Mitochondrial Ataxias: Molecular Classification and Clinical Heterogeneity

Round 1

Reviewer 1 Report

Mitochondrial ataxias: molecular classification and clinical heterogeneity

This is a review of primary mitochondrial diseases that have ataxia as part of the clinical disease spectrum. This is an important point, as ataxia is recognized as a relatively common feature of mitochondrial disorders and may be missed in the initial differential diagnosis of hereditary ataxias. There are some aspects of this review that are done well – a discussion of heteroplasmy, diagnostic modalities, and the overall approach to Tables 2 and 3. The individual disorders are discussed in significant detail with associated mutations. However, there are several significant concerns.

Major points

• This work critically requires review and editing by a native speaker of English. The sentence structure is obtuse with tendency towards run-on sentences. For instance, two of the three sentences in the abstract are run-on with a total of 9 commas or semicolons just within those two sentences. This pattern unfortunately persists throughout and makes the text extremely difficult to read.
• There are extensive lists of genetic diagnoses and syndromes/symptoms without context. The purpose is unclear other than to place information about specific genetic diagnoses together – if there are defining clinical features between these diagnoses, this is not clearly delineated. Discussion regarding the imaging approach is also not organized. MRI findings are peppered throughout the different syndromes, but whether there are findings suggestive of specific genetics is unclear. Overall organization could be significantly improved.
• The authors categorize ataxias into sensory, cerebellar, and spinocerebellar but do not define how they delineate/differentiate between these categories. Incorrectly, they divide all the nuclear and mitochondrial mutations into only one of these three ataxia categories each, without overlap, which is not what is suggested by the literature. For example, FRDA is listed in Table 3 as cerebellar ataxia, when sensory degeneration is a cardinal feature of FRDA.
• Although the authors reference other papers (e.g. “recent studies report ataxia being the most common movement disorder at onset”) the actual numbers/results are not presented (what percent? Is it a lot or a little?)

Minor points

• The phenotypes listed in table 1 are incomplete – for instance dementia, infertility/pregnancy loss, encephalopathy/coma are not included and is reviewed at greater depth in numerous other reviews where it might be best to direct the reader to such a review.
• Several spelling errors (e.g., heart on line 153)
• Multiple genes are mentioned throughout without being defined or placed in any context (e.g. DLAT, DLD, PDHX to name only a few).

Author Response

MAJOR POINTS

• As suggested, we performed an extensive review of English language and style with the help of a native English speaker;
• We removed or contextualized redundant information and extensive list of genetic and clinical details, especially in the paragraphs describing single disorders. We reduced the volume of “hereditary ataxia” paragraph;
• We highlighted a section regarding clinical features of ataxias (sensory, cerebellar, spinocerebellar) in “hereditary ataxia” paragraph;
• We added in the last paragraph (“discussion and conclusions”) a vast section regarding MRI finding. Overall organization has been improved and peppered informations have been synthesized in the above-mentioned section. Finally, we added a table summarizing neuroimaging findings in PMDs (Table 4) and a figure showing a diagnostic algorithm for mitochondrial ataxias (Figure 1);
• We added a brief comment regarding overlap ataxias and the didactic aim of the tables 2 and 3 in “mitochondrial ataxia” paragraph;
• Number/results from cited papers have been added.

MINOR POINTS

• We updated phenotypes list in table 1 as suggested;
• We identified and corrected spelling and punctuation errors;
• We better defined gene name and functions.

Please note that all significant changes in the draft have been highlighted in bold.

Author Response File: Author Response.docx

Reviewer 2 Report

Authors provide an extensive review on mitochondrial molecular disorders in various ataxia models. I would suggest authors to consider conveying key information with 2-3 figures, which helps readers understand/follow contents more easily.

Author Response

Following your comment we added a new table summarizing neuroimaging findings suggestive of PMDs (Table 4) and a figure showing a diagnostic algorithm for mitochondrial ataxias (Figure 1). Moreover, we performed an extensive review of English language and style to make reading easier.

Author Response File: Author Response.docx

Reviewer 3 Report

In the present manuscript the authors raise a relevant issue such as ataxias presented in mitochondrial disorders. This topic constitutes a relevant chapter of rare diseases and is becoming more and more complex. The proposal is more than relevant and interesting. However, given the complexity of the topic, the reading is not very fluid and still complex. Although tables have been included, I suggest including additional ones or algorithms that facilitate and summarize the content of each of the item 5, particularly those where phenotypic Pcr variants and genetic defects are more extensives

Author Response

Following your comment we added a new table summarizing neuroimaging findings suggestive of PMDs (Table 4) and a figure showing a diagnostic algorithm for mitochondrial ataxias (Figure 1). Moreover, we performed an extensive review of English language and style to make reading easier.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

 

Major comments

Figure 1 is a helpful addition. FGF-21 and GDF-15 are certainly useful in this setting. However, both are mentioned briefly only once, without specificity or sensitivity of current studies. While more sensitive than other biomarkers, these are not universally positive and should be placed in context as the key decision point in Figure 1. 

 

Author Response

- As suggested, we modified Figure 1 revoving biomarkers as key decision point for PMDs molecular diagnosis;
- In the paragraph “PMDs molecular diagnosis” we added a brief comment which specify FGF-21 and GDF-15 specificity and sensitivity of current studies (see reference 21);
- In the paragraph “discussion and conclussion” we better presented diagnostic algorithm and its interpretation.

Author Response File: Author Response.docx