The Clinical Phenotype of CNGA3-Related Achromatopsia: Pretreatment Characterization in Preparation of a Gene Replacement Therapy Trial.
The purpose of this study was to clinically characterize patients with CNGA3-linked achromatopsia (CNGA3-ACHM) in preparation of a gene therapy trial.



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).



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, Vmax 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.



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.
Center for Ophthalmology, University of Tübingen, Tübingen, Germany.
Ditta
D
Zobor
Center for Ophthalmology, University of Tübingen, Tübingen, Germany.
Annette
A
Werner
Department of Pediatrics, Genetic Counseling Service, Hospital of Bolzano, Bolzano, Italy.
Franco
F
Stanzial
Department of Pediatrics, Genetic Counseling Service, Hospital of Bolzano, Bolzano, Italy.
Francesco
F
Benedicenti
Department of Ophthalmology, Ludwig-Maximilians-University, Munich, Germany.
Günther
G
Rudolph
Rare Retinal Disease Center, AugenZentrum Siegburg, Siegburg, Germany.
Ulrich
U
Kellner
Institute of Neurosciences of Montpellier, Hôpital Saint Eloi, Montpellier, France.
Christian
C
Hamel
Department of Ophthalmology, Lund University, Lund, Sweden.
Sten
S
Andréasson
Center for Ophthalmology, University of Tübingen, Tübingen, Germany.
Gergely
G
Zobor
Center for Ophthalmology, University of Tübingen, Tübingen, Germany.
Torsten
T
Strasser
Center for Ophthalmology, University of Tübingen, Tübingen, Germany.
Bernd
B
Wissinger
Center for Ophthalmology, University of Tübingen, Tübingen, Germany.
Susanne
S
Kohl
Center for Ophthalmology, University of Tübingen, Tübingen, Germany 7Werner Reichardt Center for Integrative Neuroscience, University of Tübingen, Tübingen, Germany.
Eberhart
E
Zrenner
D000293:Adolescent; D000328:Adult; D002648:Child; D003118:Color Perception / Q000502:physiology; D003117:Color Vision Defects / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics*; D003623:Dark Adaptation / Q000502:physiology; D004596:Electroretinography; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011446:Prospective Studies; D011601:Psychophysics; D012160:Retina / Q000473:pathology* / Q000503:physiopathology*; D012684:Sensory Thresholds; D041623:Tomography, Optical Coherence; D014792:Visual Acuity / Q000502:physiology; D014794:Visual Fields / Q000502:physiology; D055815:Young Adult
C518238:CNGA3 protein, human; D054815:Cyclic Nucleotide-Gated Cation Channels