Review for 10.1186/s12876-020-01280-5 (2020)

Reviewer ’s report  
 
Title: Clinical and Molecular Characterization of a Patient with Mitochondrial 
Neurogastrointestinal  Encephalomyopathy  
 
Version: 0 Date: 31 Jan 2020  
 
Reviewer: Bridget Bax  
 
Reviewer's report:  
 
In this manuscript the authors present the characterization of a novel pathogenic mutation 
causing Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE) in a single patient 
referred to their centre. This is an important paper for those with an interest in the field of 
MNGIE, particularly as data on the natural history of this disorder is under -reported. Would 
the authors please consider the following feedb ack? 
 
* Background, Line 21. Could the authors please replace reference 4 (a review article) 
with the original reference which discovered the association between elevated metabolites 
and disease phenotype.  
 
* Background, Line 27. Please could the authors st ate that the usual age of 
presentation is within the first and second decades of life, with an average of 18.5 years of 
age. There are a few cases where onset was as early as five months of age and as late as the 
fifth decade.  
 
* Background, Line 36. Could the authors be more precise about the number of 
mutations using data from the Human Gene Mutation Database which is freely accessible.  
 
* Case presentation, Line 4. The authors state that the patient lost a significant 
amount of weight. What was the weight loss?  
 
* Molecular analysis, Line 27. The blood samples were collected, rather than 
"prepared" in an ETDA tube  
 
* Discussion and conclusion, Line 44. Could the authors please clarify the sentence 
regarding the protein catalysing the phosphorylation of mitoch ondrial thymidine and 
deoxyuridine and put this reaction in context with the disease? Thymidine phosphorylase 
catalyses the reversible phosphorylation of thymidine and deoxyuridine to 2 -deoxyribose 1 -
phosphate and their respective bases, thymine and uracil  and this occurs in the cytosol.  
 
* Discussion and conclusion, Line 46. Thymidine phosphorylase does not play any 
role in the metabolic pathways of the RBC.  
 
* Figure 4. Could the authors supply their own figure showing the reaction and its 
relevance to MNGI E, rather include a KEGG pathway where a majority of the information is 
superfluous.  
 
 
* Figure 4 legend. Could the authors correct the following: "this enzyme with its 
phosphorolysis activity on thymidine…". Thymidine phosphorylase does not have a 
phosphoro lysis activity on thymidine, the activity is phosphorylation in this direction. It 
maybe clearer just to say the enzyme catalyses the reversible phosphorylation of thymidine 
and deoxyuridine to thymine and uracil.  
 
* What is the relevance of reference 16 to  this manuscript?  
 
* Discussion and conclusion, Line 55. Could the authors amend this statement 
regarding most of the patients dying from transplant -related deaths.  Of the fifteen patients 
who had died, nine had died from transplant -related mortality, and six from their disease.  
 
* Discussion and conclusion: peritoneal dialysis has not been able to demonstrate a 
removal of nucleosides from the circulation, although has been shown to remove 
approximately 100 µ moles per day of thymidine and 2' -deoxyuridine fr om the peritoneal 
cavity.  
 
* Discussion and conclusion. In the discussion of other therapeutic modalities, the 
authors should also reference erythrocyte encapsulated thymidine phosphorylase (EE -TP) 
enzyme replacement therapy. This approach has clinical tria l approval (Bax et al)  
 
* My major comment is that in the event of a non -identified mutation or variant of 
uncertain significance being detected, it is good practice to conduct metabolite and thymidine 
phosphorylase activity testing to confirm or exclude a diagnosis of MNGIE.  Could the 
authors justify why neither of these where conducted, particularly when testing facilities are 
available in the countries in which some of the authors reside.  
 
 
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 th e 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.  
 
Not relevant to this manuscript  
 
Quality of wri tten 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 rei mbursements, 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 future?  
 
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 fr om 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.  
 
I declare that I have no competing  interests  
 
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