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.
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ABSTRACT: A literature review and case presentation are used to discuss the diagnostic value of spectral domain optical coherence tomography (SD-OCT) in the assessment and management of congenital achromatopsia. A 24-year-old Hispanic man presented to the clinic with a longstanding history of decreased vision and associated possible recent progression. A comprehensive eye examination and a battery of tests including SD-OCT, fundus photography, electroretinogram (ERG) and Farnsworth D-15 were completed. SD-OCT and photopic ERG confirmed the clinical diagnosis of congenital achromatopsia. There was the classic subfoveal flattened hyporeflective ‘punched out’ zone, resulting from an absence of inner segment/outer segment junction.SD-OCT findings associated with congenital achromatopsia have been documented recently, helping in the diagnosis of the condition. The SD-OCT findings have further expanded our knowledge of congenital achromatopsia, while also aiding in the management of the disease.Clinical and Experimental Optometry 08/2014; 97(6). DOI:10.1111/cxo.12175 · 1.26 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: Purpose: To longitudinally characterize retinal structure and function in achromatopsia (ACHM) in preparation for clinical gene therapy trials. Methods: 38 molecularly confirmed ACHM subjects underwent serial assessments, including spectral domain optical coherence tomography (SD-OCT), microperimetry, and fundus autofluorescence (FAF). Foveal structure on SD-OCT was graded and compared for evidence of progression, along with serial measurements of foveal total retinal thickness (FTRT) and outer nuclear layer (ONL) thickness. FAF patterns were characterized and compared over time. Results: Mean follow-up was 19.5 months (age range at baseline: 6-52 years). Only 2 of 37 subjects (5%) demonstrated change in serial foveal SD-OCT scans. There was no statistically significant change over time in FTRT (p=0.83), ONL thickness (p=0.27), hyporeflective zone (HRZ) diameter (p=0.42), visual acuity (p=0.89), contrast sensitivity (p=0.22), mean retinal sensitivity (p=0.84), and fixation stability (p=0.58). Three distinct FAF patterns were observed (n=30): central increased FAF (n=4), normal FAF (n=11), and well-demarcated reduced FAF (n=15); with the latter group displaying a slow increase in the area of reduced FAF of 0.03 mm2 over 19.3 months (p=0.002). Conclusions: Previously published cross-sectional studies have described conflicting findings with respect to the age-dependency of progression. This study, which constitutes the largest and longest prospective longitudinal study of ACHM to date, suggests that although ACHM may be progressive, any such progression is slow and subtle in most patients, and does not correlate with age or genotype. We also describe the first serial assessment of FAF, which is highly variable between individuals, even of similar age and genotype.Investigative Ophthalmology & Visual Science 08/2014; 55(9). DOI:10.1167/iovs.14-14937 · 3.66 Impact Factor