Cone Structure in Patients With X-Linked Cone Opsin Mutations , 2018, Investigative ophthalmology & visual science.

[11]  P. Royle,et al.  Treatments for dry age-related macular degeneration and Stargardt disease: a systematic review. , 2018, Health technology assessment.

[12]  N. Bressler,et al.  Maximum Reading Speed in Patients With Geographic Atrophy Secondary to Age-Related Macular Degeneration. , 2018, Investigative ophthalmology & visual science.

[13]  P. Ramulu,et al.  Reading Speed and Reading Comprehension in Age-related Macular Degeneration. , 2018, American journal of ophthalmology.

[14]  Gordon E. Legge,et al.  Comparing performance on the MNREAD iPad application with the MNREAD acuity chart , 2018, Journal of vision.

[15]  M. Michaelides,et al.  Achromatopsia: clinical features, molecular genetics, animal models and therapeutic options , 2018, Ophthalmic genetics.

[16]  M. Steinbach,et al.  The reading accessibility index and quality of reading grid of patients with central vision loss , 2018, Ophthalmic & physiological optics : the journal of the British College of Ophthalmic Opticians.

[17]  N. Bressler,et al.  Functional Reading Independence (FRI) Index: A New Patient-Reported Outcome Measure for Patients With Geographic Atrophy. , 2017, Investigative ophthalmology & visual science.

[18]  F. Ferris,et al.  Report From the NEI/FDA Endpoints Workshop on Age-Related Macular Degeneration and Inherited Retinal Diseases , 2017, Investigative ophthalmology & visual science.

[19]  F. Holz,et al.  Effective Dynamic Range and Retest Reliability of Dark-Adapted Two-Color Fundus-Controlled Perimetry in Patients With Macular Diseases. , 2017, Investigative ophthalmology & visual science.

[20]  G. Virgili,et al.  Reading Ability and Quality of Life in Stargardt Disease , 2017, European journal of ophthalmology.

[21]  J. Kremers,et al.  Perifoveal S-cone and rod-driven temporal contrast sensitivities at different retinal illuminances. , 2017, Journal of the Optical Society of America. A, Optics, image science, and vision.

[22]  R. Massof,et al.  Outcomes of the Veterans Affairs Low Vision Intervention Trial II (LOVIT II): A Randomized Clinical Trial , 2017, JAMA ophthalmology.

[23]  Gordon E Legge,et al.  Reading Digital with Low Vision. , 2016, Visible language.

[24]  G. Legge,et al.  Baseline MNREAD Measures for Normally Sighted Subjects From Childhood to Old Age , 2016, Investigative ophthalmology & visual science.

[25]  G. Legge,et al.  Development of a Reading Accessibility Index Using the MNREAD Acuity Chart. , 2016, JAMA ophthalmology.

[26]  A. V. Cideciyan,et al.  Blue Cone Monochromacy: Visual Function and Efficacy Outcome Measures for Clinical Trials , 2015, PloS one.

[27]  H. Taylor,et al.  Visual impairment and blindness due to macular diseases globally: a systematic review and meta-analysis. , 2014, American journal of ophthalmology.

[28]  G. Holder,et al.  Three Different Cone Opsin Gene Array Mutational Mechanisms with Genotype–Phenotype Correlation and Functional Investigation of Cone Opsin Variants , 2014, Human mutation.

[29]  A. Dubra,et al.  Imaging Cone Structure in Patients with OPN1LW and OPN1MW Mutations , 2014 .

[30]  A. V. Cideciyan,et al.  Human cone visual pigment deletions spare sufficient photoreceptors to warrant gene therapy. , 2013, Human gene therapy.

[31]  Gary S Rubin,et al.  Measuring reading performance , 2013, Vision Research.

[32]  L. Peichl,et al.  S cones: Evolution, retinal distribution, development, and spectral sensitivity , 2013, Visual Neuroscience.

[33]  David Williams,et al.  The effect of cone opsin mutations on retinal structure and the integrity of the photoreceptor mosaic. , 2012, Investigative ophthalmology & visual science.

[34]  T. Aleman,et al.  Macular function in macular degenerations: repeatability of microperimetry as a potential outcome measure for ABCA4-associated retinopathy trials. , 2012, Investigative ophthalmology & visual science.

[35]  C. Curcio,et al.  ANATOMICAL CORRELATES TO THE BANDS SEEN IN THE OUTER RETINA BY OPTICAL COHERENCE TOMOGRAPHY: Literature Review and Model , 2011, Retina.

[36]  G. Rubin,et al.  Test-retest variability of reading performance metrics using MNREAD in patients with age-related macular degeneration. , 2011, Investigative ophthalmology & visual science.

[37]  D. Sharon,et al.  Variable retinal phenotypes caused by mutations in the X-linked photopigment gene array. , 2010, Investigative ophthalmology & visual science.

[38]  S. Pardhan,et al.  Repeatability of reading ability indices in subjects with impaired vision. , 2009, Investigative ophthalmology & visual science.

[39]  M. Crossland,et al.  FIXATION STABILITY MEASUREMENT USING THE MP1 MICROPERIMETER , 2009, Retina.

[40]  G. Rubin,et al.  Foveal-Sparing Scotomas in Advanced Dry Age-Related Macular Degeneration , 2008, Journal of visual impairment & blindness.

[41]  Edwin M Stone,et al.  Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics , 2008, Proceedings of the National Academy of Sciences.

[42]  G. Legge,et al.  Relationship between visual span and reading performance in age-related macular degeneration , 2008, Vision Research.

[43]  F. Ferris,et al.  Report from the NEI/FDA Ophthalmic Clinical Trial Design and Endpoints Symposium. , 2008, Investigative ophthalmology & visual science.

[44]  Shahina Pardhan,et al.  The Repeatability of MNREAD Acuity Charts and Variability at Different Test Distances , 2006, Optometry and vision science : official publication of the American Academy of Optometry.

[45]  Helga Kolb,et al.  The mammalian photoreceptor mosaic-adaptive design , 2000, Progress in Retinal and Eye Research.

[46]  D. Bonett,et al.  Sample size requirements for estimating pearson, kendall and spearman correlations , 2000 .

[47]  J. Nathans,et al.  Genetic heterogeneity among blue-cone monochromats. , 1993, American journal of human genetics.

[48]  A. Milam,et al.  Distribution and morphology of human cone photoreceptors stained with anti‐blue opsin , 1991, The Journal of comparative neurology.

[49]  A. Hendrickson,et al.  Human photoreceptor topography , 1990, The Journal of comparative neurology.

[50]  GORDON E. LEGGE,et al.  Psychophysics of Reading. VIII. The Minnesota Low- Vision Reading Test , 1989, Optometry and vision science : official publication of the American Academy of Optometry.

[51]  K. Mullen,et al.  Human photopic vision with only short wavelength cones: post‐receptoral properties. , 1989, The Journal of physiology.

[52]  R. Hess,et al.  The photoreceptors in atypical achromatopsia. , 1989, The Journal of physiology.

[53]  C. M. Davenport,et al.  Molecular genetics of human blue cone monochromacy. , 1989, Science.

[54]  C. Stromeyer,et al.  Selective chromatic adaptation at different spatial frequencies , 1978, Vision Research.

[55]  I L Bailey,et al.  New Design Principles for Visual Acuity Letter Charts* , 1976, American journal of optometry and physiological optics.

[56]  J M Enoch,et al.  Contrast sensitivity, Westheimer function and Stiles-Crawford effect in a blue cone monochromat. , 1973, Vision research.

[57]  C. Clemente.  HISTOLOGY OF THE HUMAN EYE : An Atlas and Textbook , 1973 .

[58]  A. Ramé.  [Age-related macular degeneration]. , 2006, Revue de l'infirmiere.