Therapeutic Advances in Major NBIA Disorders: Current Strategies and Translational Challenges
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsI feel pleased to have an opportunity to review a review article entitled “Therapeutic advances in major NBIA disorders: current strategies and translational challenges” submitted by Cascone and co workers to neurology international. This review article reviews the data on advances in the therapeutic approach for neurodegenerative disorders belonging to NBIA (Neurodegeneration with brain iron accumulation) category. This review provides critical information regarding the current strategies and translational challenges in this field. Authors have reviewed a collection of 174 articles. In the current form, it is quite well presented, organised, and described; however, there are some suggestions:
- It is suggested to revise the abstract to make it clearer and easier understandable.
- I would suggest to revise the initial part/start of the introduction portion as it starts abruptly with a heading No. 1.
- The formatting can be improved. There can be a better way to present these data.
- I would suggest to rearrange the data in the introduction portion. Some information on the NBIA related genes and then epidemiology of these rare diseases. It is suggested to revise this portion.
- Addition of diagrams related important pathways can add more value and can attract the interest of the readers.
- There are frequent issues with formatting and text. Very short sentences can be avoided. The quality of language can be improved.
- It is suggested to add summary section at the end.
Author Response
Comment 1: It is suggested to revise the abstract to make it clearer and easier understandable.
Response 1: We thank the reviewer for this helpful suggestion. We substantially revised the Abstract to make it clearer and easier to understand. The revised version now follows the structure of the manuscript more closely, moving from disease definition and pathogenic mechanisms to emerging therapeutic strategies and translational limitations. We also clarified the aim of the review and simplified the discussion of iron dyshomeostasis to improve readability.
Comment 2: I would suggest to revise the initial part/start of the introduction portion as it starts abruptly with a heading No. 1.
Response 2: We thank the Reviewer for this suggestion. We revised the beginning of the Introduction to make it less abrupt. Specifically, we changed the first section heading to “Introduction” and added an opening paragraph that frames NBIA disorders as a clinically and genetically heterogeneous group in which iron accumulation represents a shared neuroradiological feature rather than a unifying primary mechanism. This provides a smoother transition into the subsequent genetic and mechanistic classification.
Comment 3: The formatting can be improved. There can be a better way to present these data.
Response 3: We thank the Reviewer for this comment. We revised the formatting of the manuscript to improve readability and data presentation. In particular, we harmonized section headings, corrected typographical and formatting inconsistencies, and added a new summary table that organizes the main therapeutic strategies according to the targeted pathway, NBIA subtype, level of evidence, and translational status. This table is intended to help readers compare therapeutic approaches across disorders while preserving the narrative structure of the review.
Comment 4: I would suggest to rearrange the data in the introduction portion. Some information on the NBIA related genes and then epidemiology of these rare diseases. It is suggested to revise this portion.
Response 4: We thank the Reviewer for this suggestion. We revised the introductory overview to improve the order of presentation. The revised section now first introduces NBIA-associated genes and their mechanistic classification, then presents epidemiological information, and finally summarizes the main clinical and neuroradiological features. We also revised the title of Table 1 to make the gene-pathway classification clearer and added a transition sentence to better connect genetic heterogeneity with the shared clinical features of NBIA disorders.
Comment 5: Addition of diagrams related important pathways can add more value and can attract the interest of the readers.
Response 5: We thank the Reviewer for this valuable suggestion. We generated a new figure (Figure 1) illustrating the main pathways/functions involved in target genes. The previous figure is now Figure 2.
Comment 6: There are frequent issues with formatting and text. Very short sentences can be avoided. The quality of language can be improved.
Response 6: We revised the manuscript throughout to improve English clarity, sentence flow, and consistency of terminology. We also combined overly short or fragmented sentences where appropriate, corrected typographical errors, harmonized section headings, and removed redundancies.
Comment 7: It is suggested to add summary section at the end.
Response 7: As suggested, we added a dedicated final “Conclusions” section summarizing the main messages of the review.
Reviewer 2 Report
Comments and Suggestions for AuthorsThis article is a review about NBIA disorders. Some points to consider in a revision are below:
Authors should present in a clear way in the abstract the aim of this review. It is not clear.
In addition, is this a narrative review or a systematic review. This point should be added in the title.
Authors should provide a more extended Introduction with more recent references regarding this topic.
A systematic review seems to be more appropriate as a methodology for search and in the Methods section the search terms and methods should be reported (databases searched, periods of search, inclusion/exclusion criteria for the studies, types of studies included).
The flow of the sections is not clear and it might be useful to have a specific aim for this research, a more focused question to explore, thus it is necessary to rewrite/reorganize the sections.
Authors should discuss the cognitive deficits of this groups of disorders as well and the links to the therapeutic approaches (e.g. https://pmc.ncbi.nlm.nih.gov/articles/PMC4307362/) and the possible links to mental disorders (as reported in recent global statistics https://pubmed.ncbi.nlm.nih.gov/42167272/) given that there are patients with comorbid neurological and psychiatric conditions.
In the section 6. Translational gaps and future perspective, more references are needed in order to support statements and proposals.
Studies in humans and studies in animals should be grouped and presented accordingly (preferably in a table).
Author Response
Comment 1: Authors should present in a clear way in the abstract the aim of this review. It is not clear.
Response 1: We thank the Reviewer for this comment. We revised the Abstract to state the aim of the review more explicitly. The revised sentence now clarifies that the aim of this narrative review is to examine how pathogenic mechanisms in five major NBIA disorders are guiding the development of mechanism-based therapeutic strategies.
Comment 2: In addition, is this a narrative review or a systematic review. This point should be added in the title.
Response 2: We thank the Reviewer for this suggestion. The manuscript is conceived as a Narrative Review. We agree that the nature of the review should be clearly stated, and we have therefore clarified this point in the Abstract and at the end of the new Introduction section. However, we respectfully preferred not to modify the title, in order to keep it concise and focused on the scientific content. The revised text now explicitly states that this is a narrative, mechanism-oriented review rather than a systematic review.
Comment 3: Authors should provide a more extended Introduction with more recent references regarding this topic.
Response 3: We thank the Reviewer for this suggestion. We expanded the Introduction to provide a broader genetic and clinical framework for NBIA disorders. In particular, we revised the section to first summarize NBIA-associated genes and their mechanistic classification, then present epidemiological information and the rationale for focusing on the five major forms discussed in the review. We also added recent references describing newly recognized NBIA-associated genes and recent phenotypic expansions, thereby updating the Introduction and better reflecting the current evolution of the field.
Comment 4: A systematic review seems to be more appropriate as a methodology for search and in the Methods section the search terms and methods should be reported (databases searched, periods of search, inclusion/exclusion criteria for the studies, types of studies included).
Response 4: We thank the Reviewer for this important point. We agree that a systematic review requires a dedicated Methods section reporting databases searched, search terms, search period, inclusion and exclusion criteria, and study selection procedures. However, the present manuscript was conceived as a narrative, mechanism-oriented review rather than a systematic review. Its aim is to critically integrate pathogenic mechanisms, therapeutic rationales, preclinical evidence, and translational challenges across major NBIA forms. To avoid ambiguity, we have clarified in the Abstract that this is a narrative review and have further emphasized its mechanism-oriented scope in the Introduction. Because of this narrative design, we did not add a systematic review Methods section, as this would imply a different methodology and article type from the one actually used. We believe that the revised wording now makes the nature and scope of the review sufficiently clear.
Comment 5: The flow of the sections is not clear and it might be useful to have a specific aim for this research, a more focused question to explore, thus it is necessary to rewrite/reorganize the sections.
Response 5: We thank the Reviewer for this helpful comment. We revised the manuscript to make the flow of the review clearer and to state the focused question more explicitly. In the revised version, the Introduction now defines the scope of the review and explains why we focus on PKAN, CoPAN, PLAN, MPAN, and BPAN. We also added a more explicit statement indicating that the central question addressed by the review is how genetic and pathway-specific disease mechanisms can guide therapeutic development beyond iron-centered approaches.
The structure of the manuscript was also clarified. The review now moves from a genetic and clinical overview of NBIA disorders to mechanism-based sections organized around CoA metabolism, lipid metabolism, and autophagy-related defects. These sections are followed by a therapeutic section that discusses symptomatic, metabolic, antioxidant, autophagy-modulating, and gene-based strategies, and by a final section on translational gaps and conclusions. We believe that this organization better reflects the aim of the review and improves the logical progression from pathogenesis to therapy.
Comment 6: Authors should discuss the cognitive deficits of this groups of disorders as well and the links to the therapeutic approaches (e.g. https://pmc.ncbi.nlm.nih.gov/articles/PMC4307362/) and the possible links to mental disorders (as reported in recent global statistics https://pubmed.ncbi.nlm.nih.gov/42167272/) given that there are patients with comorbid neurological and psychiatric conditions.
Response 6: We thank the Reviewer for this helpful suggestion. We agree that cognitive and neuropsychiatric manifestations are clinically relevant in NBIA disorders and should be more explicitly connected to therapeutic development. We therefore revised the clinical overview to better discuss cognitive deficits, behavioral abnormalities, psychiatric manifestations, and dementia across major NBIA forms. We also added text emphasizing that these manifestations are relevant not only for patient management, but also for trial design, because cognition, behavior, adaptive function, and caregiver-reported outcomes may represent meaningful clinical endpoints. In addition, we cited the suggested literature to contextualize the clinical importance of neuropsychiatric manifestations and the broader global burden of mental disorders.
Comment 7: In the section 6. Translational gaps and future perspective, more references are needed in order to support statements and proposals.
Response 7: We revised the “Translational gaps and future perspective” section and added appropriate references.
Comment 8: Studies in humans and studies in animals should be grouped and presented accordingly (preferably in a table).
Response 8: A Table 2 has been added in section 6 in order to clarify evidence levels and translational status of discussed therapeutic strategies.
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsMost points raised by the reviewers have been included in this revision.
