Blue-cone monochromacy and achromatopsia

Summary

Cone dysfunction syndromes are a heterogenous subset of inherited retinal diseases that primarily affect the function of cone cells. Classic examples are blue cone monochromacy (BCM) and achromatopsia (ACHM) (216). In both cases, there is substantial loss of some or all cone-cell function while retaining rod function.

Blue Cone Monochromacy (BCM) is an X-linked congenital color vision disorder caused by OPN1LW/OPN1MW gene clusters mutations (135) (196). We have found evidence of L/M cone survival, suggesting possible candidacy for gene augmentation therapy (135). These findings were supported by intriguing results from some of our BCM patients that presented with residual L/M cones within the central 1.5 mm of the retina, applying further emphasis on gene therapy and outcome measures (other than ocular examination) (147). We have also performed a comparative study in which we identified distinctive presentations of disease progression between the two well-known mutations, OPN1LW/OPN1MW and C203R, urging the implementation of this data when designing gene therapy clinical trials (196). We have performed many experiments focusing on developing and testing optimal outcome measures for future BCM clinical trials. These include machine learning techniques (212), MNREAD acuity charts (214), Farnsworth-Munsell arrangement tests (235), and Color Assessment and Diagnosis (CAD) tests (235). We have also applied the use of chromatic perimetry and microperimetry to illustrate their potential as outcome measures for identifying changes in L-opsin expression in BCM patients during gene therapy trials (262).

Achromatopsia (ACHM) is a congenital autosomal recessive condition that is caused by at least five different genes, resulting in the full absence of color discrimination and rod-dependent photoreceptors. We have considered detailed phenotype of ACHM caused by CNGA3 variants. Our findings suggest ACHM is a good candidate for gene augmentation therapy trial (144).

As standard automatic perimetry (SAP) does not have the capacity for measuring photoreceptor-specific sensitivities, we designed a protocol, using commercial (unmodified) perimeters, that could be utilized to quantify these specific measurements in both BCM and ACHM patients (273).

To identify cone vision function in cone-affected diseases with retained rod vision, we developed a cone-specific orientation device (151). In addition, we have designed a modified microperimeter to test cone-specific spatial vision that could be used as an outcome measure for gene therapy trials focusing on cone-affected diseases (161).

CHRD investigators have made substantial contributions to the understanding of cone dysfunction syndromes. Listed below are the papers highlighting our developments and participation in studying these debilitating diseases.

12 Publications on Blue-cone Monochromacy and Achromatopsia

273. Wu V, Roman AJ, Galsterer EL, Ansari G, Erdinest I, Righetti G, Viarbitskaya I, Russell RC, Kim RJ, Charlier J, Pfau K, Stingl K, Banin E, Pfau M, Stingl K, ALEMAN TS, CIDECIYAN AV. Measuring rod- and cone-photoreceptor-specific vision in inherited retinal diseases using a commercial perimeter. Investigative Ophthalmology & Visual Science 66:31, 2025. [PubMed] [DOI]

262. CIDECIYAN AV, Roman AJ, Warner RL, Sumaroka A, Wu V, Jiang YY, Swider M, Garafalo AV, Viarbitskaya I, Russell RC, Kohl S, Wissinger B, Ripamonti C, Barbur JL, Bach M, Carroll J, Morgan JIW, ALEMAN TS. Evaluation of retinal structure and visual function in blue cone monochromacy to develop clinical endpoints for L-opsin gene therapy. International Journal of Molecular Sciences 25:10639, 2024. [PubMed] [DOI]

235. Mascio AA, Roman AJ, CIDECIYAN AV, Sheplock R, Wu V, Garafalo AV, Sumaroka A, Pirkle S, Kohl S, Wissinger B, Jacobson SG, Barbur JL. Color vision in blue cone monochromacy: Outcome measures for a clinical trial. Translational Vision Science & Technology, 12:25, 2023. [PubMed] [DOI]

216. Garafalo AV, Sheplock R, Sumaroka A, Roman AJ, CIDECIYAN AV, Jacobson SG. Childhood-onset genetic cone-rod photoreceptor diseases and underlying pathobiology. EBioMedicine, 63:103200, 2021. [PubMed] [DOI]

214. Semenov EP, Sheplock R, Roman AJ, McGuigan DB, Swider M, CIDECIYAN AV, Jacobson SG. Reading performance in blue cone monochromacy: Defining an outcome measure for a clinical trial. Translational Vision Science & Techology, 9:13, 2020. [PubMed] [DOI]

212. Sumaroka A, CIDECIYAN AV, Sheplock R, Wu V, Kohl S, Wissinger B, Jacobson SG. Foveal therapy in blue cone monochromacy: Predictions of visual potential from artificial intelligence. Frontiers in Neuroscience, 14:800, 2020. [PubMed] [DOI] [Retinal Degeneration and Therapy Approaches]

196. Sumaroka A, Garafalo AV, CIDECIYAN AV, Charng J, Roman AJ, Choi W, Saxena S, Aksianiuk V, Kohl S, Wissinger B, Jacobson SG. Blue cone monochromacy caused by the C203R missense mutation or large deletion mutations. Investigative Ophthalmology & Visual Science 59:5762-5772, 2018. [PubMed]

161. CIDECIYAN AV, Roman AJ, Jacobson SG, Yan B, Pascolini M, Charng J, Pajaro S, Nirenberg S. Developing an outcome measure with high luminance for optogenetics treatment of severe retinal degenerations and for gene therapy of cone diseases. Investigative Ophthalmology & Visual Science 57:3211-3221, 2016. [PubMed]

151. Roman AJ, CIDECIYAN AV, Matsui R, Sheplock R, Schwartz SB, Jacobson SG. Outcome measure for the treatment of cone photoreceptor diseases: Orientation to a scene with cone-only contrast. BMC Ophthalmology 15:98, 2015. [PubMed] [PDF]

147. Luo X, CIDECIYAN AV, Iannaccone A, Roman AJ, Ditta LC, Jennings BJ, Yatsenko SA, Sheplock R, Sumaroka A, Swider M, Schwartz SB, Wissinger B, Kohl S, Jacobson SG. Blue cone monochromacy: Visual function and efficacy outcome measures for clinical trials. PLoS One 10(4): e0125700, 2015. [PubMed] [PDF]

144. Zelinger L, CIDECIYAN AV, Kohl S, Schwartz SB, Rosenmann A, Eli D, Sumaroka A, Roman AJ, Luo X, Brown C, Rosin B, Blumenfeld A, Wissinger B, Jacobson SG,Banin E, Sharon D. Genetics and disease expression in the CNGA3 form of achromatopsia: Steps on the path to gene therapy. Ophthalmology 122:997-1007, 2015.[PubMed]

135. CIDECIYAN AV, Hufnagel RB, Carroll J, Sumaroka A, Luo X, Schwartz SB, Dubra A, Land M, Michaelides M, Gardner JC, Hardcastle AJ, Moore AT, Sisk RA, Ahmed ZM, Kohl S, Wissinger B, Jacobson SG. Human cone visual pigment deletions spare sufficient photoreceptors to warrant gene therapy. Human Gene Therapy 24:993–1006, 2013. [PubMed]

Last updated April 27th, 2026