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The clinical phenotype of CNGA3-related achromatopsia : Pretreatment characterization in preparation of a gene replacement therapy trial

Zobor, Ditta; Werner, Annette; Stanzial, Franco; Benedicenti, Francesco; Rudolph, Günther; Kellner, Ulrich; Hamel, Christian P; Andréasson, Sten LU ; Zobor, Gergely and Strasser, Torsten, et al. (2017) In Investigative Ophthalmology and Visual Science 58(2). p.821-832
Abstract

PURPOSE. The purpose of this study was to clinically characterize patients with CNGA3-linked achromatopsia (CNGA3-ACHM) in preparation of a gene therapy trial. METHODS. Thirty-six patients (age 7-56 years) with complete (cACHM) or incomplete (iACHM) CNGA3-ACHM were examined, including detailed psychophysical tests, extended electrophysiology, and assessment of morphology by fundus autofluorescence and spectral-domain optical coherence tomography (SD-OCT). RESULTS. Mean best-corrected visual acuity was 0.78 ± 0.14 logMAR. Color vision tests were consistent with a rod-dominated function in every cACHM patient. Microperimetry indicated an overall lowered retinal sensitivity within 20° of visual field. In electroretinography (ERG), photopic... (More)

PURPOSE. The purpose of this study was to clinically characterize patients with CNGA3-linked achromatopsia (CNGA3-ACHM) in preparation of a gene therapy trial. METHODS. Thirty-six patients (age 7-56 years) with complete (cACHM) or incomplete (iACHM) CNGA3-ACHM were examined, including detailed psychophysical tests, extended electrophysiology, and assessment of morphology by fundus autofluorescence and spectral-domain optical coherence tomography (SD-OCT). RESULTS. Mean best-corrected visual acuity was 0.78 ± 0.14 logMAR. Color vision tests were consistent with a rod-dominated function in every cACHM patient. Microperimetry indicated an overall lowered retinal sensitivity within 20° of visual field. In electroretinography (ERG), photopic responses were nondetectable in cACHM patients, but residual cone responses were observed in the iACHM patients. Scotopic responses were altered referring to anomalies of photoreceptor and postreceptor signaling, whereas in voltage versus intensity functions, V was significantly below normal values (P < 0.05). In contrast, slope (n) and semisaturation intensity (K) were found to be within normal limits. Spectral-domain OCT examination showed no specific changes in 14.7%, disruption of the ellipsoid zone (EZ) at the fovea in 38.2%, absent EZ in 17.7%, a hyporeflective zone in 20.5%, and outer retinal atrophy in 8.9% of all cases and foveal hypoplasia in 29 patients (85%). No correlation of retinal morphology with visual function or with a specific genotype was found. The severity of morphologic and functional changes lacked a robust association with age. CONCLUSIONS. Our extended investigations prove that even among such a genetically homogenous group of patients, no specific correlations regarding function and morphology severity and age can be observed. Therefore, the therapeutic window seems to be wider than previously indicated.

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published
subject
keywords
Achromatopsia, CNGA3, Gene therapy, Genotype-phenotype
in
Investigative Ophthalmology and Visual Science
volume
58
issue
2
pages
12 pages
publisher
ASSOC RESEARCH VISION OPHTHALMOLOGY INC
external identifiers
  • scopus:85012028627
  • wos:000396939600014
ISSN
0146-0404
DOI
10.1167/iovs.16-20427
language
English
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yes
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2b94090c-1269-435c-9d73-22477a1fdb15
date added to LUP
2017-02-28 08:47:29
date last changed
2018-06-24 05:10:55
@article{2b94090c-1269-435c-9d73-22477a1fdb15,
  abstract     = {<p>PURPOSE. The purpose of this study was to clinically characterize patients with CNGA3-linked achromatopsia (CNGA3-ACHM) in preparation of a gene therapy trial. METHODS. Thirty-six patients (age 7-56 years) with complete (cACHM) or incomplete (iACHM) CNGA3-ACHM were examined, including detailed psychophysical tests, extended electrophysiology, and assessment of morphology by fundus autofluorescence and spectral-domain optical coherence tomography (SD-OCT). RESULTS. Mean best-corrected visual acuity was 0.78 ± 0.14 logMAR. Color vision tests were consistent with a rod-dominated function in every cACHM patient. Microperimetry indicated an overall lowered retinal sensitivity within 20° of visual field. In electroretinography (ERG), photopic responses were nondetectable in cACHM patients, but residual cone responses were observed in the iACHM patients. Scotopic responses were altered referring to anomalies of photoreceptor and postreceptor signaling, whereas in voltage versus intensity functions, V was significantly below normal values (P &lt; 0.05). In contrast, slope (n) and semisaturation intensity (K) were found to be within normal limits. Spectral-domain OCT examination showed no specific changes in 14.7%, disruption of the ellipsoid zone (EZ) at the fovea in 38.2%, absent EZ in 17.7%, a hyporeflective zone in 20.5%, and outer retinal atrophy in 8.9% of all cases and foveal hypoplasia in 29 patients (85%). No correlation of retinal morphology with visual function or with a specific genotype was found. The severity of morphologic and functional changes lacked a robust association with age. CONCLUSIONS. Our extended investigations prove that even among such a genetically homogenous group of patients, no specific correlations regarding function and morphology severity and age can be observed. Therefore, the therapeutic window seems to be wider than previously indicated.</p>},
  author       = {Zobor, Ditta and Werner, Annette and Stanzial, Franco and Benedicenti, Francesco and Rudolph, Günther and Kellner, Ulrich and Hamel, Christian P and Andréasson, Sten and Zobor, Gergely and Strasser, Torsten and Wissinger, Bernd and Kohl, Susanne and Zrenner, Eberhart},
  issn         = {0146-0404},
  keyword      = {Achromatopsia,CNGA3,Gene therapy,Genotype-phenotype},
  language     = {eng},
  month        = {02},
  number       = {2},
  pages        = {821--832},
  publisher    = {ASSOC RESEARCH VISION OPHTHALMOLOGY INC},
  series       = {Investigative Ophthalmology and Visual Science},
  title        = {The clinical phenotype of CNGA3-related achromatopsia : Pretreatment characterization in preparation of a gene replacement therapy trial},
  url          = {http://dx.doi.org/10.1167/iovs.16-20427},
  volume       = {58},
  year         = {2017},
}