Genetic and Clinical Characterization of Danish Achromatopsia Patients

Abstract

Achromatopsia is a rare congenital condition with cone photoreceptor dysfunction causing color blindness, reduced vision, nystagmus and photophobia. New treatments are being developed, but the current evidence is still conflicting regarding possible progression over time, and there is no clear genotype-phenotype correlation. This natural history study aimed to further explore the course of disease and potential clinical differences between various genotypes. The retrospective design allowed for the study of a large cohort with a long follow-up. Patients were identified from the Danish national registries. If not already available, genetic analysis was offered to the patient. Clinical data from 1945–2022 were retrieved from medical records and included best-corrected visual acuity (BCVA), color vision, refractive error, nystagmus, visual fields and fundoscopic findings. We identified variants believed to be disease causing in five of the known achromatopsia genes: CNGA3; CNGB3; GNAT2; PDE6C and PDE6H; and novel variants were identified in CNGB3 and PDE6C. Progressive deterioration of BCVA only attributable to achromatopsia was found in three of 58 patients. Progressive phenotype was seen with variants in CNGB3 and PDE6C. The results indicate that myopia could be more frequently occurring with variants in GNAT2, PDE6C and PDE6H and support the evidence that achromatopsia is a predominantly stationary condition with respect to BCVA. Although a clear genotype-phenotype correlation can still not be concluded, there may be differences in phenotypical characteristics with variants in different genes.

Vision-related quality of life, photoaversion, and optical rehabilitation in achromatopsia

“…Even though the majority of patients were completely colorblind, it cannot be excluded that if they are used to perceiving the world through one color of filter, this is the one they would generally prefer. As genotype-phenotype and structure-function correlation is typically sparse in achromatopsia, 22,30,31 we do not expect the genotype and differences in structural findings, e.g., grading of optical coherence tomography images, to impact which filter individual patients prefer. Many of our patients commented that the red filter was perceived as too dark, which could be explained by a red filter blocking most wavelengths of light below 600 nm, so this may lead to less bleaching of rod photoreceptors with an absorption maximum of around 498 nm but then also compromises rod-dominated vision, even though we did not see a reduced best-corrected visual acuity with the red filter.…”

“…Medical records were first reviewed to confirm the registered diagnosis, and if genetic analysis had not already been performed, patients were offered genetic testing by next-generation sequencing of a panel of genes associated with genetic eye disease. The current study was conducted as part of a larger study investigating the phenotypic characteristics and genetic causes of achromatopsia in Denmark, 22,23 where the diagnosis was clinically verified by in-depth phenotyping including electroretinography, color vision testing, and imaging. 22 Investigations for the current study included a questionnaire exploring the vision-related quality of life and the impact of photoaversion and clinical evaluation by an ophthalmologist and an optometrist trained in low vision optics, special aids, and optical rehabilitation at the Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.…”

“…Medical records were first reviewed to confirm the registered diagnosis, and if genetic analysis had not already been performed, patients were offered genetic testing by next-generation sequencing of a panel of genes associated with genetic eye disease. The current study was conducted as part of a larger study investigating the phenotypic characteristics and genetic causes of achromatopsia in Denmark, 22,23 where the diagnosis was clinically verified by in-depth phenotyping including electroretinography, color vision testing, and imaging 22 …”

Molecular Mechanisms Governing Sight Loss in Inherited Cone Disorders

“…Some cone diseases, such as blue-cone monochromacy and Bornholm eye disease (BED), do not fall into these groups. In Europe, ICDs have a combined prevalence of 1 in 30,000/40,000 ( Figure 3 ), although this varies between populations [ 19 , 20 , 21 , 22 , 23 ].…”

Morphological and Functional Aspects and Quality of Life in Patients with Achromatopsia

“…The fundus examination usually does not show pathological changes, but sometimes there can be a constriction of blood vessels and pathological macular findings in the adult age [3][4][5]. Mutations of the six genes CNGA3 [6], CNGB3 [7], GNAT2 [8], PDE6H [9], PDE6C [10], which play a vital role in the phototransduction cascade and ATF6 [11], which regulates the unfolded protein response, have been identified in achromatopsia.…”