Early signs of longitudinal progressive cone photoreceptor degeneration in achromatopsia
ABSTRACT To characterise longitudinal progressive retinal changes in achromatopsia.
Ultrahigh-resolution spectral optical coherence tomography (Copernicus, 3 μm axial resolution) was used to obtain tomograms of the fovea from five children and three adults with achromatopsia. Each patient was scanned twice with a mean follow-up time of 16 months. Progressive changes in reflectivity at the inner segment/outer segment (IS/OS) junction, the central macular and outer nuclear layer thickness were analysed.
Younger patients (<10 years; patient 1-5) showed progressive morphological changes at the IS/OS junction between visits 1 and 2. However, older patients (>40 years; patients 6-8) did not have any changes in the retinal morphology between visits 1 and 2. In patients 1 and 2, IS/OS discontinuities (visit 1) developed into a hyper-reflective zone confined to the fovea (visit 2). In patient 3, the hyper-reflective zone (visit 1) progressed to form an IS/OS disruption and early formation of a small hypo-reflective zone (visit 2). Patients 4 and 5 had a hypo-reflective zone (visit 1) which subsequently increased in size (visit 2). There was a decrease in central macular and outer nuclear layer thickness between visits 1 and 2 in children.
For the first time, we show progressive longitudinal changes in retinal morphology in achromatopsia. Early changes include subtle IS/OS reflectivity alterations. The dynamic retinal changes in younger patients provide evidence that it represents a progressive disorder, and implementation of gene therapy during the early stages of the disease may provide best prognosis.
- Ophthalmology 09/2014; 121(9). DOI:10.1016/j.ophtha.2014.03.030 · 6.17 Impact Factor
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ABSTRACT: IMPORTANCE Mutations in CNGA3 are the most common cause of achromatopsia and cone-rod dystrophies. OBJECTIVE To identify CNGA3 mutations in patients with cone dystrophies or Leber congenital amaurosis. DESIGN, SETTING, AND PARTICIPANTS Clinical data and genomic DNA in 267 Chinese probands from 138 families with cone dystrophies and 129 families with Leber congenital amaurosis collected at the Zhongshan Ophthalmic Center, Guangzhou, China. MAIN OUTCOMES AND MEASURES Variants in CNGA3 and associated phenotypes, assessed by Sanger sequencing of CNGA3, bioinformatics of variants, and segregation analysis. RESULTS Homozygous or compound heterozygous mutations in CNGA3, including 26 novel and 13 known mutations, were identified in 46 probands from 138 families with cone dystrophies, but none were found in any of the probands from 129 families with Leber congenital amaurosis. The 46 probands with CNGA3 mutations could be further classified as likely having achromatopsia (18 probands) and cone-rod dystrophies (28 probands) based on electroretinographic recordings. Analysis of family members in 17 of 46 families demonstrated good segregation of the disease with the CNGA3 mutations. CONCLUSIONS AND RELEVANCE To our knowledge, this study is the first systemic analysis of CNGA3 in Chinese patients and expands the mutational spectrum and associated phenotypes. Our results suggest that CNGA3 mutations are a common cause of cone-rod dystrophies and achromatopsia in the Chinese population. These data indicate that CNGA3-associated cone dystrophies may be a common form of early-onset severe retinal dystrophies. Therapeutic potential such as gene therapy targeting this gene may benefit some children with early-onset severe retinal dystrophies.Jama Ophthalmology 06/2014; 132(9). DOI:10.1001/jamaophthalmol.2014.1032 · 3.83 Impact Factor
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ABSTRACT: IMPORTANCE While older children and adults with achromatopsia have been studied, less is known of young children with achromatopsia. OBJECTIVES To characterize the macular and foveal architecture of patients with achromatopsia during early childhood with handheld spectral-domain optical coherence tomographic imaging and to make phenotype-genotype correlations. DESIGN, SETTING, AND PARTICIPANTS Comparative case series of 9 patients with achromatopsia and 9 age-matched control participants at a tertiary ophthalmology referral center. MAIN OUTCOMES AND MEASURES Patients underwent complete ocular examination, full-field electroretinography, handheld spectral-domain optical coherence tomographic imaging, and screening for genetic mutations. RESULTS The mean (SD) age of the patients with achromatopsia was 4.2 (2.4) years, and the mean (SD) age of the control participants was 4.0 (2.1) years. Cone-driven responses to photopic single-flash or 30-Hz stimuli were nonrecordable in 7 patients and severely attenuated in 2. Rod-driven responses to dim scotopic single-flash stimuli were normal in 7 patients and mildly subnormal in 2. Six patients (67%) had foveal ellipsoid zone disruption, of which 1 had a hyporeflective zone. Four patients (44%) had foveal hypoplasia. The average total retinal thicknesses of the macula and fovea in the patients with achromatopsia were 14% and 17% thinner than in the control participants (P < .001 and P = .001), which was mostly due to the outer retina that was 18% and 26% thinner than in control participants (both P < .001), respectively. Genetic testing revealed a common homozygous mutation in CNGB3 in 5 patients with complete achromatopsia and heterozygous mutations in CNGA3 in 2 patients with incomplete achromatopsia. The youngest and worst-affected patient harbored compound heterozygous mutations in CNGB3 and a single mutation in CNGA3. CONCLUSIONS AND RELEVANCE In early childhood, there is a spectrum of foveal pathology that is milder than reported in older individuals with achromatopsia, which suggests the need for early therapeutic intervention. Neither age alone nor genotype alone predicts the degree of photoreceptor loss or preservation. Thus, in anticipation of future gene therapy trials in humans, we propose that handheld spectral-domain optical coherence tomography is an important tool for the early assessment and stratification of macular architecture in young children with achromatopsia.Jama Ophthalmology 03/2014; 132(7). DOI:10.1001/jamaophthalmol.2014.685 · 3.83 Impact Factor