Ocular Manifestations in Congenital Insensitivity to Pain with Anhidrosis: A Window into a Rare Syndrome

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript by M. Baker et.,al., is a good review of the rare disease CIPA. While the manuscript is correct and thorough there is some major and minor errors that should be corrected for a publication:

• Mental retardation should be changed for intellectual disability or intellectual developmental disorder. In the DSM-5, the term "mental retardation" has been replaced by "intellectual disability (intellectual developmental disorder)". This change reflects a shift towards less stigmatizing language and a greater emphasis on the individual's adaptive functioning alongside intellectual abilities.
• Line 125-127 “The reviewers subsequently evaluated the full texts of the included studies from the title/abstract phase and excluded those studies that didn’t meet the exclusion criteria.” I understand that the correct phrasing here would be “excluded those studies that didn’t meet the inclusion criteria”
• Line 130: Needs citation of the preformed extraction tool or specification if it’s an original macro from the authors or AI.
• Line 140: The study by Amano 2006, is classified in Suppl. Table 1 as “low” with a score of 3 while it is stablished in section “2.6. Quality Assessment of Studies”: that low is 1-2 points. In Supplementary table it states that 0-3 is “low” so the criteria should be clear.
• In Figure 1 there are several asterisks (*) in the first and fourth quadrants that are not related to anything. It is misleading and either the explanation should be included in the figure legend or the asterisks removed.
• It is very important to have a big clarification of the numbers: From a total of 6243 records identified, 2227 were duplicates, leaving 4002 records. But 6243-2227=4016. Then in page 151 says that 3702 records were excluded in the first abstract screening while in Figure 1 is 3707. The reports assessed for eligibility are 229, but then the excluded ones are 261 (is that number there because more than one exclusion criteria were found in the same report?). Also 160+26+4+11 amounts to 201, not 261. Overall numbers should be thoroughly reviewed for Figure 1 and section 3.1.
• Line 170: text reports n=46 on corneal ulcerations while in the table the sample size is 47. Repeats in line 176.
• Reference 35 Title is in Turkish. Should be changed to English.

Author Response

Editor-in-Chief

Vision

 

Re: The Eyes in Congenital Insensitivity to Pain with Anhidrosis: A Window into the Ocular Manifestations of a Rare Syndrome. Manuscript ID: vision-3717092

 

Dear Editor and Reviewers,

My self and the co-authors are pleased to resubmit the manuscript entitled ‘The Eyes in Congenital Insensitivity to Pain with Anhidrosis: A Window into the Ocular Manifestations of a Rare Syndrome” to be considered for publication in Vision. The revised manuscript takes into consideration both the editorial and reviewers’ comments. Kindly find below a point-by-point response to those comments, along with an uploaded copy marked with “red highlighter” changes indicating changes to the manuscript.

 

 

 

 

 

 

 

 

 

 

 

Point-to-point response to Reviewer 1 comments.

 

Comment 1:

• “Mental retardation should be changed for intellectual disability or intellectual developmental disorder. In the DSM-5, the term "mental retardation" has been replaced by "intellectual disability (intellectual developmental disorder)". This change reflects a shift towards less stigmatizing language and a greater emphasis on the individual's adaptive functioning alongside intellectual abilities.”

Response 1:

• We thank Reviewer 1 for this comment. We changed the term “Mental retardation” to “Intellectual disability” wherever it was mentioned, which are the lines: 18, 35, 65, 134, 161, 274,298, 329.

 

Comment 2:

• “Line 125-127 “The reviewers subsequently evaluated the full texts of the included studies from the title/abstract phase and excluded those studies that didn’t meet the exclusion criteria.” I understand that the correct phrasing here would be “excluded those studies that didn’t meet the inclusion criteria” “

Response 2:

• We thank Reviewer 1 for this comment. We agree that this was a form of typo. We have corrected the mentioned mistake and replaced the word “exclusion” with “inclusion”.

 

Comment 3 :

• Line 130: Needs citation of the preformed extraction tool or specification if it’s an original macro from the authors or AI.

Response  3:

• We thank Reviewer 1 for this comment. We want to clarify that this extraction tool is an Excel sheet file that was made by the authors according to their discussion and the review objectives and target outcomes. It was not based on AI assistance in any form.
• The following sentence was added to line 130 for clarification : “which is an Excel sheet file that the authors made based on their discussion and according to the review objectives and target outcomes without any AI assistance”.

 

Comment 4:

• “Line 140: The study by Amano 2006, is classified in Suppl. Table 1 as “low” with a score of 3 while it is stablished in section “2.6. Quality Assessment of Studies”: that low is 1-2 points. In Supplementary table it states that 0-3 is “low” so the criteria should be clear.”

Response  4:

• We thank Reviewer 1 for this comment. To correct this contradiction, we adjusted the criteria to be as the following : 0-2 is low, 3-6 is intermediate, and 7-8 is high quality.
• We have corrected the scoring criteria written in Supplementary file 2. Based on this, we have corrected the quality assessment of Amano 2006 to be “Intermediate”.
• We also edited the criteria written in the manuscript in Line 142 to be as follows : “ … Studies were rated out of 8 points as low (0-2 points), … “

 

Comment 5:

• In Figure 1 there are several asterisks (*) in the first and fourth quadrants that are not related to anything. It is misleading ,and either the explanation should be included in the figure legend or the asterisks removed.

Response 5:

• We thank Reviewer 1 for this comment. We have removed the asterisks that were left unintentionally.

 

Comment 6:

• It is very important to have a big clarification of the numbers: From a total of 6243 records identified, 2227 were duplicates, leaving 4002 records. But 6243-2227=4016. Then in page 151 says that 3702 records were excluded in the first abstract screening while in Figure 1 is 3707. The reports assessed for eligibility are 229, but then the excluded ones are 261 (is that number there because more than one exclusion criteria were found in the same report?). Also 160+26+4+11 amounts to 201, not 261. Overall numbers should be thoroughly reviewed for Figure 1 and section 3.1.

Response 6:

• We thank Reviewer 1 for this comment. After a comprehensive review of the screening process and their exact numbers, we found that some mistakes occurred in reporting these numbers.
• We have modified the following sections with the correct numbers :
• Records excluded = 3731
• Reports sought retrieval = 285
• Reports not retrieved = 69
• Reports assessed for eligibility = 216
• Accordingly, we have modified Figure 1. Also, the following corrections were made in section 3.1:
• Line 152 : “… , leaving 4016 records.”
• Line 153 : “… A total of 3731 records were excluded after title/abstract screening, …”
• Lines 153 – 156 : “…leaving 285 records for full text screening, of which69 were available as abstracts only. After the exclusion of 188 records that didn’t meet inclusion criteria, a total of 28 articles, comprising 118 individual patients from 14 countries, were included in this review. “

 

Comment 7 :

• Line 170: text reports n=46 on corneal ulcerations while in the table the sample size is 47. Repeats in line 176.

Response 7:

• We thank Reviewer 1 for this comment. We have corrected the number in the text in Line 170 to be (39.83%, n=47).

 

Comment 8:

• Reference 35 Title is in Turkish. Should be changed to English.

Response 8:

• We thank Reviewer 1 for this comment. We have replaced the mentioned reference with the English version in Lines 424+425 as follows :

Kucukdurmaz F, Imren Y, Uruc V, Sen C. Kronik Congenital Insensitivity to Pain with Anhidrosis (CIPA) Manifested with Chronic Osteomyelitis; A Case Report. J Clin Anal Med. 2015;6(2):230-232. doi:10.4328/JCAM.912

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript provides a valuable and comprehensive review of ocular manifestations in patients with Congenital Insensitivity to Pain with Anhidrosis (CIPA). The systematic approach to the literature search and inclusion/exclusion criteria is well defined and strengthens the study’s validity. The detailed summary of both common and rare ocular features, along with management strategies, will be of significant interest to clinicians and researchers working with this rare syndrome.

Comments for author File: Comments.pdf

Author Response

Editor-in-Chief

Vision

 

Re: The Eyes in Congenital Insensitivity to Pain with Anhidrosis: A Window into the Ocular Manifestations of a Rare Syndrome. Manuscript ID: vision-3717092

 

Dear Editor and Reviewers,

My self and the co-authors are pleased to resubmit the manuscript entitled ‘The Eyes in Congenital Insensitivity to Pain with Anhidrosis: A Window into the Ocular Manifestations of a Rare Syndrome” to be considered for publication in Vision. The revised manuscript takes into consideration both the editorial and reviewers’ comments. Kindly find below a point-by-point response to those comments, along with an uploaded copy marked with “red highlighter” changes indicating changes to the manuscript.

 

 

 

 

 

 

 

 

 

 

 

 

Point-to-point response letter – Reviewer 2

Many thanks for your valuable comments and remarks, the authors will address each comment separately, and alterations will be amended in the revised manuscript accordingly:

 

Title

Comment 1:

• The title is a bit long; you could make it slightly more concise if preferred, for example: “Ocular Manifestations in Congenital Insensitivity to Pain with Anhidrosis: A Window into a Rare Syndrome” “Ocular Involvement in Congenital Insensitivity to Pain with Anhidrosis (CIPA)”

Response 1: Thank you so much. The title was changed.

 

Abstract

Comment 2: 

• Lines 16-19: The abstract clearly defines the characteristics of CIPA, but adding a brief mention of the underlying genetic basis (e.g., mutations in the NTRK1 gene) would strengthen the background context.

Response 2:

• We thank Reviewer 2 for this comment. We have modified the following sentence of the background in the abstract (Lines 16-18) to be as follows : “Congenital Insensitivity to Pain with Anhidrosis (CIPA) is a rare autosomal recessive syndrome caused by loss-of-function mutations in the Neurotrophic Tyrosine Kinase Receptor 1 gene, …”

 

Comment 3:

• Lines 29-31: The description of ocular manifestations is comprehensive but specifying whether these manifestations are typically unilateral or bilateral (briefly mentioning the frequency of bilateral involvement) would better illustrate clinical significance.

Response 3:

• We thank Reviewer 2 for this comment. We added the following information to the abstract in Lines 30-33 : “The most common ocular manifestations were the absence of corneal reflex in 56 patients (47.5%, bilateral in 56), whereas corneal ulcerations were the 2nd most common manifestation in 47 patients (39.8%, bilateral in 8), followed by corneal opacity in 33 patients (27.96%, bilateral in 19).”

 

Comment 4:

• Lines 35-39: The conclusion effectively summarizes the findings; however, the phrase “Proper
• detection” (line 37) should be modified to “Early detection” or “Timely detection” to emphasize the importance of prompt clinical intervention.

Response 4:

• We thank Reviewer 2 for this comment. We replaced the phrase “Proper detection” with “Early detection" – Line 39.

 

Introduction :

Comment 5: (Epidemiological Data Clarification)

• Lines 46–48: While the text mentions the increased prevalence of CIPA in Japanese and Israeli Bedouin populations, it would be beneficial to clarify if the cited prevalence (1 in 600,000–950,000 live births) specifically pertains to a global estimate or these particular populations.

Response 5:

• We thank Reviewer 2 for this comment. We have added the phrase “… In Japan” (Line 51) to indicate that this statistic is related to the Japanese population.

 

Comment 6:  (Neuropathological Mechanisms)

• Lines 54–59: The description of neuropathological findings is robust. However, explicitly mentioning the downstream effects or clinical significance of reduced innervation could improve the understanding of how these pathologic changes directly correlate to clinical features.

Response 6:

• We thank Reviewer 2 for this comment. We added the following sentence to the introduction in Lines 62-64 : “The impaired innervation leads to reduced or absent pain sensation against traumatic insults, in addition to loss of normal sweating in response to elevated body temperatures.”

 

Comment 7:

• Lines 74–80: The rationale for conducting this systematic review is provided. However, a brief statement clarifying how this review specifically differs from previous literature—such as addressing gaps or compiling new insights into rare ocular manifestations or genetic variations—could reinforce the novelty and significance of this study.

Response 7:

• We thank Reviewer 2 for this comment. We have added the following part to the introduction in Lines 79 – 83 : “Although multiple reports describing ocular findings of CIPA patients worldwide have been published, no single literature review gathering and organizing these findings and their associations has been conducted, which leaves a gap in our understanding of the long-term effects and contributing variables. To fill this gap, our systematic review provides a comprehensive approach to the ocular involvement in CIPA, … “.

 

 

 Patients and Methods:

Comment 8: (Search Strategy and Eligibility Criteria (Lines 86–114))

• Please clarify if any language restrictions were applied during the database search or whether non-English studies were considered for inclusion/translation. This information is essential for transparency and reproducibility.

Response 8:

• We thank Reviewer 2 for this comment. In subsection 2.3, we clearly stated that : “Exclusion criteria were as follows : 1) Patients diagnosed with diseases other than CIPA (including congenital insensitivity to pain); 2) Non-English papers;…” (Lines 123 – 125).
• Therefore, we excluded papers written in languages other than English, which were 10 papers as illustrated in Figure 1.
• However, we added the following sentence to subsection 2.2 (Line 90) : “No language restriction was made during the search process.”

 

Comment 9:  (Study Selection and Screening (Lines 123–128))

• While you note that two reviewers independently screened studies, please specify whether inter-rater reliability (e.g., Cohen’s Kappa) was calculated, or simply state if disagreements were resolved by consensus or third reviewer—this adds methodological rigor.

Response 9:

• We thank Reviewer 2 for this comment. We didn’t calculate the inter-rater reliability index. However, in subsection 2.4 (Lines 135 & 136), we clearly stated that : “Any dispute between the two reviewers was resolved through a meeting with a third reviewer.”

 

Comment 10 : (Quality Assessment (Lines 136–141))

• The use of the JBI checklist is appropriate. To further strengthen your methods, consider briefly summarizing the overall quality ratings (how many included studies were high/intermediate/low quality) in the main text.

Response 10:

• We thank Reviewer 2 for this comment. We added the following text to subsection 3.1 (Lines 164 & 165): “In terms of quality assessment, 13 studies were of high quality, whereas 15 studies were of intermediate quality. No study scored low quality. [see supplementary file 1].”

 

Results

1. Clarify Reporting of Ocular Manifestations and Demographics (Lines 147–173,

Table 1–2))

1. Comment 11:

• Presenting proportions (%) alongside absolute numbers throughout the text (not just in tables), to make key findings more accessible.

Response 11:

• To address this issue, we made the following changes :
• We added the following text to subsection 3.2 (Lines 180 – 182) : “100% of patients with absent corneal reflex have bilateral involvement, whereas 8 and 19 of those with corneal ulceration and corneal opacity, respectively, have bilateral involvement.”
• We added percentages alongside numbers in the bilateral involvement column in Table 1.
• We added percentages to absolute numbers in the following Lines : 188 – 190, 192 – 202, 204, 206.

 

 

2. Comment 12 :

• Commenting briefly on regional/geographic variation in the prevalence or spectrum of ocular manifestations (e.g., is the distribution different between regions, or is it influenced by genetic or environmental factors?).

Response 12 :

• We thank Reviewer 2 for this comment. We added the following paragraph to subsection 3.2.1 (Lines 210 – 215) :

“Regarding geographical distribution, we found that some manifestations tend to be more in certain countries. Absent corneal reflex was notably reported in Israel (n=29, 51.8 %) and to a less extent in Japan (n=6, 10.7 %) and China (n=5, 8.9 %). The same applies to decreased lacrimation (Israel : n=10 (38.5 %), Japan : n=7 (26.9%)), Corneal ulceration (Israel : n=35, 76%), and Corneal opacity (Israel : n=22, 68.7%). However, Superficial punctate keratopathy was reported more in Japan (n=12, 63.1%) compared to Israel (n=6, 31.6%).”

 

3. Comment 13:

• Clarifying whether any patients were included more than once (e.g., in multi-center studies or overlapping case series) to avoid potential duplication.

Response 13 :

• We added the following sentence to subsection 3.1. (Lines 163 & 164)

“We checked and ensured that data of each patient was included only once in the final analysis.”

 

1. Summarize Outcomes of Medical/Surgical Interventions (Lines 205–232):

Comment 14:

• Clearly summarize which interventions were most effective (if such conclusions can be drawn), or at least note the variability in treatment success and follow-up.

Response 14 :

• We added the following paragraph to subsection 3.3. (Lines 252 – 256) :

“The outcomes reported in most of these studies show that medical treatment can be considered as an effective 1st line therapy in managing critical lesions such as corneal ulceration and corneal opacity, while considering surgical procedures, such as lateral tarsorrhaphy and penetrating keratoplasty, as a definitive treatment for recurrent nonhealing lesions.”.

 

Comment 15 :

• Highlight any patterns or lessons for clinical management—e.g., are some modalities associated with better outcomes or fewer complications?

Response 15 :

• We highlighted the effectiveness of surgical procedures, especially lateral tarsorrhaphy, in treating critical lesions by adding the aforementioned paragraph (Lines 252 – 256).

 

 

1. Genetic Defects and Family History (Lines 233–269):

Comment 16 :

• Provide a brief summary table or schematic that categorizes the NTRK1 mutations found and their associated ocular phenotypes, if possible.

Response 16 :

• We added Table 3 to address this concern.

 

Comment 17 :

• Highlight any apparent genotype–phenotype correlations or lack thereof, and discuss whether family history (e.g., consanguinity) is linked to more severe ocular findings.

 

Response 17:

• We thank Reviewer 2 for this comment. We added the following sentence to subsection 3.4. (Lines 181 – 183) :

“Table 3 shows the association between reported mutations and corresponding ocular manifestations. We only observed an association between corneal ulcerations and “TrkA: 1926-ins-T” mutation, which was found in 20 cases (43.47 %).”

• However, we couldn’t find whether family history (e.g., consanguinity) is linked to more severe ocular findings.

 

 

Discussion

Comment 18:

• The authors briefly discuss the genetic mutations causing CIPA; however, they should clearly link genetic findings with the clinical ocular phenotype. A discussion of genotype–phenotype correlations, or lack thereof, would substantially enrich this section.

Response 18:

• We thank Reviewer 2 for this comment. We added the following paragraph to the discussion section (Lines 318 – 325) to solve this concern :

“ Interestingly, we found a link between corneal ulcerations and the mutation “TrkA: 1926-ins-T” , which was found in 20 cases (43.47 %). This may reflect certain pathological processes on the molecular level that contributes to conrenal pathologies. Also, this provide a valuable guide to predict certain ocular lesions and improve the timely detection of ocular lesions in patients at risk, thereby avoiding further complications. Although we couldn’t find a link with other manifestations, we recommend that further analytical studies to be conducted to find if certain mutations can be considered as genetic markers for certain manifestations.”

 

Comment 19:

• Clarify the sentence on lines 275–278 (“The difference in our results…”) to specify exactly which differences (e.g., prevalence, severity) are being referred to, and explicitly discuss possible implications for patient care or prognosis.

Response 19:

• We removed the mentioned sentence as we thought it was vague and didn’t reflect the exact conclusions of our review. Therefore, we replaced it with the following sentence :

“Our systematic review resembles the first attempt to determine the distribution of the ocular manifestations in CIPA patients.”

 

Comment 20:

• Although management approaches are described, the discussion would benefit from a more explicit summary of which treatments appear most successful or widely accepted. Consider briefly discussing if certain interventions (e.g., lateral tarsorrhaphy) had better outcomes, based on available data.

Response 20:

• We thank Reviewer 2 for this comment. We added the following paragraph to the discussion section to address this issue (Lines 331 – 335) :

“ However, although limited, reported data from included studies showed that medical treatment can be considered as the first choice when managing vision-threatening lesions like corneal ulcerations and opacities, while surgical interventions such as lateral tarsorrhaphy were commonly more effective in treating such pathologies, especially for recurrent and non-healing lesions.”

 

Comment 21:

• Add a clear statement regarding the need for standardized ophthalmologic management protocols or guidelines for CIPA patients, given the complexity and heterogeneity of ocular manifestations.

Response 21:

• We thank Reviewer 2 for this comment. We added the following text to the discussion section to address this concern (Lines 335 – 338) :

“… The absence of a reliable management approach for ocular pathologies in CIPA patients highlights the importance of establishing standardized management guidelines to improve decision-making when dealing with such patients.”

 

Comment 22:

• The limitations section correctly notes methodological constraints but could be expanded by explicitly stating the impact of excluding non-English studies and geographical concentration of reports on the generalizability of findings.

Response 22:

• To address this concern, we added the following sentences to the discussion section :
• Lines 359 – 362 : “Additionally, in our study selection process, we excluded papers written in non-English languages. This may affect the generalizability of our results as some findings reported in these studies may reflect geographical variation if the distribution of certain ocular manifestations.”
• Lines 363 – 365 : “Moreover, most of the included studies were from Asia, which limits the generalizability of our findings outside the mentioned countries due to genetic variations and differences in social behaviors regarding familial disease inheritance.”

 

Comment 23 :

• Clearly suggest specific directions for future research, such as multicenter studies, international registries, or genetic studies, to better understand disease mechanisms and improve clinical outcomes.

Response 23:

• We thank Reviewer 2 for this comment. We removed the following sentence from the discussion section (Furthermore, studies on a larger series of patients with CIPA are needed to confirm the differences in severity between the entities and to elucidate their mechanism, and further analysis is required to confirm the precise effect of this mutation on the transcript.), and added the following paragraph (Lines 371 – 375):

“As for future research, we recommend establishing international registries for CIPA patients to improve international collaborative studies to improve our understanding of the disease mechanism. Also, we encourage conducting genetic studies in those patients to help find genetic biomarkers for diagnosis and follow-up, which will contribute to the discovery of genetic therapies based on identified molecular targets.”

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The review manuscript by Baker et al is well-written and delivers a summarized outlook of the clinical ocular manifestations reported in the CIPA patients. This study highlights the ocular challenges faced by these patients, steering our attention towards the need for the potential treatment strategies.

Although, the authors have described the medical treatments in clinical use for CIPA patients, I would suggest addition of plausible treatment avenues in future (as a separate section), such as pharmacological agents (opioids), gene or stem cell therapies, and their scope in the treatment of ocular pathologies associated with CIPA. I think that would add more value to the existing manuscript.

I have a few concerns:

1. The authors have very well explained the potential medical treatments (section 3.3). This information should be added to Table 1 (for eg. as ‘current clinical treatments’) in a separate column to provide an idea of the in-use clinical treatments to the readers. Just a suggestion, Table 1 could be squeezed slightly by combining the sex  information into one column to make some space.

2. Table 1 could be prepared year-wise (recent to earliest documented cases).
3. Since CIPA is a neuropathic disease, are there any clinical defects reported in the CNS components, such as retina?
4. There is a discrepancy; Another pilot study in 2024 by the same group (Ref #50) with the exact number of total/included study and number of patients, had reported 43 patients with bilateral ocular manifestations, 8.01 yrs as mean age and corneal ulcerations (instead of absence of corneal reflex) as the most common ocular manifestation, which is quite inconsistent with what they have reported here. An explanation is required by the authors for this.

Author Response

Editor-in-Chief

Vision

 

Re: The Eyes in Congenital Insensitivity to Pain with Anhidrosis: A Window into the Ocular Manifestations of a Rare Syndrome. Manuscript ID: vision-3717092

 

Dear Editor and Reviewers,

My self and the co-authors are pleased to resubmit the manuscript entitled ‘The Eyes in Congenital Insensitivity to Pain with Anhidrosis: A Window into the Ocular Manifestations of a Rare Syndrome” to be considered for publication in Vision. The revised manuscript takes into consideration both the editorial and reviewers’ comments. Kindly find below a point-by-point response to those comments, along with an uploaded copy marked with “red highlighter” changes indicating changes to the manuscript.

 

 

 

 

 

 

 

 

 

 

 

Point-to-point response – Reviewer 3

Many thanks for your valuable comments and remarks, the authors will address each comment separately, and alterations will be amended in the revised manuscript accordingly:

 

Comment 1:

• The authors have very well explained the potential medical treatments (section 3.3). This information should be added to Table 1 (for eg. as ‘current clinical treatments’) in a separate column to provide an idea of the in-use clinical treatments to the readers. Just a suggestion, Table 1 could be squeezed slightly by combining the sex information into one column to make some space.

Response  1:

• We thank Reviewer 3 for this comment. Although we wished to do so, only 8 studies reported their management modalities in treating CIPA cases. Therefore, we see that the appropriate action is to summarize the treatment approaches reported by those studies instead of putting them in Table 1.

 

Comment 2:

• Table 1 could be prepared year-wise (recent to earliest documented cases).

Response  2:

• We thank Reviewer 3 for this comment. We re-ordred references in Table 1 from the most recent to the earliest.

 

Comment 3:

• Since CIPA is a neuropathic disease, are there any clinical defects reported in the CNS components, such as retina?

Response 3:

• We thank Reviewer 3 for this comment. Only 1 patient was reported to have unusually tortuous retinal arteries (Verity et al. 1982). Some studies reported results of neurophysiological tests (such as nerve conduction studies of certain nerves), which are not the main focus of this systematic review and were therefore not reported in our review.

 

Comment 4:

• There is a discrepancy; Another pilot study in 2024 by the same group (Ref #50) with the exact number of total/included study and number of patients, had reported 43 patients with bilateral ocular manifestations, 8.01 yrs as mean age and corneal ulcerations (instead of absence of corneal reflex) as the most common ocular manifestation, which is quite inconsistent with what they have reported here. An explanation is required by the authors for this.

Response 4:

• We thank Reviewer 3 for this comment. The mentioned data were published as a conference abstract related to the American Academy of Neurology (AAN) annual meeting after a preliminary analysis of the extracted data, in which the ocular manifestation “Absent corneal reflex” was considered a neurological sign rather than an ocular manifestation of the disease. However, after scientific revision of the extracted data and their results by our authors Dr. Abdelwahab Aleshawi (An ophthalmology specialist) and Dr. Rami Al-Dwairi (An ophthalmology consultant), they decided that “Absent corneal reflex” is an ocular manifestation. Therefore, the data extraction stage was repeated, and then the data analysis step. Also, the screening step was revised to ensure that no paper was lost due to this issue.

Author Response File: Author Response.pdf