Dear Dr. Korathanakhun,

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: I Don't Know

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3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: The article is well written and the description of this rare entity is a valuable contribution to the scientific community.

However, the article is a little too long, and in my opinion, some parts should be removed to make it easier to read and avoid drowning out the main message:

- I don't believe that quantitative sequences are necessary

- in view of the small number of myopathy cases I've noted typed for comparison, I don't think their description is necessary either a single fsh is not relevant for comparison with the GNE myopathy panel

- a single descriptive analysis of your population already seems very relevant to me

- to improve overall reading, a diagram with a color scale representing the frequency of muscles affected by anatomical region could be suggested.

Reviewer #2: The novelty of this study lies in the whole body protocol, evaluating cranial and upper limb muscles, and in the partial homogeneity of the population (the common c.2179G>A variant). Nevertheless, I do not understand how the comparison group adds anything to the study and find numerous inaccuracies and redundant concepts.

The author claims that the inclusion criteria for the "control" group are young adult-onset hereditary myopathies (confirmed through genetic tests, muscle biopsies, or MRI). It is unclear whether some of the other myopathies used as controls have a genetic diagnosis. (e.g. generic limb-girdle muscular dystrophy?). If they do not, it must be indicated how the diagnosis of GNE has been excluded. Calpainopathy is an LGMD, why is it listed separately? It would also be useful to specify why those myopathies were chosen: typically, GNE has a foot drop onset (This is also acknowledged in the author’s discussion (p. 18 line 398)) and many other myopathies (e.g. distal early onset myopathies such as MYH7, TTN) are not considered.

Many data are similar between T1 and DIXON image analysis, so it is preferrable to eliminate repetitions and focus on muscle groups where DIXON images are more accurate for their best resolution. In fact, in the discussion paragraph "Variations in findings across MRI sequences" there is absolutely no comparison between the two techniques and it is not clear why I should prefer either one or the other.

In lower limb analysis, it is well known that Biceps femoris short head is the first muscle involved in GNE and is therefore configured as a pathognomic for diagnosis along with quadriceps sparing. By not differentiating the two ends of the femoral biceps in the analysis, the author loses an important muscle, if not the pivotal muscle, able to differentiate this pathology from the others included. It is indeed surprising that a difference was NOT identified between the two groups in the thigh section.

":Herein, in patients with GNE with GNEM-FAS scores indicative of more severe disease, pathological changes were seen in advanced stages in the vastus lateralis on STIR imaging". This sentence is not supported by the data reported in the results

p 17 line 389-391 the author should comment on the results of his study and comparisons with the "small" control group e.g., the obturator internus which is mentioned here, does not appear among the muscles analyzed by the author nor among those significant. The comparison with FSHD (there is only one FSHD in the comparison group) or myofibrillar myopathies (they are not present in the comparison group) is mentioned several times in the discussion. The differential diagnosis with LGMD that would have led the author to include them is never addressed.

p 17 line 392, ST involvement is typical of ONE myofibrillar myopathy = desminopathy, and also an early feature of HMERF (10.1016/j.nmd.2017.12.002)

In all this discussion It’s not clear what the author means with "the correlation between disease severity and certain muscles"

Other comments:

please use either QUANT or quant in the text

pag 6 line 122 PDFF should de spelled also in the text not only in the figure

Avoid using p-value when the finding is not significant.

p 17 lines 362-363 a reference seems missing while reference 26 is unnecessary

p 17 lined 369-371: this phrase is in contrast with the results of the study and not clear

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Reviewer #1: Yes:  Marie FARUCH BILFELD

Reviewer #2: No

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Dear Dr. Korathanakhun,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Oct 29 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Mainak Bardhan, MD

Academic Editor

PLOS ONE

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Additional Editor Comments:

Reviewer #2: Please revise the type setting errors and other points as suggested

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #2: I Don't Know

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4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #2: No

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Reviewer #2: The authors made significant improvement to the manuscript that now sums up the main finding.

However I suggest to double check the English translation in the tracked change text as some concept are not clear e.g. pg.3 “ some patients, especially in case of longstanding inconclusive diagnosis, may present with late stage which all muscle were involved and the patient may not recognize the sequential symptoms accurately”

In the abstract, the conclusion are not supported by the results (anterior forearm, biceps femoris involvement is not enumerated in the results section of the abstract. Moreover, anterior leg involvement is not even a finding of this study as “The soleus and tibialis anterior were severely affected in the early stages” (pg 14 and pg 25 line 525)

minor comment - vastus intermedius instead of intermedialis (e.g. Fig 1)

please replace decimal commas with point throughout the text (e.g. pg 15)

pg 23 line 488 typo “several ltechnical imitations were considered”—> several technical limitations…

pg 26 line 547 and pg 26 line 566 typo “LGDM” —> LGMD

pg 26 line 551 typo “LGMDR36” —> LGMDR3-6

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Reviewer #2: No

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Comparison of whole-body muscle imaging findings between GNE myopathy and other young adult-onset hereditary myopathies

PONE-D-25-08873R2

Dear Dr. Korathanakhun,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Vinay Kumar, Ph.D.

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #2: Yes

Reviewer #3: No

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3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #2: Yes

Reviewer #3: N/A

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4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #2: Yes

Reviewer #3: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #2: The final version of the manuscript has improved. Please carefully review minor typos as STIR spelling in Fig 3 legend

Reviewer #3: This study aimed to use whole-body MRI to differentiate between GNE myopathy and other young adult-onset hereditary myopathies.

The retrospective study considered a significant number of patients MRI with a technically sound methodology.

However out of 103 patients, file only with GNE myopathy and 10 with young adult-onset hereditary myopathy were included.

Unfortunately I regret to notice that either the premises or the conclusion of the manuscript contain incorrect statements.

In fact, it is reported that:

“Previous muscle imaging studies of GNE myopathy are limited to the lower

extremities.” This is not correct (see Torchia E. et al.)

The main conclusion again is not correct:

“The latissimus dorsi sparing out of proportion to periscapular weakness

would be a novel differentiative feature of GNE myopathy”

This has been already shown and published by Torchia E. et al.

The use of the mDIXON Quant technique to quantify the percentage of fat replacement

is basically the only new contribution.

Some of the reported features in the comparison between LGMD and GNE myopathy may be interesting clues, but after all the limited size of the analysed sample makes difficult the generalizability of these observations.

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Reviewer #2: No

Reviewer #3: No

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