Transitioning into Adulthood with PKU: The Role of Diet, Coping Strategies, and Quality of Life in Adolescents and Young Adults

Round 1

Reviewer 1 Report

The topic is relevant, but the study doesn’t bring new insights or significant advancements to the field. The findings confirm what is already well known, without offering a fresh perspective or deeper analysis.

The manuscript would benefit from a more cautious and evidence-based interpretation of the results.

The discussion doesn’t reflect the most recent or relevant studies. .

The statistical analysis is quite simple and lacks important details. 

Key study limitations like self-reported data or cross-sectional design are not clearly discussed. 

1. Abstract style should be changed. Should focus more on objectives, methods, main findings, and conclusions.

2. Introduction is too long, with some repetitive ideas. Briefly explain PKU, emphasize the exisiting gap.

3. Materials and methods are lacking essential details like sample size calculation, recruitment method. The statistical plan is underdeveloped: No mention of how missing data were handled, if any correction for multiple comparisons was used, or sample size justification.

4. Results rection should be improved. Tables/Figures are not always integrated into the text well. Label clearly which differences are significant (*p < 0.05). Mention the small sample size limiting statistical power.

5. Please expand limitations, especially possible selection bias (single center, motivated patients more likely to participate), use of self-reported questionnaires introduces bias.

Author Response

Reviewer 1

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding corrections highlighted in the re-submitted files.

 

Does the title describe the article's topic with sufficient precision?

Yes

R: Thank you for your comment

Does the introduction provide a comprehensive yet concise overview about the state of knowledge in the area of research?

No

The introduction style should be changed. The introduction frequently repeats how adolescence and young adulthood are challenging periods for PKU management, which should be improved by merging overlapping sections. Transitions between clinical and psychosocial themes are unclear. Smoother linking phrases would improve the text. Several sentences are too long and contain multiple ideas, reducing clarity. The gap in literature regarding coping strategies in PKU is mentioned, but not elaborated enough. The study aim is not introduced clearly.

R: Thank you very much for pointing this out. 

We have revised the entire introduction according to the recommendations. The paragraph has been shortened, restructured, and clarified to improve the logical flow. Repetitions have been reduced, and transitions have been made clearer and more fluid, enhancing overall clarity. The study objectives have been clarified, and presented in the final section of the introduction.

Is the research design appropriate and are the methods adequately described?

No

The study design is not specified. Sampling method are not clearly introduced. It’s not clear how participants were selected. The questionnaire details are missing. No mention of specific tools used. No recruitment outcome provided.

 

R: Thank you very much for your comment.

The study design has been added to the Procedure section (line 121). 

Regarding participant selection, due to the strict inclusion criteria dictated by our research question, all eligible participants were contacted, in order to have a larger sample. We specifically chose to focus on patients with the classical form of PKU, which is the most severe manifestation of the disorder and therefore requires strict dietary therapy. PKU is a rare disease, with a total incidence of approximately 1:10,000 live births (Loeber, 2008). Consequently, the number of patients with the classical form is limited. Moreover, in Italy, newborn screening for PKU became mandatory only in 1992; therefore, adult patients remain relatively few, and specialized adult care centers are nearly non-existent.

More information on sampling methods have been added in the Procedure section  (lines 120-121).

Regarding the characteristics of questionnaires and tools used, all information is reported in the section Questionnaires (lines 137-197).

The characteristics of the sample recruited are reported in the Results section (“Sample characteristics, lines 219-227).

 

Reference:

Loeber, J.G. Neonatal screening in Europe; the situation in 2004. J. Inherit. Metab. Dis. 2007, 30, 430–438; Erratum in J. Inherit. Metab. Dis. 2008, 31, 469.

 

Are the results presented clearly and in sufficient detail, are the conclusions supported by the results and are they put into context within the existing literature?

No

While the manuscript presents a valuable dataset the results are not consistently presented with the clarity and depth needed to fully support the conclusions. Several key findings are not quantified in the results section. Moreover, some of the conclusions, particularly those related to psychological interventions and social support mechanisms, feel more interpretative than evidence-based within the current presentation of data. Although the discussion references existing literature, the integration could be stronger. More direct comparisons with previous studies would help contextualize the findings and clarify how this study contributes new insights or confirms known trends. Strengthening the linkage between results and literature would enhance the overall scientific value of the paper.

R: Thank you very much for pointing this out.

We have revised the Results section to improve clarity and coherence with our research objectives. In particular, section 4.4 has been clarified to better align with the aims of the study.

The Discussion section has also been thoroughly revised in accordance with your suggestions. We have emphasized the comparison between our findings and the existing literature. However, we acknowledge that such comparisons are sometimes limited due to the rarity of PKU, especially the classical form, and the lack of studies focusing specifically on adolescent and young adult patients.

Patients with classical PKU require a strict low-protein dietary regimen, which significantly impacts daily life and overall quality of life. Given the severity of the condition and the specificity of its management, a highly personalized approach is essential. Multidisciplinary teams should include psychologists to support both patients and families in adapting to the disease and its demanding treatment, particularly during adolescence and young adulthood, when individuals are assuming greater responsibility for their care.

The aim of our study was to investigate multiple aspects related to PKU: the challenges associated with the disease and its dietary management, treatment adherence, coping strategies, and quality of life. The innovative aspect of this study lies in having examined all these dimensions together and exploring the correlations among them. A complex disease such as PKU requires research that goes beyond isolated variables and seeks to identify the interactions between medical, behavioral, and psychological aspects, with the ultimate goal of providing increasingly patient-centered and tailored support.

We fully agree on the importance of strengthening the link between our findings and those in the literature; accordingly, we have revised the Discussion to give greater emphasis to this comparison.

 

Are all of the cited references relevant to the research?

Yes

R: Thank you for your comment

 

Does this article provide a relevant contribution to the scientific discussion of this topic?

No

The lack of a robust comparison to existing studies, as well as the absence of clear hypotheses or defined research questions limit the paper’s contribution.

R: Thank you for your comment.

We agree with this point. We have included clearer comparisons with studies on PKU as well as other chronic conditions, as reflected in the revised Discussion section.

Moreover, the research questions have been explicitly stated in the Introduction (lines 94-108).

 

Is the quality and presentation of the figures satisfactory?

Yes

R: Thank you for your comment

 

English language and style

The English could be improved to more clearly express the research.

R: Thank you for your comment.

We have revised the English language with the support of a language editor, in the hope that the overall clarity and readability of the paper have been improved.

 

Comments for Authors

 

Major comments

 

The topic is relevant, but the study doesn’t bring new insights or significant advancements to the field. The findings confirm what is already well known, without offering a fresh perspective or deeper analysis.

R: Thank you for pointing this out.
To the best of our knowledge, no previous studies have investigated the use of coping strategies in young patients (adolescents and young adults) with PKU, although these aspects have been explored in many other chronic conditions. We believe that examining coping strategies in this specific population is crucial, as they represent a high-risk group, both in terms of poor metabolic control and greater disease impact on quality of life.

Moreover, we aimed to explore the associations between coping strategies and various aspects related to the disease, dietary therapy, and quality of life. Our goal was to identify factors that could inform a more comprehensive and multidisciplinary approach to the care of such vulnerable patients. This population requires the integrated expertise of professionals including physicians, neuropsychiatrists, dietitians, and psychologists. Bringing together these different dimensions allows for a broader and more unified understanding of patients’ needs and is essential to providing specialized and effective care.

The manuscript would benefit from a more cautious and evidence-based interpretation of the results.

R: Thank you for your comment.
We have revised the Discussion section to strengthen the comparisons with existing literature, highlighting both similarities with previous studies and the novel findings that emerged from our research. We also aimed to provide a possible interpretative framework for our results.

In this process, we considered not only the relevant scientific literature but also our clinical experience, developed through daily work with patients and their families, which we believe offers valuable insights for interpreting and contextualizing the findings.

The discussion doesn’t reflect the most recent or relevant studies.

R: Thank you for your comment.

We have revised the Discussion section to make the comparisons with existing literature more explicit, aiming to highlight both the commonalities with previous studies and the novel findings emerging from our research. Additionally, we have provided a possible interpretative hypothesis to contextualize our results.

 

The statistical analysis is quite simple and lacks important details. 

R: Thank you for your comment.

All analyses were conducted in collaboration with a researcher specialized in statistics. The limited sample size, due to the low incidence of the classical form of PKU, prevented us from performing more in-depth statistical analyses. Future studies may apply more specific statistical analyses by expanding the study sample.

 

Key study limitations like self-reported data or cross-sectional design are not clearly discussed. 

R: Thank you very much for your comment.

We have expanded the Limitations section to incorporate the aspects you suggested (lines 518-523). Future studies may address these limitations and explore these aspects of PKU from different and more comprehensive perspectives.

 

Detail comments

1. Abstract style should be changed. Should focus more on objectives, methods, main findings, and conclusions.

R: Thank you very much for the comment.

We have revised the abstract by including the suggested sections and focusing more specifically on the key points highlighted.

 

2. Introduction is too long, with some repetitive ideas. Briefly explain PKU, emphasize the exisiting gap.

R: Thank you for pointing this out.

We have revised the introduction according to the recommendations, aiming to make it shorter and clearer in both content and structure. The paragraph has been shortened, restructured, and clarified to improve the logical flow. 

More information regarding the existing gap in literature has been added.

 

3. Materials and methods are lacking essential details like sample size calculation, recruitment method. The statistical plan is underdeveloped: No mention of how missing data were handled, if any correction for multiple comparisons was used, or sample size justification.

R: Thank you for the comment.
The Procedure section has been clarified to more explicitly describe the sample collection method. All patients meeting the inclusion criteria were contacted, and 21 of those contacted agreed to participate in the study. Due to the low incidence of the disease in Italy, the sample size was limited; however, it is consistent with other studies on PKU and coping strategies (Evans et al., 2019; Awiszus & Unger, 1990; Zwiesele et al., 2015; Roberts et al., 2014). Therefore, no sample size calculation was made; but all possible patients have been contacted.

Regarding the statistical analyses, the small sample size allowed for complete data without missing values. 

Group comparisons were conducted without adjustment for specific covariates.

References:

Evans, S., Daly, A., Wildgoose, J., Cochrane, B., Ashmore, C., Kearney, S., & MacDonald, A. (2019). Mealtime Anxiety and Coping Behaviour in Parents and Children During Weaning in PKU: A Case-Control Study. Nutrients, 11(12), 2857. https://doi.org/10.3390/nu11122857

 

Awiszus, D., & Unger, I. (1990). Coping with PKU: results of narrative interviews with parents. European journal of pediatrics, 149 Suppl 1, S45–S51. https://doi.org/10.1007/BF02126299

 

Zwiesele, S., Bannick, A., & Trepanier, A. (2015). Parental strategies to help children with phenylketonuria (PKU) cope with feeling different. American journal of medical genetics. Part A, 167A(8), 1787–1795. https://doi.org/10.1002/ajmg.a.37088

 

Roberts, R. M., Muller, T., Sweeney, A., Bratkovic, D., & Gannoni, A. (2014). Promoting psychological well-being in women with phenylketonuria: Pregnancy-related stresses, coping strategies and supports. Molecular genetics and metabolism reports, 1, 148–157. https://doi.org/10.1016/j.ymgmr.2014.03.002

 

4. Results section should be improved. Tables/Figures are not always integrated into the text well. Label clearly which differences are significant (*p < 0.05). Mention the small sample size limiting statistical power.

R: Thank you for the comment.

The tables and figures have been better integrated into the text and made clearer. Statistical significance is indicated only in Table 2, with the label explicitly provided below the table.

The limitation posed by the small sample size has been acknowledged in the Limitations section (lines 508-509) and expanded upon according to your suggestion.

 

5. Please expand limitations, especially possible selection bias (single center, motivated patients more likely to participate), use of self-reported questionnaires introduces bias.

R: Thank you for the comment.

The Limitations section has been revised and expanded to address a broader range of limitations.

Author Response File: Author Response.docx

Reviewer 2 Report

The study is well-designed, and the findings are adequate. Minor revision.

The aim of this study is to examine the impact of PKU on daily life, dietary adherence, coping strategies, and quality of life.

Comments:

• The abstract should include key findings. Emphasis should be placed on the most significant results.

• The introduction is sufficient. However, the study’s originality and contribution to the literature should be articulated more clearly.

• The division of participants into two groups—adolescents (13–17) and adults (18–25)—is a major strength of the study. I congratulate the author(s) for this valuable approach.

• The methods used are appropriate.

• The statistical analyses are correctly applied.

• In Tables 1 and 2, decimal separators should be periods rather than commas.

• In the discussion section, Line 441 begins with “Finally.” This sentence could be rephrased for improved clarity and style.

Author Response

Reviewer 2

 

Does the title describe the article's topic with sufficient precision?

Yes

R: Thank you for the comment. 

Does the introduction provide a comprehensive yet concise overview about the state of knowledge in the area of research?

No

The study’s originality and contribution to the literature should be articulated more clearly.

R: Thank you very much for pointing this out.

We have revised the entire introduction according to the recommendations.  The paragraph has been shortened, restructured, and clarified to improve logical flow.

We agree that the originality of the article and the research objectives needed to be stated more clearly. Therefore, the study aims have been revised and are now presented in a more direct and structured way in the final part of the introduction. In addition, the novelty of the study compared to previous research has been more clearly articulated (lines 87-108).

 

Is the research design appropriate and are the methods adequately described?

Yes

R: Thank you for the comment. 

 

Are the results presented clearly and in sufficient detail, are the conclusions supported by the results and are they put into context within the existing literature?

No

In Tables 1 and 2, decimal separators should be periods rather than commas.

R: Thank you very much for pointing this out.

We have addressed the issue as recommended.

 

Are all of the cited references relevant to the research?

Yes

R: Thank you for the comment. 

 

Does this article provide a relevant contribution to the scientific discussion of this topic?

Yes

R: Thank you for the comment. 

 

Is the quality and presentation of the figures satisfactory?

Yes

R: Thank you for the comment. 

 

English language and style

The English is fine and does not require any improvement.

R: Thank you for the comment. 

 

Comments for Authors

Major comments

The study is well-designed, and the findings are adequate. Minor revision.

R: Thank you for your comment. 

 

Detail comments

The aim of this study is to examine the impact of PKU on daily life, dietary adherence, coping strategies, and quality of life.

Comments:

• The abstract should include key findings. Emphasis should be placed on the most significant results.

R: Thank you very much for the comment.

We have revised the abstract by rewriting it, dividing it into sections, and placing greater emphasis on the main results, as suggested.

• The introduction is sufficient. However, the study’s originality and contribution to the literature should be articulated more clearly.

R: Thank you very much for pointing this out.

The originality of the article has been more clearly expressed in the Introduction section; and the research objectives have been deeply explicited. 

• The division of participants into two groups—adolescents (13–17) and adults (18–25)—is a major strength of the study. I congratulate the author(s) for this valuable approach.

R: Thank you for your comment. 

• The methods used are appropriate.

R: Thank you for your comment. 

• The statistical analyses are correctly applied.

R: Thank you for your comment. 

• In Tables 1 and 2, decimal separators should be periods rather than commas.

R: Thank you for your comment.

The tables have been revised according to your suggestions.

• In the discussion section, Line 441 begins with “Finally.” This sentence could be rephrased for improved clarity and style.

R: Thank you for your comment.

The sentence have been revised according to your suggestions.

 

Author Response File: Author Response.docx

Reviewer 3 Report

1. The study has been conducted using one small area only and the sample size is too small. Due to the sampling method, it is not useful to generalize the results.

2. Also, the study do not provide any additional source of information except some behavioral aspects.

3. No new method of analysis was used to show methodological upgrade.

 

I have put all the details in the above table.

Author Response

Reviewer 3

 

Does the title describe the article's topic with sufficient precision?

Yes

R: Thank you for your comment. 

 

Does the introduction provide a comprehensive yet concise overview about the state of knowledge in the area of research?

Yes

R: Thank you for the comment. 

 

Is the research design appropriate and are the methods adequately described?

Yes

R: Thank you for your comment. 

 

Are the results presented clearly and in sufficient detail, are the conclusions supported by the results and are they put into context within the existing literature?

 

No

At one stage, authors chose to use Mann Whtiney Test which is non-parametric. But with the Age, they have calculated the Mean and SD. If the sample size is too small, it is good to use Median and IQR. In Table 2, means and SD have been calculated and then Mann Whitney U test has been run. How?

R: Thank you for pointing this out.

We agree that this aspect can be improved. The Mann–Whitney test was conducted as the sample size was limited. Means and standard deviations were reported in the table to provide a descriptive overview of the values. 

However, we acknowledge that this may be confusing and potentially misleading; therefore, we have decided to report means and standard deviations in Table 1 to explicitly describe average levels through descriptive analyses, while Table 2, where the Mann–Whitney test was applied, now reports median values.

Are all of the cited references relevant to the research?

Yes

R: Thank you for the comment.

 

Does this article provide a relevant contribution to the scientific discussion of this topic?

No

I have put the details in comments for authors

R: Thank you for your comment.

 

Is the quality and presentation of the figures satisfactory?

Yes

R: Thank you for the comment.

 

English language and style

The English is fine and does not require any improvement.

R: Thank you for the comment.

 

Major comments

1. The study has been conducted using one small area only and the sample size is too small. Due to the sampling method, it is not useful to generalize the results.

 

R: Thank you for your comment.
Conducting the study at a single center does indeed impose limitations concerning the representativeness of the sample. This limitation has been acknowledged in the Limitations section (lines 513-518). However, our center serves patients from all over Italy, which helps to mitigate potential regional biases.

Regarding the sample size, we agree that it constitutes a limitation, and this has also been addressed in the Limitations section (lines 507-512). Due to the strict inclusion criteria dictated by our research objectives, all eligible participants were contacted. We deliberately focused on patients with the classical form of PKU, which represents the most severe phenotype and necessitates the strictest dietary management. PKU is a rare disorder, with an incidence of approximately 1 in 10,000 live births (Loeber, 2008), resulting in a limited number of individuals with the classical form.

Nonetheless, our sample size is consistent with those reported in other studies investigating PKU and coping strategies (Evans et al., 2019; Awiszus & Unger, 1990; Zwiesele et al., 2015; Roberts et al., 2014).

 

Reference:

Loeber, J.G. Neonatal screening in Europe; the situation in 2004. J. Inherit. Metab. Dis. 2007, 30, 430–438; Erratum in J. Inherit. Metab. Dis. 2008, 31, 469.

 

Evans, S., Daly, A., Wildgoose, J., Cochrane, B., Ashmore, C., Kearney, S., & MacDonald, A. (2019). Mealtime Anxiety and Coping Behaviour in Parents and Children During Weaning in PKU: A Case-Control Study. Nutrients, 11(12), 2857. https://doi.org/10.3390/nu11122857

 

Awiszus, D., & Unger, I. (1990). Coping with PKU: results of narrative interviews with parents. European journal of pediatrics, 149 Suppl 1, S45–S51. https://doi.org/10.1007/BF02126299

 

Zwiesele, S., Bannick, A., & Trepanier, A. (2015). Parental strategies to help children with phenylketonuria (PKU) cope with feeling different. American journal of medical genetics. Part A, 167A(8), 1787–1795. https://doi.org/10.1002/ajmg.a.37088

 

Roberts, R. M., Muller, T., Sweeney, A., Bratkovic, D., & Gannoni, A. (2014). Promoting psychological well-being in women with phenylketonuria: Pregnancy-related stresses, coping strategies and supports. Molecular genetics and metabolism reports, 1, 148–157. https://doi.org/10.1016/j.ymgmr.2014.03.002

2. Also, the study do not provide any additional source of information except some behavioral aspects.

R: Thank you for the comment.

Data were collected through self-report questionnaires, which may present certain limitations. Future studies could incorporate additional assessment tools alongside self-report measures. These considerations have been added to the Limitations section (lines 521-523).

 

3. No new method of analysis was used to show methodological upgrade.

R: Thank you for your comment.

The limited sample size did not allow for the use of more sophisticated analytical methods, as the sample size was insufficient to support more complex tests. Future studies could certainly conduct more comprehensive and advanced analyses.

Detail comments

I have put all the details in the above table.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

The authors made significant changes and were very constructive. 

The paper can be published in a current form. 

Author Response

Thank you very much for taking the time to review this manuscript. We are pleased to know that our revisions were adequate and aligned with your suggestions and comments.

Author Response File: Author Response.docx

Reviewer 3 Report

The quality of tables are not satisfactory. The numbers cannot be understood in its current form. IQR were also not calculated.

NA

Author Response

Reviewer 3

 

Are the results presented clearly and in sufficient detail, are the conclusions supported by the results and are they put into context within the existing literature?

Yes

X No

The results in Table 2 are still confusing. I had great difficulty in understanding what the numbers are.

R: Thank you very much for your comment. The formatting of the tables was likely compromised due to a technical issue on our side. We have therefore revised the table according to your suggestions in order to clarify the meaning of the figures.

Does this article provide a relevant contribution to the scientific discussion of this topic?

Yes

X No

It cannot provide a relevant scientific contribution till the results are understood.

R: Thank you for your comment. We have revised Table 2 according to your indication.

Are all figures and tables clear and well-presented?

Yes

X No

Confusing numbers in Table 2.

R: Thank you for your comment. The numbers in Table 2 have been reformatted and reorganized to improve clarity.

Major comments

The quality of tables are not satisfactory. The numbers cannot be understood in its current form. IQR were also not calculated.

R: Thank you for pointing this out. The formatting of Table 2 was likely compromised due to a technical issue on our side. We have therefore revised the table according to your suggestions to clarify the meaning of the figures. Additionally, the IQR values have been added as per your indication.

 

 

 

Author Response File: Author Response.docx