Disease Progression in CNGA3 and CNGB3 Retinopathy; Characteristics of Slovenian Cohort and Proposed OCT Staging Based on Pooled Data from 126 Patients from 7 Studies

Round 1

Reviewer 1 Report

Disease progression in CNGA3 and CNGB3 retinopathy; characteristics of Slovenian cohort and proposed OCT staging based on pooled data from 126 patients from 7 studies

In this population-based study, Pompe et al. evaluate the structure and function of 12 patients with Achromatopsia, all with genetic defects in two genes encoding for the cyclic nucleotide-gated ion channels (CNGA3 and CNGB3). They then pool their findings with data from 6 other studies evaluating the structure of patients with defects in those same two genes via optical coherence tomography. Their findings point towards an age-related morphological retinal degeneration for patients with achromatopsia. The genetic analysis of their 12 patients corroborates the understanding that 70% of achromatopsia come from defects in the CNGA3 and CNGB3 genes, additionally finding new genetic variants. The strength in their study comes from pooling their optical coherence tomography data with previous studies, but their datasets lack homogeneity. This is understandable as they are dealing with patients which are not necessarily easy to manage.  ACHM has previously been considered a predominately stable condition, this evidence does not directly contradict this, but starts building on the possibility that it may be progressively degenerative. The way forward is certainly more patients and more follow ups. We look forward to more longitudinal studies from the authors. I recommend this study for publication, but suggest a few changes to improve the overall quality of the manuscript

Comments

• Fig 2 is an N = 1. Although this is an interesting finding and method, this cannot be published. I suggest to increase the number of patients this has been tested on, and submit a separate, independent paper.
• Figure 3: Only 3 of 10 patients had OCT changes and the differences in the follow up years is quite high. This needs to be reflected in the text.
• The “Strength/Weaknesses of the study” section needs to emphasize the lack of rigorous, follow up patient data
• Lines 227-230. The text in this section needs to change:
  • Left eye progressed from Grade 4 to Grade 3 between age 70 to 71 year
  • Considering only the right eye from the last exam, significant correlation of grade with age
    • Need a Zoom of that patient #3: loss of RPE
    • How does someone go down a grade with age progression?
    • Fig 4: Grade 5 based on a very low resolution picture from another study/
    • How many patients do you have with RPE loss?

Author Response

Dear Reviewer, 

We would like to thank you for the revision and helpful comments on ways to improve the manuscript. Please, find our answers in the table below and updated manuscript with implemented changes attached.

Kind regards.

Reviewer 2 Report

This study reports a longitudinal analysis of a Slovenian cohort of patients with achromatopsia caused by CNGA3 and CNGB3 genes mutations. Authors suggest four stages of disease progression based on OCT images of macula, correlate findings with ERG, fundoscopic, and AF measurements. They also reconcile their findings with other reported cases of achromatopsia caused by mutations in the same genes.

The study is well written and good reconciliation of existing data on the topic. The study has a good introduction, description of results, and discussion.

Minor points:

It would be good to add an example of a normal OCT, allowing the study to be appreciated by a general audience.

It would be helpful that authors also show actual data points in figures 6 and 7, allowing readers to appreciate data distribution/presence of outliers.

Author Response

Dear Reviewer, 

We would like to thank you for the revision and helpful comments on ways to improve the manuscript. Please, find our answers in the table below and updated manuscript with implemented changes attached.

Kind regards.