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

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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; Zobor, Gergely; Strasser, Torsten; Wissinger, Bernd; Kohl, Susanne; Zrenner, Eberhart.

In: Investigative Ophthalmology and Visual Science, Vol. 58, No. 2, 01.02.2017, p. 821-832.

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Zobor, D, Werner, A, Stanzial, F, Benedicenti, F, Rudolph, G, Kellner, U, Hamel, CP, Andréasson, S, Zobor, G, Strasser, T, Wissinger, B, Kohl, S & Zrenner, E 2017, 'The clinical phenotype of CNGA3-related achromatopsia: Pretreatment characterization in preparation of a gene replacement therapy trial', Investigative Ophthalmology and Visual Science, vol. 58, no. 2, pp. 821-832. https://doi.org/10.1167/iovs.16-20427

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Zobor D, Werner A, Stanzial F, Benedicenti F, Rudolph G, Kellner U, Hamel CP, Andréasson S, Zobor G, Strasser T, Wissinger B, Kohl S, Zrenner E. 2017. The clinical phenotype of CNGA3-related achromatopsia: Pretreatment characterization in preparation of a gene replacement therapy trial. Investigative Ophthalmology and Visual Science. 58(2):821-832. https://doi.org/10.1167/iovs.16-20427

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Zobor, Ditta ; Werner, Annette ; Stanzial, Franco ; Benedicenti, Francesco ; Rudolph, Günther ; Kellner, Ulrich ; Hamel, Christian P ; Andréasson, Sten ; Zobor, Gergely ; Strasser, Torsten ; Wissinger, Bernd ; Kohl, Susanne ; Zrenner, Eberhart. / The clinical phenotype of CNGA3-related achromatopsia : Pretreatment characterization in preparation of a gene replacement therapy trial. In: Investigative Ophthalmology and Visual Science. 2017 ; Vol. 58, No. 2. pp. 821-832.

RIS

TY - JOUR

T1 - The clinical phenotype of CNGA3-related achromatopsia

T2 - Investigative Ophthalmology & Visual Science

AU - Zobor, Ditta

AU - Werner, Annette

AU - Stanzial, Franco

AU - Benedicenti, Francesco

AU - Rudolph, Günther

AU - Kellner, Ulrich

AU - Hamel, Christian P

AU - Andréasson, Sten

AU - Zobor, Gergely

AU - Strasser, Torsten

AU - Wissinger, Bernd

AU - Kohl, Susanne

AU - Zrenner, Eberhart

PY - 2017/2/1

Y1 - 2017/2/1

N2 - 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.

AB - 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.

KW - Achromatopsia

KW - CNGA3

KW - Gene therapy

KW - Genotype-phenotype

UR - http://www.scopus.com/inward/record.url?scp=85012028627&partnerID=8YFLogxK

U2 - 10.1167/iovs.16-20427

DO - 10.1167/iovs.16-20427

M3 - Article

VL - 58

SP - 821

EP - 832

JO - Investigative Ophthalmology & Visual Science

JF - Investigative Ophthalmology & Visual Science

SN - 1552-5783

IS - 2

ER -