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

Research output: Contribution to journalArticle

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 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.

Details

Authors
  • Ditta Zobor
  • Annette Werner
  • Franco Stanzial
  • Francesco Benedicenti
  • Günther Rudolph
  • Ulrich Kellner
  • Christian P Hamel
  • Sten Andréasson
  • Gergely Zobor
  • Torsten Strasser
  • Bernd Wissinger
  • Susanne Kohl
  • Eberhart Zrenner
Organisations
External organisations
  • University of Tübingen
  • Ludwig-Maximilian University of Munich
  • Hôpital Saint Eloi
  • Regional Hospital of Bolzano
  • AugenZentrum Siegburg
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Ophthalmology

Keywords

  • Achromatopsia, CNGA3, Gene therapy, Genotype-phenotype
Original languageEnglish
Pages (from-to)821-832
Number of pages12
JournalInvestigative Ophthalmology and Visual Science
Volume58
Issue number2
Publication statusPublished - 2017 Feb 1
Publication categoryResearch
Peer-reviewedYes