with foveal hypoplasia. This is reminiscent of ﬁndings in
albinism, where the absence of a fovea does not necessarily
However, a structural grading system for
foveal hypoplasia reported by Thomas et al
a r elationship between foveal development and acuity. It is
also likely that varying degrees of nystagmus amplitude or
frequency between subjects contribute to determining
BCVA and retinal sensitivity in ACHM and other
Implications for Gene Therapy
Gene replacement trials for both CNGA3 and CNGB3 are
planned in the near future. Our ﬁndings of no age depen-
dence of cone loss demonstrate that the potential window of
opportunity for therapeutic intervention in ACHM is wider
than has previously been suggested; subjects with no
evidence of ISe disruption were aged between 6 and 52
years and we found no correlation of cone photoreceptor
disruption or loss with increasing age.
Because this was a cross-sectional study, it has not
assessed whether subjects who have any form of outer
retinal change develop progressive degeneration, and, if so,
how variable the rate of change may be. With respect to
cone photoreceptor structure, we therefore suggest that
candidates should be considered for potential gene therapy
intervention on an individual basis, irrespective of their age.
In addition, we did not observe decreas ed visual function in
subjects with foveal hypoplasia; in fact, signiﬁcantly better
BCVA and reading acuity were found in subjects with
foveal hypoplasia, suggesting that foveal hypoplasia per se
should not be an exclusion criterion for potential therapy
trials. In the 9 subjects with no ISe disruption evident on
SD-OCT, their mean ISe intensity ratio was considerably
lower than in healthy controls, illustrating that assessment of
the degree of residual cone structure using this metric may
be useful in determining the suitability of potential trial
participants. Direct visualization of the cone mosaic is
afforded through the use of adaptive optics imaging.
There is a need to elucidate the relationship between these
various measures of cone structure in ACHM to establish
the most appropriate means to identify suitable patients and
track therapeutic efﬁ cacy.
In addition to cone photoreceptor integrity, anothe r factor
likely to inﬂuence the response to gene therapy is the ability
of the visual system to respond to newly acquired input.
Functional magnetic resonance imaging has shown evidence
of visual cortex reorganization in ACHM subjects, with the
area of visual cortex normally active after cone-derived
foveal stimulation being active instead after rod stimuli.
Conversely, recovery of cone-driven cortical activity has
been observed in a canine model of ACHM (Gingras G.
Cortical recovery following gene therapy in a canine model
of achromatopsia. Paper presented at: The Vision Sciences
Society Meeting, May 8, 2009; Florida). The extent to
which the visual cortex is able to adapt to and process new
input from cone photoreceptors is an additional consider-
ation likely to inﬂuence the efﬁcacy of gene replacement
1. Michaelides M, Hunt DM, Moore AT. The cone dysfunction
syndromes. Br J Ophthalmol 2004;88:291–7.
2. Johnson S, Michaelides M, Aligianis IA, et al. Achromatopsia
caused by novel mutations in both CNGA3 and CNGB3 [report
online]. J Med Genet 2004;41:e20. Available at:, http:
//jmg.bmj.com/content/41/2/e20.long. Accessed August 7, 2013.
3. Kohl S, Baumann B, Rosenberg T, et al. Mutations in the cone
photoreceptor G-protein alpha-subunit gene GNAT2 in patients
with achromatopsia. Am J Hum Genet 2002;71:422–5.
4. Thiadens AA, den Hollander AI, Roosing S, et al. Homozy-
gosity mapping reveals PDE6C mutations in patients with
early-onset cone photoreceptor disorders. Am J Hum Genet
5. Kohl S, Coppieters F, Meire F, et al. European Retinal Disease
Consortium. A nonsense mutation in PDE6H causes
autosomal-recessive incomplete achromatopsia. Am J Hum
6. Thiadens AA, Somervuo V, van den Born LI, et al. Progres-
sive loss of cones in achromatopsia: an imaging study using
spectral-domain optical coherence tomography. Invest Oph-
thalmol Vis Sci 2010;51:5952–7.
7. Thomas MG, Kumar A, Kohl S, et al. High-resolution in vivo
imaging in achromatopsia. Ophthalmology 2011;118:882–7.
8. Genead MA, Fishman GA, Rha J, et al. Photoreceptor struc-
ture and function in patients with congenital achromatopsia.
Invest Ophthalmol Vis Sci 2011;52:7298–308.
9. Proudlock F, Gottlob I. Foveal development and nystagmus.
Ann N Y Acad Sci 2011;1233:292–7.
10. Alexander JJ, Umino Y, Everhart D, et al. Restoration of cone
vision in a mouse model of achromatopsia. Nat Med 2007;13:
11. Michalakis S, Muhlfriedel R, Tanimoto N, et al. Restoration of
cone vision in the CNGA3-/- mouse model of congenital
complete lack of cone photoreceptor function. Mol Ther
12. Pang JJ, Alexander J, Lei B, et al. Achromatopsia as a poten-
tial candidate for gene therapy. Adv Exp Med Biol 2010;664:
13. Carvalho LS, Xu J, Pearson RA, et al. Long-term and age-
dependent restoration of visual function in a mouse model of
CNGB3-associated achromatopsia following gene therapy.
Hum Mol Genet 2011;20:3161–75.
14. Komaromy AM, Alexander JJ, Rowlan JS, et al. Gene therapy
rescues cone function in congenital achromatopsia. Hum Mol
15. Hood DC, Zhang X, Ramachandran R, et al. The inner
segment/outer segment border seen on optical coherence
tomography is less intense in patients with diminished cone
function. Invest Ophthalmol Vis Sci 2011;52:9703–9.
16. Huang Y, Cideciyan AV, Papastergiou GI, et al. Relation of
optical coherence tomography to microanatomy in normal and
rd chickens. Invest Ophthalmol Vis Sci 1998;39:2405–16.
17. Spaide RF, Curcio CA. Anatomical correlates to the bands
seen in the outer retina by optical coherence tomography:
literature review and model. Retina 2011;31:1609–19.
18. Crossland MD, Dunbar HM, Rubin GS. Fixation stability
measurement using the MP1 microperimeter. Retina 2009;29:
19. Kohl S, Marx T, Giddings I, et al. Total colourblindness is
caused by mutations in the gene encoding the alpha-subunit of
the cone photoreceptor cGMP-gated cation channel. Nat Genet
Ophthalmology Volume 121, Number 1, January 2014