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Retinal morphology of patients with achromatopsia during early childhood: implications for gene therapy
Paul Yang1, Keith V Michaels1, Robert J Courtney1
1Casey Eye Institute, Oregon Health & Science University, Portland.
Insights
Young children with achromatopsia show milder foveal pathology than older individuals, highlighting the need for early intervention. Handheld OCT imaging is crucial for assessing macular architecture in these young patients.
Area of Science:
- Ophthalmology
- Genetics
- Pediatrics
Background:
- Achromatopsia is a rare inherited retinal disorder affecting cone photoreceptors, leading to reduced visual acuity, photophobia, and color blindness.
- While achromatopsia has been studied in older populations, there is limited information on its presentation in young children.
Purpose of the Study:
- To characterize the macular and foveal architecture in young children with achromatopsia using handheld spectral-domain optical coherence tomography (SD-OCT).
- To establish phenotype-genotype correlations in pediatric achromatopsia patients.
- To identify the potential of SD-OCT for early assessment in anticipation of gene therapy trials.
Main Methods:
- A comparative case series included 9 young patients with achromatopsia and 9 age-matched controls.
- Ocular examinations, full-field electroretinography (ffERG), and handheld SD-OCT imaging were performed.
- Genetic testing was conducted to identify mutations in achromatopsia-associated genes (CNGB3 and CNGA3).
Main Results:
- Patients with achromatopsia exhibited thinner macular and foveal retinal thicknesses compared to controls, primarily in the outer retina.
- Foveal ellipsoid zone disruption was observed in 67% of patients, and 44% had foveal hypoplasia.
- Genetic analysis revealed mutations in CNGB3 (5 patients) and CNGA3 (2 patients), with complex mutations in the most severely affected child.
Conclusions:
- Pediatric achromatopsia presents with a spectrum of foveal pathology that appears milder than in older individuals, suggesting potential for early therapeutic intervention.
- Neither patient age nor specific genotype alone reliably predicts the extent of photoreceptor damage.
- Handheld SD-OCT is proposed as a valuable tool for early assessment and stratification of macular structure in young children with achromatopsia, aiding in gene therapy trial readiness.
Importance:
While older children and adults with achromatopsia have been studied, less is known of young children with achromatopsia.
Objectives:
To characterize the macular and foveal architecture of patients with achromatopsia during early childhood with handheld spectral-domain optical coherence tomographic imaging and to make phenotype-genotype correlations.
Design, Setting, And Participants:
Comparative case series of 9 patients with achromatopsia and 9 age-matched control participants at a tertiary ophthalmology referral center.
Main Outcomes And Measures:
Patients underwent complete ocular examination, full-field electroretinography, handheld spectral-domain optical coherence tomographic imaging, and screening for genetic mutations.
Results:
The mean (SD) age of the patients with achromatopsia was 4.2 (2.4) years, and the mean (SD) age of the control participants was 4.0 (2.1) years. Cone-driven responses to photopic single-flash or 30-Hz stimuli were nonrecordable in 7 patients and severely attenuated in 2. Rod-driven responses to dim scotopic single-flash stimuli were normal in 7 patients and mildly subnormal in 2. Six patients (67%) had foveal ellipsoid zone disruption, of which 1 had a hyporeflective zone. Four patients (44%) had foveal hypoplasia. The average total retinal thicknesses of the macula and fovea in the patients with achromatopsia were 14% and 17% thinner than in the control participants (P < .001 and P = .001), which was mostly due to the outer retina that was 18% and 26% thinner than in control participants (both P < .001), respectively. Genetic testing revealed a common homozygous mutation in CNGB3 in 5 patients with complete achromatopsia and heterozygous mutations in CNGA3 in 2 patients with incomplete achromatopsia. The youngest and worst-affected patient harbored compound heterozygous mutations in CNGB3 and a single mutation in CNGA3.
Conclusions And Relevance:
In early childhood, there is a spectrum of foveal pathology that is milder than reported in older individuals with achromatopsia, which suggests the need for early therapeutic intervention. Neither age alone nor genotype alone predicts the degree of photoreceptor loss or preservation. Thus, in anticipation of future gene therapy trials in humans, we propose that handheld spectral-domain optical coherence tomography is an important tool for the early assessment and stratification of macular architecture in young children with achromatopsia.
