Syndromic Retinitis Pigmentosa: A Narrative Review
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors· Reference terms alter between diagnostic terminology to description of signs. Example, the use of “droopy eyelid (ptosis)” (line 99), “tunnel vision” (line 129) whereas in other areas diagnostic terms such as rod-cod dystrophy. Suggestion to clearly demarcate, diagnosis, signs and symptoms.
· Congenital blindness (amaurosis) Line 116 – preference for ‘ultra-low vision’ unless ‘total’ blindness is the most common finding i.e. no perception of light. Define for clarity as there is commonly confusion over whether ‘blindness’ is total blindness or ultra-low vision, or some sight remaining. To avoid this confusion, define what you mean by blindness upfront. There is reference to “legal blindness” – see point below – again define.
· Discretion between diagnostic terminology, signs and symptoms. There are several places where the terms are all used together. Suggest keep consistent i.e. refer to signs in the one sentence then explicitly state symptoms for clarity.
Example lines 128-130: Ophthalmological signs include chorioretinal dystrophy, nyctalopia (night blind-ness), tunnel vision, myopia, strabismus, astigmatism, lens opacification, iris atrophy, and colobomas of the eyelid or retina
Another example: Ophthalmological signs include congenital blindness (amaurosis) or severe, progressive retinitis pigmentosa (RP), sometimes diagnosed as Leber’s Congenital Amaurosis (LCA) or as a milder form of RP that is discovered later in life.
· Line 149 –Suggest correct/remove the term “typical”. RP in this condition is not ‘typical’ – there are the types which you note, however they vary in onset, severity and progression.
· Line 177 – Legal blindness should be defined.
· How is “narrowing of the visual field” (line 201) different from “tunnel vision” (line 129). Clinically, we refer to constriction of the visual field and specify to what degree. Similarly tunnel vision could represent visual field constriction to the central 10 degrees. Again, there is interchange between medical terms and symptoms. Suggest be consistent throughout the paper.
· Suggest define medical terminology. Example line 195 steatorrhea (excess fat in stools) – consider your audience and define all medical terminology. This includes retinal or eye related terminology or provide a reference. Another example, retinitis punctata albescens (line 203).
· The description of ophthalmological manifestations or rod-cone dystrophy under Hooft disease can refer back to where the symptoms and signs are first described If the presentation is similar. In other words, provide more detail here.
· The term „Zellweger spectrum disease” encompasses a range of conditions, including Refsum disease (both the adult and infantile forms), rhizomelic chondrodysplasia punctata, X-linked adrenoleukodystrophy (ALD), Zellweger syndrome (ZS), and neonatal adrenoleukodystrophy (NALD). Correct quotation marks, add a reference for further information as many complex conditions noted here. Also suggest make a comment, even in brackets (these are described in more detail below).
· Reference needed for line 285 for ALD.
· 3.2.6 incorrect title – this should be Bietti crystalline dystrophy (BCD).
· Line 316 – Patients experience progressive retinitis pigmentosa (RP), which evolves toward chorioretinal atrophy. Why is RP in brackets here and no where else where retinitis pigmentosa is mentioned? Secondly, RP is not associated with this condition. The clinical signs and symptoms fall under a different category of disease namely vitreoretinopathies. See paper: Stone EM, Andorf JL, Whitmore SS, DeLuca AP, Giacalone JC, Streb LM, Braun TA, Mullins RF, Scheetz TE, Sheffield VC, Tucker BA. Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. Ophthalmology 2017; 124: 1314-31.
· Overall, a flowchart would be helpful to see the main categories of disease and their sub-groups. Additionally, a table of contents would be helpful to help navigate the review.
Author Response
Reference terms alter between diagnostic terminology to description of signs. Example,
the use of “droopy eyelid (ptosis)” (line 99), “tunnel vision” (line 129) whereas in other areas
diagnostic terms such as rod-cod dystrophy. Suggestion to clearly demarcate, diagnosis,
signs and symptoms.
· Discretion between diagnostic terminology, signs and symptoms. There are several
places where the terms are all used together. Suggest keep consistent i.e. refer to signs in
the one sentence then explicitly state symptoms for clarity.
Example lines 128-130: Ophthalmological signs include chorioretinal dystrophy, nyctalopia
(night blind-ness), tunnel vision, myopia, strabismus, astigmatism, lens opacification, iris
atrophy, and colobomas of the eyelid or retina
Another example: Ophthalmological signs include congenital blindness (amaurosis) or
severe, progressive retinitis pigmentosa (RP), sometimes diagnosed as Leber’s Congenital
Amaurosis (LCA) or as a milder form of RP that is discovered later in life.
R: This is a very important observation. We have revised all discussed conditions accordingly.
Please note that in some cases, the category is context-dependent. For instance, we consider the
blindness of the newborn a sign, because in this case blindness is detected/reported by other
persons than the patient. In other cases, the categorization may not be obvious. Yet, we did our
best to separate (clinical) signs from symptoms.
Congenital blindness (amaurosis) Line 116 – preference for ‘ultra-low vision’ unless ‘total’
blindness is the most common finding i.e. no perception of light. Define for clarity as there
is commonly confusion over whether ‘blindness’ is total blindness or ultra-low vision, or
some sight remaining. To avoid this confusion, define what you mean by blindness upfront.
There is reference to “legal blindness” – see point below – again define.
R: Actually, both ultra-low vision and complete blindness occur, so we have added ultra-low vision
(thanks for the suggestion) and defined blindness as no light perception as well.
· Line 149 –Suggest correct/remove the term “typical”. RP in this condition is not ‘typical’
– there are the types which you note, however they vary in onset, severity and progression.
R: Thanks for this observation; the term has been removed.
· Line 177 – Legal blindness should be defined.
R: It has been clarified in the revised version that legal blindness is not a medical term, instead a
category used to determine who is entitled to disability benefits, so the precise definition may
depend on the jurisdiction. We brought the US definition as an example based on Lee et al. (2024),
as follows:
“a person is considered legally blind if he/she has central visual acuity of 20/200 or worse in the
better-seeing eye with the best correction (using glasses or contact lenses) at a distance or if
he/she has visual field restriction where the widest diameter is 20 degrees or less in the better-
seeing eye.”
· How is “narrowing of the visual field” (line 201) different from “tunnel vision” (line 129).
Clinically, we refer to constriction of the visual field and specify to what degree. Similarly
tunnel vision could represent visual field constriction to the central 10 degrees. Again, there
is interchange between medical terms and symptoms. Suggest be consistent throughout the
paper.
R: Thank you for your observation. The exact extent of visual field constriction may vary case by
case, which is why we did not specify the degree of constriction. However, we appreciate the
suggestion to use the term "constriction" instead of "narrowing" and have revised the manuscript
accordingly. Regarding "tunnel vision" in the context of Jeune syndrome, we follow the definition
provided by Ronquillo et al. (Vision Res 2012), which describes it as significant peripheral visual
field reduction, and we have added this reference to the manuscript for clarity.
· Suggest define medical terminology. Example line 195 steatorrhea (excess fat in stools)
– consider your audience and define all medical terminology. This includes retinal or eye
related terminology or provide a reference. Another example, retinitis punctata albescens
(line 203).
R: We greatly appreciate and respect your suggestion regarding the definition of medical
terminology. That said, Vision is a journal primarily aimed at medical professionals, particularly
those in the field of ophthalmology. As such, we believe the readership is familiar with common
medical and ophthalmological terminology. While we understand the value of clarity, translating
all medical terms into plain English may not align with the expectations or preferences of our
target audience. We aim to strike a balance that respects the expertise of our readers, ensuring
the content remains accessible without oversimplifying it. Of course, we are happy to adjust this
approach if the editor feels differently.
· The description of ophthalmological manifestations or rod-cone dystrophy under Hooft
disease can refer back to where the symptoms and signs are first described If the
presentation is similar. In other words, provide more detail here.
R: We have added a brief paragraph on rod-cone dystrophies with two new references.
· The term “Zellweger spectrum disease” encompasses a range of conditions, including
Refsum disease (both the adult and infantile forms), rhizomelic chondrodysplasia punctata,
X-linked adrenoleukodystrophy (ALD), Zellweger syndrome (ZS), and neonatal
adrenoleukodystrophy (NALD). Correct quotation marks, add a reference for further
information as many complex conditions noted here. Also suggest make a comment, even in
brackets (these are described in more detail below).
R: The quotation marks around “Zellweger spectrum disease” have been removed as requested.
The comment indicating that these conditions are described in more detail later has been added. As the conditions are discussed thoroughly later in the text, references have not been included
here to avoid redundancy. However, if additional references are preferred at this point, we are
happy to add them. Please let us know your preference.
· Reference needed for line 285 for ALD.
R: The reference has been added as requested.
· 3.2.6 incorrect title – this should be Bietti crystalline dystrophy (BCD).
R: 3.2.6 has been removed, see below.
· Line 316 – Patients experience progressive retinitis pigmentosa (RP), which evolves
toward chorioretinal atrophy. Why is RP in brackets here and no where else where retinitis
pigmentosa is mentioned? Secondly, RP is not associated with this condition. The clinical
signs and symptoms fall under a different category of disease namely vitreoretinopathies.
See paper: Stone EM, Andorf JL, Whitmore SS, DeLuca AP, Giacalone JC, Streb LM, Braun TA,
Mullins RF, Scheetz TE, Sheffield VC, Tucker BA. Clinically Focused Molecular Investigation
of 1000 Consecutive Families with Inherited Retinal Disease. Ophthalmology 2017; 124:
1314-31.
R: After careful consideration, we have decided that the reviewer’s opinion is correct on this
matter, and subsection 3.2.6 has been completely removed from the text.
· Overall, a flowchart would be helpful to see the main categories of disease and their sub-
groups. Additionally, a table of contents would be helpful to help navigate the review.
R: Regarding the flowchart, we experimented with several variations; however, due to the large
number of diseases and categories discussed, the resulting diagrams were consistently
overwhelming and/or difficult to read. As a result, we decided not to include one. That said, we
fully agree with the reviewer that a table of contents would greatly assist readers in navigating the
review. Accordingly, we have included a table of contents at the beginning of the text. Its final
formatting has been left to the production team, as we were unable to remove the page numbers
while ensuring the table of contents remained compliant with the MDPI template.
Reviewer 2 Report
Comments and Suggestions for AuthorsThis is a comprehensive narrative review with a lot of information about very complex and rare diseases. It is written for clinicians but lacks figures, images and tables . Where did you obtain most information, did you review textbooks, online databases and libraries , laboratory resources or reports , and how did you find the peer reviewed articles ? Some of the syndromes lack genetic information (NALD and Sanfilippo), some of the genes have been renamed and the spectrum of Bardet Biedl syndrome has been recently expanded. This should be mentioned. For example CEP290 is now BBS 14. And many other genes are now considered "BBS" and because of the key symptom of obesity and hyperphagia suggestive of a common MC4R pathway. Please explain the triallelic digenic mutation in at least 11 genes and give a reference. The syndromes appear to be named with the person who first described the syndrome rather than with the OMIM name or better the name of the gene or all (Hooft Syndrome, Marie's ataxia). A number of diseases can be syndromic or non syndromic ( USH2A, POMGNT1 and muscle-eye-brain disease , HGSNAT and San Filippo3 mucopolysaccharidosis ,..) .
there is a typo in ophthalmological (line 257), typo in 'snydrome' line 401 page 9.
Author Response
This is a comprehensive narrative review with a lot of information about very complex and
rare diseases. It is written for clinicians but lacks figures, images and tables. Where did you
obtain most information, did you review textbooks, online databases and libraries,
laboratory resources or reports, and how did you find the peer reviewed articles ?
R: Thank you for your observation and suggestions.
While we agree that adding images of various symptoms could enhance the visual appeal of the
article, we believe this would significantly increase the length and complexity of the review,
potentially resembling a textbook chapter rather than a concise narrative review. Moreover, since
this is a comprehensive summary for clinicians, we assume that readers will be familiar with these
visual presentations or can easily access them through other resources, such as medical image
repositories or clinical atlases, for specific details.
As for the search methodology: Our review follows the format of a narrative review, which differs
from a systematic review in terms of methodology and objectives. Narrative reviews are designed
to provide a broad synthesis of the existing knowledge on a topic, drawing from a variety of sourcesto present a comprehensive overview, rather than adhering to the rigid inclusion and exclusion
criteria of a systematic review.
To gather information, we conducted targeted searches across academic databases such as
PubMed, Scopus, and Web of Science, focusing on peer-reviewed articles that address key
aspects of syndromic retinitis pigmentosa and associated conditions. Additionally, we consulted
well-regarded textbooks and online resources such as OMIM (Online Mendelian Inheritance in
Man) to include established foundational knowledge.
While we did not use a predefined systematic methodology, we ensured a thorough and balanced
approach by cross-referencing sources and considering the quality and relevance of the literature.
This approach aligns with the purpose of narrative reviews, which aim to synthesize and
contextualize information rather than perform exhaustive or quantitative analyses.
We hope this clarifies our methodology and approach, and we appreciate your feedback in helping us improve our work.
Some of the syndromes lack genetic information (NALD and Sanfilippo),
R: Thanks for pointing this out. The missing information has been added.
Some of the genes have been renamed and the spectrum of Bardet Biedl syndrome has been
recently expanded. This should be mentioned. For example CEP290 is now BBS 14. And
many other genes are now considered "BBS" and because of the key symptom of obesity and
hyperphagia suggestive of a common MC4R pathway.
R: In the revised version, all 20 subtypes are mentioned (along with their OMIM IDs), and a section
has been added on the MC4R pathway.
Please explain the triallelic digenic mutation in at least 11 genes and give a reference.
R: The reference has been added and we also added a brief explanation.
The syndromes appear to be named with the person who first described the syndrome rather
than with the OMIM name or better the name of the gene or all (Hooft Syndrome, Marie's
ataxia). A number of diseases can be syndromic or non syndromic ( USH2A, POMGNT1 and
muscle-eye-brain disease , HGSNAT and San Filippo3 mucopolysaccharidosis ,..).
R: Thank you for your suggestion. We have added the OMIM references to the titles as
recommended. Additionally, we would like to clarify that we have never stated that these
conditions exist exclusively in syndromic forms; they can indeed occur independently as well.
there is a typo in ophthalmological (line 257), typo in 'snydrome' line 401 page 9.
R:The typos have been corrected, thanks for pointing them out to us.
Reviewer 3 Report
Comments and Suggestions for AuthorsIn this manuscript, Janaky and Braunitzer provide a comprehensive overview of syndromic retinitis pigmentosa. The authors describe all the current knowledge regarding the syndromes with ophthalmological signs, such as retinitis pigmentosa, from a genetic and clinical point of view. This review is very well organised and could be very useful for the scientific community.
However, there are some minor concerns that could be addressed:
-Please provide the OMIM reference number in all the diseases that are described.
-The gene names have to be written in italics. Please correct properly.
-In some diseases that causative gene(s) are not mentioned (eg sections 3.2.3, 3.3.1, 3.3.2, 3.3.3, 4.1.1 etc). Please add the information missing.
-In the section 3.4.1 the authors state that the inheritance pattern is X-linked. However the genes mentioned are located in autosomal chromosomes. Please correct properly.
-There are some typing errors, so please check the whole text.
Author Response
In this manuscript, Janaky and Braunitzer provide a comprehensive overview of syndromic
retinitis pigmentosa. The authors describe all the current knowledge regarding the
syndromes with ophthalmological signs, such as retinitis pigmentosa, from a genetic and
clinical point of view. This review is very well organised and could be very useful for the
scientific community.
However, there are some minor concerns that could be addressed:
-Please provide the OMIM reference number in all the diseases that are described.
R: The reference numbers have been added as requested.
-The gene names have to be written in italics. Please correct properly.
R: Thank you for pointing this out. The gene names are all in italics now.
-In some diseases that causative gene(s) are not mentioned (eg sections 3.2.3, 3.3.1, 3.3.2,
3.3.3, 4.1.1 etc). Please add the information missing.
R: Thanks for pointing this out. The missing information has been added.
-In the section 3.4.1 the authors state that the inheritance pattern is X-linked. However the
genes mentioned are located in autosomal chromosomes. Please correct properly.
R: Thank you for this observation. Of course, the inheritance is autosomal recessive. This has been
corrected.
-There are some typing errors, so please check the whole text.
R: The following changes have been made to the manuscript:
-Corrected "Four distict forms" in section 3.2.6. to "Four distinct forms."
-Resolved the redundancy in section 2.1. Bardet-Biedl Syndrome by removing the repeated
"autosomal recessive."
-Clarified the sentence structure in section 2.4. Senior-Løken Syndrome for better readability.
Original: Nephronophthisis can also appear in various syndromes that affect multiple body
systems, known as nephronophthisis-associated ciliopathies.
New: Nephronophthisis may also occur as part of various syndromes that impact multiple body
systems, collectively referred to as nephronophthisis-associated ciliopathies.
-Rephrased "Heart problems tend to develop later" in section 2.5. Jeune Syndrome to "Heart
problems typically develop in later stages." (this was just a stylistic issue, but it seems to read
better like this)
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsNone.
Author Response
We sincerely thank the reviewer for their time and efforts in providing detailed feedback, which has helped us improve the manuscript.
Reviewer 2 Report
Comments and Suggestions for Authorsthe authors still list StatPearls. This is not a very scientific source of information and this "not so well regarded" reference might as well be left out. Please also list the various "well-regarded" textbooks you have consulted in the material and methods.
Author Response
The authors still list StatPearls. This is not a very scientific source of information and this "not so well regarded" reference might as well be left out. Please also list the various "well-regarded" textbooks you have consulted in the material and methods.
R: We sincerely thank the reviewer for their time and efforts in providing detailed feedback, which has helped us improve the manuscript.
We appreciate the reviewer’s observation regarding StatPearls. While we were initially unaware of the reputation concerns surrounding this source, especially since it is PubMed-indexed, we now understand that StatPearls does not necessarily operate with the scientific rigor required to be regarded as a reliable scientific source. After reviewing the matter further, we agree with the reviewer’s assessment and have removed all references to StatPearls (Ref. nos 55, 72, 224, and 235).
For two of these instances (Ref. nos 55 and 72), we have replaced them with citations to non-web-based, peer-reviewed sources to ensure the integrity and reliability of our references.
As for the mention of textbooks, we did consult recognized titles, such as Kanski’s Clinical Ophthalmology, during the preparation of this manuscript for background information and guidance. However, since we did not directly cite any information from these books, they are not included in the (already quite lengthy) reference list. That said, the reviewer is correct: the sentence in question could give the impression that information directly from books is included, which it is not, making it potentially misleading. We also acknowledge that the choice of words was a stylistic mistake. Therefore, we have decided to delete the sentence entirely.
Reviewer 3 Report
Comments and Suggestions for AuthorsThe authors addressed all my comments. I accept this manuscript for publication.
Author Response
We sincerely thank the reviewer for their time and efforts in providing detailed feedback, which has helped us improve the manuscript.
Round 3
Reviewer 2 Report
Comments and Suggestions for AuthorsThe manuscript has been revised satisfactorily. Unfortunately the authors have not been able to produce clinical vignettes or table or figures to enhance interest in this narrative manuscript.
