Two Cases of Myofibrillar Myopathies: Genetic and Quality of Life Study
Round 1
Reviewer 1 Report
The authors describe 2 patients with myofibrillar myopathies. Although this is an interesting topic, however the report does not add any novel information to the field. Additionally, the title regarding muscle-bone interaction is not justified from the content of the study, whereas the authors are dealing with multiple unrelated issues, e.g. genetic, economic, therapeutic etc, thereby creating confusion to the reader of the text.
Author Response
We appreciate all suggestion and added genetic, economic, therapeutic issues and subtitled the discussion. Also, the title has been rewritten and the part of “muscle-bone interaction” has been eliminated.Reviewer 2 Report
This is an interesting report of 2 MFM patients, especially focusing on symptoms' management and the role of exercise.
I would suggest to include some biopsy slides and MRI images with the most characteristic findings.
Author Response
We appreciate all suggestions and we added MRI images as suggested.
Reviewer 3 Report
Angelini et al present two interesting cases. Firstly, authors present their report on MFM with cardiac transplantation and secondly, Case 2 is presented as an asymmetric limb-girdle myopathy associated with the LDB3 variant.
This reviewer greatly enjoyed this read. Yet, difficulty arose in relation to grammar. There are many grammatically issues which need to be addressed in this manuscript and these may take some time to finalize. These are throughout the document. I have commented on a few below within the minor corrections list (it is likely that I missed some). This article needs some greater attention to detail.
Further, as per Muscles guidelines for Case Reports, I would highly recommend sectioning this case report into the recommended headings as suggested. This will enable a clearer understanding of the points in discussion.
It is recommended that Angelini and colleagues include a short methodology paragraph per Case. This will help the reader in their own conclusions based on the detail reported. At present, this reviewer was unable to conclude the same findings as the authors given the lack of detail in relation to techniques used.
A greater emphasis on patient characteristics is needed. Given these conditions are multifactorial, an understanding into the patient is necessary to conclude on the information provided.
Lastly, I would like to thank authors for their work. MFM is an extremely important condition and requires more investigation both clinically and scientifically. Case reports like this aid in the understanding of this complex condition.
Minor corrections:
1. Line 14: the second is a male patient. - grammatical
2. Line 15: two muscle biopsies were complete/performed. – grammatical
3. Line 23: you don’t include any keywords – this needs to be addressed
4. Line 28: features. First of all, - grammatical
5. Line 32: refrain from using “etc.” be more specific
6. Line 32: grammatical issues with this sentence – needs rewording
7. Line 34: while less frequently these diseases are transmitted by either autosomal recessive or X-linked dominant traits - grammatical
8. Line 37: and might (not – andmight)
9. Line 37: Here we report two cases of childhood-onset MFM resulting from two different gene mutations – grammatical
10. Line 45: You include a title for Case 2 yet you don’t have one for Case 1. For consistency reasons, you should include one for Case 1.
11. Line 46: …18-year old girl. This case was followed from 3 to 18 years…
12. Participant characteristics should be presented in two separate tables for Case 1 and Case 2. This should include subject weight (kg), height (m), BMI, race, gender, age and other measures of body composition
13. Line 53: grammatically incorrect. Needs to be reworded/addressed.
14. Line 54 & 55: At age 11 years a mutation 54 for a heterozygous variant (p.Pro290Leu.was – this needs to be addressed as this is grammatically incorrect. Authors need to close the parentheses
15. Further to p.Pro290Leu; this needs to be explained. This sequence change replaces proline with leucine at codon 290 of the TREX1 protein. This is not mentioned.
16. Line 56: …BAG3 gene. She… (manuscript is currently missing the period at the end of the sentence) - grammatical
17. Line 59: What was the concentration and dosage of bisoprolol and aldactazide? Further provide the reference for these drugs with lot numbers (i.e. Sigma-Aldrich, 151D-250)
18. Line 60: During cardiac catheterization Case 1 had episodes - grammatical
19. Line 61: A cardiac biopsy was done – how? A methodological section with clear description of procedure would prevent these questions. It also helps reproducibility of results
20. Line 62: How did you perform the muscle biopsy? – Bergstrom technique? A methodological section would clarify this.
21. Line 63: Do you have images of these splitting fibers?
22. Line 63: you mention internal nuclei cytoplasmic bodies. This needs to be clarified with evidence provided – immunohistochemistry?
23. Line 65: … presented nocturnal episodes of apnea Her scoliosis… - requires period between “apnea” and “Her”.
24. Line 72: How did you perform the muscle MRI?
25. Line 75: INQoL à Define this acronym
26. Line 79 & 80: grammatically incorrect.
27. Lines 82-84: grammatically incorrect
28. Line 85: You present it as BAG3 throughout, yet here you present it as Bag3. Try to be consistent with these.
29. Line 94: You need to define “CK” before using the acronym
30. You should present the definition of the LDB3 gene - LIM domain binding 3 (LDB3) gene ….
31. Line 96: characteristics of the mother and father is needed (i.e. age, weight, height, - similar to what was asked earlier) – within the same sentence – i.e. The mother of Case 2 (60 yrs., 65kg, 5.8m, 30kg/m2) had… (apply the same for the father)
32. Patient characteristics for Case 2 should also be presented in table format – similar to what has been asked for Case 1
33. Line 98: CPK? – explain acronym before its use
34. Line 104: LGMD? – explain acronym before its use
35. Line 106: NYHA? – explain acronym before its use
36. Line 107: FRKP? – explain acronym before its use
37. At each age range, the patient characteristics should be included, as these will be changing with the aging of the patient and have the potential to impact upon clinical results – particularly if the patient is overweight/has a high BMI
38. Line 112: TIGEM – if this institution performed DNA analysis was performed a breakdown of how this was performed should be included in the methodology
39. Line 112: Dual energy x-ray absorptiometry (DEXA)
40. Line 120: Electromyography (EMG)
41. Line 134: deflazacort therapy – as before, provide a reference
42. Line 136-140: I don’t think its neccesary to define what a muscle-strengthening activity is. Yet, what is important is to define what was done. What was the load? What where the repetitions? What was the frequency and time spent exercising per week?
43. Line 146: this is repetition on what was stated on line 84
44. Line 165: Patient 1 or Case 1?
45. Is figure 3 necessary? – readers of this journal should be aware of muscle structure. Further, was this produced by the authors? If not the site/journal where this was attained from needs to be referenced. Lastly, it is not discussed within the manuscript – it seems irrelevant.
46. Line 276: The author contributions should be input
47. Line 277: No funding was recorded
48. Line 278: Was this approved by an institutional review board? – you state in the introduction that this was? Ideally this kind of information should be within the methodology of the manuscript
49. Line 279: Informed consent was not attained – ethics
Major corrections:
1. Authors should refer to Muscles guidelines and attempt to frame this case report under the following headings: symptoms, signs, diagnosis, treatment and outcomes of an individual patient – this will help for a clearer story at present the presented information reads more ad-lib than methodical.
2. A methodological section may help – subheading under diagnosis. There is much clinical jargon surrounding disease diagnosis yet there is no information for the reader as to how this was addressed. This can be brief.
3. Line 85-90: I think this is a very astute conclusion based on the clinical diagnoses. Yet, without measure BAG3 or it’s folding, it is a conclusion you are unable to make.
Author Response
We thank the reviewer for his insightful comments, as suggested Muscle guidelines for case reports were followed and a short methodology section was added, the patients' characteristics were added
Minor corrections:
- Line 14: the second is a male patient. – grammatical
It has been rewritten as suggested.
- Line 15: two muscle biopsies were complete/performed. – grammatical
It has been rewritten as suggested.
- Line 23: you don’t include any keywords – this needs to be addressed
Keywords have been included.
- Line 28: features. First of all, - grammatical
It has been rewritten as suggested.
- Line 32: refrain from using “etc.” be more specific
“Etc” has been eliminated.
- Line 32: grammatical issues with this sentence – needs rewording
An English native speaker have revised the entire manuscript.
- Line 34: while less frequently these diseases are transmitted by either autosomal recessive or X-linked dominant traits – grammatical
It has been rewritten as suggested.
- Line 37: and might (not – andmight)
It has been corrected.
- Line 37: Here wereport two cases of childhood-onset MFM resulting from two different gene mutations – grammatical
It has been rewritten as suggested.
- Line 45: You include a title for Case 2 yet you don’t have one for Case 1. For consistency reasons, you should include one for Case 1.
A title for Case 1 has been included.
- Line 46: …18-year old girl. This case was followed from 3 to 18 years…
It has been rewritten as suggested.
- Participant characteristics should be presented in two separate tables for Case 1 and Case 2. This should include subject weight (kg), height (m), BMI, race, gender, age and other measures of body composition
Participant characteristics have been included throughout the text.
- Line 53: grammatically incorrect. Needs to be reworded/addressed.
An English native speaker has revised the entire manuscript.
- Line 54 & 55: At age 11 years a mutation 54 for a heterozygous variant (p.Pro290Leu.was – this needs to be addressed as this is grammatically incorrect. Authors need to close the parentheses
An English native speaker has revised the entire manuscript.
- Further to p.Pro290Leu; this needs to be explained. This sequence change replaces proline with leucine at codon 290 of the TREX1 protein. This is not mentioned.
It has been further explained.
- Line 56: …BAG3 gene. She… (manuscript is currently missing the period at the end of the sentence) – grammatical
An English native speaker has revised the entire manuscript.
- Line 59: What was the concentration and dosage of bisoprolol and aldactazide? Further provide the reference for these drugs with lot numbers (i.e. Sigma-Aldrich, 151D-250)
Dose of bisoprolol and aldactazide was added.
- Line 60: During cardiac catheterization Case 1had episodes – grammatical
It has been rewritten as suggested.
- Line 61: A cardiac biopsy was done – how? A methodological section with clear description of procedure would prevent these questions. It also helps reproducibility of results
Cardiac biopsy was done during cathetrization.
- Line 62: How did you perform the muscle biopsy? – Bergstrom technique? A methodological section would clarify this.
All muscle biopsies were done in open way on different muscles and processed as from Dubowitz Muscle Biopsy book.
- Line 63: Do you have images of these splitting fibers?
Not at the moment, the lab is undergoing renovation.
- Line 63: you mention internal nuclei cytoplasmic bodies. This needs to be clarified with evidence provided – immunohistochemistry?
Immunohistochemistry was done but slides are in lab undergoing renovation.
- Line 65: …presented nocturnal episodes of apnea Her scoliosis… - requires period between “apnea” and “Her”.
An English native speaker has revised the entire manuscript.
- Line 72: How did you perform the muscle MRI?
With 1.5 Tesla Apparatus.
- Line 75: INQoL à Define this acronym
This acronym has been defined.
- Line 79 & 80: grammatically incorrect.
An English native speaker has revised the entire manuscript.
- Lines 82-84: grammatically incorrect
An English native speaker have revised the entire manuscript.
- Line 85: You present it as BAG3 throughout, yet here you present it as Bag3. Try to be consistent with these.
The term “BAG3” has been unified throughout the text.
- Line 94: You need to define “CK” before using the acronym
“CK” has been defined. It is explained in line 54.
- You should present the definition of the LDB3 gene - LIM domain binding 3 (LDB3) gene ….
The definition of the LDB3 gene has been presented.
- Line 96: characteristics of the mother and father is needed (i.e. age, weight, height, - similar to what was asked earlier) – within the same sentence – i.e. The mother of Case 2 (60 yrs., 65kg, 5.8m, 30kg/m2) had… (apply the same for the father)
Characteristics of mother and father have been included.
- Patient characteristics for Case 2 should also be presented in table format – similar to what has been asked for Case 1
A new Table for Case 2 has been added, similar to Case 1.
- Line 98: CPK? – explain acronym before its use
The acronym has been explained.
- Line 104: LGMD? – explain acronym before its use
The acronym has been explained.
- Line 106: NYHA? – explain acronym before its use
The acronym has been explained.
- Line 107: FRKP? – explain acronym before its use
The acronym has been explained.
- At each age range, the patient characteristics should be included, as these will be changing with the aging of the patient and have the potential to impact upon clinical results – particularly if the patient is overweight/has a high BMI
Our patient were not overweight, heght and weight details were added.
- Line 112: TIGEM – if this institution performed DNA analysis was performed a breakdown of how this was performed should be included in the methodology.
A better description of how DNA analysis was performed has been included.
- Line 112: Dual energy x-ray absorptiometry (DEXA)
The acronym has been explained.
- Line 120: Electromyography (EMG)
The acronym has been explained.
- Line 134: deflazacort therapy – as before, provide a reference
Angelini et al.Muscle &Nerve 1994 has been added.
- Line 136-140: I don’t think its neccesary to define what a muscle-strengthening activity is. Yet, what is important is to define what was done. What was the load? What where the repetitions? What was the frequency and time spent exercising per week?
1 hour 4 times per week.
- Line 146: this is repetition on what was stated on line 84
Line 84 has been eliminated.
- Line 165: Patient 1 or Case 1?
This sentence has been rewritten.
- Is figure 3 necessary? – readers of this journal should be aware of muscle structure. Further, was this produced by the authors? If not the site/journal where this was attained from needs to be referenced. Lastly, it is not discussed within the manuscript – it seems irrelevant.
Probably not very informative for a muscle expert, but not for no muscle experts explain connection with bone ,we suppose can be retained, is original.
- Line 276: The author contributions should be input
C.A and A R wrote article,C C performed Dexa,V. N genetic studies. Author contributions have been added.
- Line 277: No funding was recorded
A “funding” statement has been included.
Telethon at Tigem
- Line 278: Was this approved by an institutional review board? – you state in the introduction that this was? Ideally this kind of information should be within the methodology of the manuscript
Biopsy are under EurobioBank consensus form collected. It has been added.
- Line 279: Informed consent was not attained – ethics
Ethical Committee approved was given.
Major corrections:
- Authors should refer to Musclesguidelines and attempt to frame this case report under the following headings: symptoms, signs, diagnosis, treatment and outcomes of an individual patient – this will help for a clearer story at present the presented information reads more ad-lib than methodical.
As suggested, we followed Muscle guidelines for case report.
- A methodological section may help – subheading under diagnosis. There is much clinical jargon surrounding disease diagnosis yet there is no information for the reader as to how this was addressed. This can be brief.
Methodological and diagnostic sections were added.
- Line 85-90: I think this is a very astute conclusion based on the clinical diagnoses. Yet, without measure BAG3 or it’s folding, it is a conclusion you are unable to make.
The phrase on BAG3 folding was changed.
Round 2
Reviewer 1 Report
The fig. 4 illustrating a picture of muscle bone interaction should be removed from the manuscript.
Author Response
Thank you for your thoughtful comments. Figure 4 has been removed.
Reviewer 3 Report
Thank you for making these edits re. the manuscript - " Two cases of Myofibrillar myopathies: genetic and quality of 2 life study"
I am satisfied with the changes and believe they strengthen your manuscript.
I have left one or two points below which might also be important to rectify prior to publication:
The following edits are required:
Line 16: Two muscle biopsies were performed at ages 3 and 15, with muscle MRI, and LDB3 gene sequence analysis also carried out.
Line 106: “Hight” à should be ”height” à this is misspelled throughout (i.e. line 111 also à correct spelling should be made for all prior to publication.
Line 131 à why provide quotation marks (") following sequencing?
Many thanks for your manuscript and all of your work on this topic.
Author Response
Thank you for your thoughtful comments. We have addressed all the edits that you mentioned throughout the manuscript.
