Congenital achromatopsia is a genetically heterogeneous, predominantly autosomal recessive, retinal disorder with a prevalence of approximately 1 in 30,000 in the general population.1
It is characterized by a lack of color discrimination, poor visual acuity, photophobia, pendular nystagmus, and abnormal photopic electroretinographic (ERG) recordings with preservation of the rod-mediated ERG. A prior report by Khan and colleagues2
showed that the rod ERG function can be modestly subnormal. The disease has been categorized into complete and incomplete achromatopsia subtypes. The incomplete (atypical) form is defined as dyschromatopsia, in which the symptoms are similar to those of the complete achromatopsia (typical) form but with less visual dysfunction.3
Patients with the complete form have nondetectable cone function on ERG testing, whereas those with the incomplete form retain some residual cone function on ERG, and often more preserved color vision and a higher level of visual acuity (up to 0.20).3–5
Funduscopy is usually normal in both forms, although not infrequently macular pigmentary mottling and even occasionally atrophic changes have been described.6
The known causes of congenital achromatopsia are all due to malfunction of the retinal phototransduction pathway. Specifically, recessive forms of achromatopsia result from the inability of cone photoreceptors to properly respond to a light stimulus by hyperpolarizing. To date, mutations in four genes have been identified to cause achromatopsia in human patients, including the α- and β-subunits of the cone cyclic nucleotide-gated ion channels, CNGA3
(ACHM2, OMIM600053) and CNGB3
(ACHM3, OMIM605080), which are located in the plasma membrane of the cone outer segments, the α-subunit of the cone photoreceptor transducin, GNAT2
(ACHM4, OMIM139340), and the catalytic α-subunit of the cone cyclic nucleotide phosphodiesterase, PDE6C
(OMIM600827). The vast majority of human cases of achromatopsia are caused by mutations in either CNGA3
Prior recent reports of animal studies showed that CNGB3
, or GNAT2
knockout mice and naturally occurring dog models of achromatopsia responded well to adenoassociated virus (AAV) gene therapy. In animal models of human achromatopsia, cone ERG amplitudes recovered to nearly normal levels.12–14
These results from proof-of-principle experiments in animals with cone-directed gene therapy offer promise for eventual translation to human patients. Identifying and then targeting retinal locations with retained photoreceptors will be a prerequisite for successful gene therapy in achromatopsia patients.
Previous observations regarding photoreceptor structure in achromatopsia have been limited primarily to histologic reports. In a previous report by Galezowski,15
the retinal cones were described as entirely absent. Larsen16
reported malformed foveal cones with normal cones in the peripheral retina, whereas Harrison et al.17
found misshaped and reduced numbers of retinal cones. In another report by Falls et al.,18
normal numbers of odd-shaped foveal cones and isolated numbers of cones in the peripheral retina were described. Glickstein and Heath19
found no evidence of foveal cones and reduced numbers of peripheral cones. Although genetic testing was not available at the time of these studies, they nevertheless highlight the fact that the picture of photoreceptor structure in achromatopsia is likely to be complex. Some clarity on this issue has begun to come from the use of noninvasive imaging techniques to assess photoreceptor structure in patients with achromatopsia. Optical coherence tomography (OCT), which provides excellent axial resolution, has been used to show a highly variable phenotype at the level of the photoreceptor inner segment (IS) and outer segment (OS),4,6,20,21
although the general interpretation has been that there is an absence or reduction of healthy cone structure. Adaptive optics (AO) provides high lateral resolution,22–24
and was used in a single case to examine photoreceptor structure on the single-cell level.25
The authors visualized a normal rod photoreceptor mosaic, but did not report any evidence of cone structure. These findings only confirm the complexity of the photoreceptor phenotype in achromatopsia, thus warranting further investigation.
Here we used noninvasive high-resolution imaging tools (spectral domain [SD]- OCT and AO scanning laser ophthalmoscopy [SLO]) together with functional measures of vision (ERG, microperimetry [MP], and color vision) to assess photoreceptor structure and function in patients with congenital achromatopsia. We sought to correlate these findings with genetic information from the same subjects. Not only is this approach expected to provide a better understanding of the disease, but also should prove useful in identifying which patients may be most likely to benefit from participating in future gene-targeted treatment trials to rescue or restore cone photoreceptors in this group of patients. Moreover, the structural and functional assays used here would be useful for evaluating the therapeutic efficacy in patients who in fact go on to receive intervention.