Reviewer ’s report  
 
Title: CYSTINOSIS BEYOND KIDNEYS: GASTROINTESTINAL SYSTEM AND MUSCLE  
INVOLVEMENT  
 
Version: 1 Date: 12 Feb 2020  
 
Reviewer: Lambertus P. W. J. van den Heuvel  
 
Reviewer's report:  
 
Please include all comments for the authors in this box rather than uploading your report as an 
attachment. Please only upload as attachments annotated versions of manuscripts, graphs, 
supporting materials or other aspects of your report which cannot be included in a text format.  
Please over write this text when adding your comments to the authors.  
 
The manuscript by Topaloglu et al. entitled "Gastrointestinal system involvement and extrarenal 
complications in cystinosis (reference BMGE -D-19-00529R1)"reports that extrarenal organs 
may be affec ted even in childhood in cytinosis patients. Especially patients incompliant to 
therapy are at risk. addressed A substantial number of patients is included in the manuscript. 
Focus is on liver and muscle (function). This is an interesting manuscript which still can be 
improved. Next issues need to be:  
 
1.)In table 1: Can you add a statement concerning level of incompliance 
(rare/moderate/frequent/almost never usage of cysteamine) and add LCL levels (highest and 
lowest observed levels)?  
 
2.)In table 1: add r eference values for controls.  
 
3.)Explain X - and Y -axis in figure 3.  
 
4.)Do the current findings in this manuscript have any consequences for patient treatment (except 
multidisciplinary approach)?  
 
5.)Include better legend for figure 1.  
 
6.)All of the pati ents studied in this manuscript had period(s) without cysteamine treatment. This 
is crucial and has to be specified. How does this feature influence the results? Is this patient 
group also representative for well treated patients?  
 
7.)Patient 14 (diagnosis  at 14 years) seems to be mildly affected. More information should be 
provided about the phenotype. CTNS mutations have not been established. Is this infantile 
cystinosis?  
 
Advise: Major revision.  
 
 
 
Are the methods appropriate and  well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the futu re? 
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
Not applicable.  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my nam ed report  
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I un derstand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title: CYSTINOSIS BEYOND KIDNEYS: GASTROINTESTINAL SYSTEM AND MUSCLE  
INVOLVEMENT  
 
Version: 1 Date: 12 Feb 2020  
 
Reviewer: Lambertus P. W. J. van den Heuvel  
 
Reviewer's report:  
 
Please include all comments for the authors in this box rather than uploading your report as an 
attachment. Please only upload as attachments annotated versions of manuscripts, graphs, 
supporting materials or other aspects of your report which cannot be included in a text format.  
Please over write this text when adding your comments to the authors.  
 
The manuscript by Topaloglu et al. entitled "Gastrointestinal system involvement and extrarenal 
complications in cystinosis (reference BMGE -D-19-00529R1)"reports that extrarenal organs 
may be affec ted even in childhood in cytinosis patients. Especially patients incompliant to 
therapy are at risk. addressed A substantial number of patients is included in the manuscript. 
Focus is on liver and muscle (function). This is an interesting manuscript which still can be 
improved. Next issues need to be:  
 
1.)In table 1: Can you add a statement concerning level of incompliance 
(rare/moderate/frequent/almost never usage of cysteamine) and add LCL levels (highest and 
lowest observed levels)?  
 
2.)In table 1: add r eference values for controls.  
 
3.)Explain X - and Y -axis in figure 3.  
 
4.)Do the current findings in this manuscript have any consequences for patient treatment (except 
multidisciplinary approach)?  
 
5.)Include better legend for figure 1.  
 
6.)All of the pati ents studied in this manuscript had period(s) without cysteamine treatment. This 
is crucial and has to be specified. How does this feature influence the results? Is this patient 
group also representative for well treated patients?  
 
7.)Patient 14 (diagnosis  at 14 years) seems to be mildly affected. More information should be 
provided about the phenotype. CTNS mutations have not been established. Is this infantile 
cystinosis?  
 
Advise: Major revision.  
 
 
 
Are the methods appropriate and  well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the futu re? 
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
Not applicable.  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my nam ed report  
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I un derstand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title: CYSTINOSIS BEYOND KIDNEYS: GASTROINTESTINAL SYSTEM AND MUSCLE  
INVOLVEMENT  
 
Version: 1 Date: 12 Feb 2020  
 
Reviewer: Lambertus P. W. J. van den Heuvel  
 
Reviewer's report:  
 
Please include all comments for the authors in this box rather than uploading your report as an 
attachment. Please only upload as attachments annotated versions of manuscripts, graphs, 
supporting materials or other aspects of your report which cannot be included in a text format.  
Please over write this text when adding your comments to the authors.  
 
The manuscript by Topaloglu et al. entitled "Gastrointestinal system involvement and extrarenal 
complications in cystinosis (reference BMGE -D-19-00529R1)"reports that extrarenal organs 
may be affec ted even in childhood in cytinosis patients. Especially patients incompliant to 
therapy are at risk. addressed A substantial number of patients is included in the manuscript. 
Focus is on liver and muscle (function). This is an interesting manuscript which still can be 
improved. Next issues need to be:  
 
1.)In table 1: Can you add a statement concerning level of incompliance 
(rare/moderate/frequent/almost never usage of cysteamine) and add LCL levels (highest and 
lowest observed levels)?  
 
2.)In table 1: add r eference values for controls.  
 
3.)Explain X - and Y -axis in figure 3.  
 
4.)Do the current findings in this manuscript have any consequences for patient treatment (except 
multidisciplinary approach)?  
 
5.)Include better legend for figure 1.  
 
6.)All of the pati ents studied in this manuscript had period(s) without cysteamine treatment. This 
is crucial and has to be specified. How does this feature influence the results? Is this patient 
group also representative for well treated patients?  
 
7.)Patient 14 (diagnosis  at 14 years) seems to be mildly affected. More information should be 
provided about the phenotype. CTNS mutations have not been established. Is this infantile 
cystinosis?  
 
Advise: Major revision.  
 
 
 
Are the methods appropriate and  well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the futu re? 
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
Not applicable.  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my nam ed report  
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I un derstand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant