Exploring Secondary Biotinidase Deficiency and Biotin Supplementation in PMM2-CDG

Abstract

Background

The congenital disorders of glycosylation (CDG) encompass >190 multiorgan disorders with predominantly neurodevelopmental phenotypes with no causative treatment available. The glycoprotein biotinidase (BTD) provides biotin, an essential cofactor for carboxylases in ubiquitous metabolic pathways. Individuals with (partial) BTD deficiency (BTDD) and CDG patients show overlapping phenotypes like movement disorders, seizures, and neurodevelopmental issues. Biotin is a water-soluble, inexpensive, and safe food supplement. Patients with primary BTDD respond well to oral biotin supplement. We here explore secondary BTDD and the effect of biotin supplementation in PMM2-CDG in an initial open-label study.

Methods

BTD activity in dried blood spots from 29 individuals with PMM2-CDG indicated a mean reduction to 27% (range: 23.0–40.5%) at group level. Patients (mean: 19.6 ± 11.9 years) were supplemented with 10 mg biotin daily for 12 months. The parents/caretaker reported positive responses in 62 to 69% of patients across seven (performance, social, at home, self-control, self-care, leisure, health) of the nine categories covered by the Adaptive Behavior Assessment System-II (ABAS-II) questionnaires. The reported positive effect of biotin supplementation differed between age groups, ranging from 54% (16–43 years) via 62% (2–5 years) to 80% (6–13 years). Its effect was reported to be the highest in the moderate to severely affected patient subgroups, with significant improvements in home functioning, health, performance, leisure, self-control. No adverse effects were reported.

Conclusion

Given the absence of other treatments, the supportive effect of Biotin in PMM2-CDG deserves further exploration.

Keywords

congenital disorders of glycosylation - therapy - vitamin H - biotinidase deficiency - treatment - seizures - movement disorder - rare disease

Synopsis

Biotin supplementation benefits PMM2-CDG patients.

Introduction

Congenital disorders of glycosylation (CDGs) are a group of >190 inborn metabolic disorders (IMDs) that affect the modification of glycoproteins and lipids with monosaccharides or complex sugar moieties (ORPHA:137). Due to the importance of glycosylation for all cell biological processes from fertilization to adulthood, CDG regularly expresses as a multiorgan disease, with a markedness dominance to central nervous system (CNS)-related phenotypes, like movement disorders, seizures, and neurodevelopmental issues. Patients present with a huge variability of phenotypes and no clear genotype–phenotype correlation can be drawn.[1]

No causative treatments are available and supportive treatment options have so far only been reported for a handful CDG types. These include the administration of oligosaccharides such as mannose, fucose, and galactose, the trace element manganese[2] [3] [4] or the repurposing of acetazolamide to reduce ataxia in PMM2-CDG.[5]

Biotin (vitamin B7 or vitamin H) is a water-soluble vitamin from the B vitamins and an essential nutrient for plenty organisms from bacteria to men. Biotin acts as prosthetic group required for the activity of the carboxylases.[6] The key tasks of biotinylated carboxylases in metabolism are related to the utilization of fats, carbohydrates, and amino acids and are as diverse as essential ([Fig. 1A]). The pyruvate carboxylase provides oxaloacetate for the citric acid cycle, gluconeogenesis, lipogenesis, and the biosynthesis of neurotransmitters. The propionyl-CoA carboxylase metabolizes amino acids and odd-chain or branched-chain fatty acids, the methylcrotonoyl-CoA carboxylase in turn metabolizes leucine and the acetyl-CoA carboxylase is involved in lipogenesis. Since biotin-auxotroph organisms have lost the ability of biotin biosynthesis, biotin must be obtained through dietary intake (e.g., liver, peanuts and walnuts, sunflower seeds, eggs, soybeans, oatmeal, and mushrooms) or by biotin salvage from proteins as part of proteolysis. Hereby, BTD is the key enzyme for the release of the vitamin from biocytin.[7] The human 56.8 kDa BTD (NM_001281723, NP_001394295.1) is a cytosolic glycoprotein and is mainly found in serum, liver, and kidney. The protein has six potential N-glycosylation sites and two potential sites for core 1 mucin-type O-glycans, leading to an overall mass of this glycoprotein of approximately 72 kDa. The extent to which N- and O-glycosylation contributes to the activity of the enzyme has not yet been conclusively clarified. In individuals with BTD deficiency (BTDD), impaired enzyme activity leads to reduced biotin recycling and thus to secondary biotin deficiency. Partial BTDD is defined as BTD activity between 10 and 30% of the mean normal activity and profound BTDD as activity below 10% of the mean normal activity.[8]

Fig. 1 Origin and use of biotin in metabolism and measurement of BTD activity in dried blood spots. (A) Biocytin, the precursor of biotin, is found in various dietary sources and as product of proteolytic breakdown of various carboxylases that carry the vitamin biotin as essential co-factor. Biotin is recycled through the action of BTD by cleaving biocytin into biotin and lysine. The carboxylases are essential proteins in metabolism concerning gluconeogenesis, fatty acid synthesis, and the catabolism of branched-chain amino acids and odd-chain fatty acids. (B) PMM2-CDG affects BTD activity leading to metabolic disruption and health problems. (C) BTD activity in individuals with different types of CDG and different disease severity levels. The majority of cases exhibited residual BTD activities between 20–30%, indicating partial BTD deficiency. (D) Oral administration of biotin leads to biochemical bypass of the BTD, thereby providing the body with sufficient cofactors for the various carboxylases and partially alleviating clinical symptoms in PMM2-CDG.

If left untreated, BTDD leads to a spectrum of CNS abnormalities (seizures, muscular hypotonia, developmental delay, ataxia), dermatologic findings (as rash, alopecia, dermatitis/eczema, hair loss, dry skin), ophthalmologic findings (like vision loss, optic atrophy, conjunctivitis), and audiological abnormalities (OMIM* 609019, MIM# 253260). The severity of BTDD can range from asymptomatic to severe and largely correlates with the residual enzyme activity.[9] Daily oral supplementation of 5 to 10 mg biotin is a very effective treatment without known side effects[7] [10] [11] [12] and can mitigate potential long-term neurological damage or even prevent the onset of symptoms, leading to inclusion of BTDD into newborn screening programs worldwide.[7]

Although BTDD and CDG are caused by different pathomechanisms, they share the common phenotypic endpoint of multisystem disorders with prominent CNS involvement. Based on our recent observations of decreased BTD activity in CDG individuals derived skin fibroblasts[13] ([Fig. 1B]), we hypothesize that hypoglycosylation of BTD leads to a secondary BTDD in CDG. This might contribute to the clinical symptoms of CDG patients, and consequently, biotin supplementation could be beneficial ([Fig. 1D]). We here explore secondary BTDD and the effect of biotin supplementation in PMM2-CDG.

Methods

Ethics Approval and Patient Consent Statement

This work was performed in accordance with the Declaration of Helsinki. Informed consent for experimental procedures and publication was obtained from the participants, parents, or legal representatives.

Recruitment, Inclusion, and Exclusion Criteria

Recruitment was conducted through online information sessions offered to the German Glycokids e.V. Patients of all ages fulfilling the inclusion criterium of a genetically confirmed PMM2-CDG defect were invited to participate. Patients already participating in other treatment studies, those who initiated additional treatment studies, as well as patients with significant changes in medication were excluded.

Phenotypic Subgroups

Patients were evaluated using the “Nijmegen CDG rating scale”[14] (NCRS) or were assessed by their treating physician experienced in CDG and classified as mildly (S), moderately (M), or severely (L) affected.

Determination of Biotinidase Activity

Biotinidase activity from dried blood spots of 29 individuals with PMM2-CDG was determined as described previously.[13] [15]

Oral Biotin Supplementation

All patients took a single dose of 10 mg of oral biotin daily ([Supplementary Fig. S1A–D], available in online version only).

Outcome Measures

This study was conducted during the pandemic, and therefore, direct assessment by the treating physician was not possible. We therefore asked patients or caretakers to complete the Adaptive Behavior Assessment System II (ABAS-II) questionnaires (ABAS-II parent/primary caregiver questionnaires)[16] before start (t1) and after 12 months of biotin supplementation (t2). ABAS-II was validated as a supplementary method for clinical follow-up and for research on functional status involving infants, children, and adults with IMDs. Thus, ABAS-II may assist the clinicians in the regular follow-up for metabolic disorders to monitor therapy effectiveness and disease progression.[17] The ABAS-II checklist provides scores based on age-related norms for conceptual, social, and practical skills of individuals between 0 and 89 years, addressing both cognitive and behavioral features. It includes subscales for communication, community use, functional academics, home living, health and safety, leisure, self-care, self-direction, and social competence/skills. Items are rated on a scale from 0 (Is Not Able) to 3 (Always/Almost Always). Biotin effectiveness was evaluated considering changes for each category in three study age groups: preschool (≤ 5 years); school-aged (6–15 years); and adulthood (≥16 years). We considered (1) all positive and negative scores changes for categories for each age group and evaluated statistically significant variations; (2) average increase for all categories in each age group; (3) the overall increase of treated cohort for each category; (4) the number of patients that reported improvement (positive response when >50%) for category in the entire treated sample and for each age group. Finally, we evaluated (5) the possible impact of baseline disease severity in promoting biotin response.

Additionally, the participants were asked to note further observations occurring under biotin supplementation, which were not addressed in the ABAS-II questionnaires.

Statistics

Statistical programming language R (version 4.4.0) was used for data analysis. The subscales of the ABAS-II questionnaires have different numbers of questions. To make the subscales comparable with each other, all answers were standardized by a min–max transformation between 0 and 100. Paired Wilcoxon tests were used to determine changes in medians from t1 (before biotin administration) to t2 (after biotin administration) for each subscale and across age groups. Because of the exploratory nature of this study, we have not corrected p-values in multiple comparisons.

Results

Biotinidase Activity in Dried Blood Spots

Medium enzyme activity in 29 individuals was reduced to 27% (range: 14.4–42.5%; reference range: 30–100%). All 29 patients showed a decreased BTD activity, of which 25 out of 29 cases (86.2%) presented even a partial BTDD ([Fig. 1C]).

Patient Cohort

A total of 29 PMM2-CDG individuals (17 males, 12 females; mean age 19.6 ± 11.9 years; [Supplementary Fig. S1], available in online version only) met the inclusion/exclusion criteria and were classified as mildly (S, n = 6), moderately (M, n = 14), and severely (L, n = 9) affected.

1. Age group-specific score changes in categories

   In general, more effects of the biotin supplementation were reported in school-aged and adult participants. ([Fig. 2A], [Supplementary Table S1A] [available in online version only]). For school-aged children, parents saw the greatest benefits in “Leisure” (+18.9) and “Social” (+14.5), however, no category reached full significance. Adults experienced significant improvements in “At home” (+1.5, p = 0.05), “Self-control” (+8.0, p = 0.0353), and “Social” (+10.2, p = 0.0230), with additional near-significant changes in “Health” (+6.7, p = 0.0878) and “Society” (+5.6, p = 0.0877). By contrast, for the preschool group mixed results were reported, with gains in “Social” (+2.78, p approaching significance) and notable declines in “Health” (−12.5).

2. Overall score changes by age group

   When aggregated across all categories ([Fig. 2B], [Supplementary Table S1B] [available in online version only]), for the adult group the greatest overall increase was mentioned, with an average improvement of +5.97 points and a p-value approaching significance (p = 0.0526). For children aged 6 to 15 years, the average improvement stated was more modest at +3.03 points but statistically significant (p = 0.0447). In contrast, for the youngest participants (0–5 years) parents noted an average decline of −1.33 points, with no significant effects (p = 0.6476).

3. Category-specific score changes across all age groups

   Significant improvements were reported in several categories following biotin supplementation ([Fig. 2C], [Supplementary Table S1C] [available in online version only]). For the subcategory “At home” a slight but statistically significant improvement (+0.33, p = 0.0034) was stated, whereas “Leisure” saw the most pronounced median change (+11.13, p = 0.0335) noted. “Health” outcomes were also described to have significantly improved (+10.0, p = 0.0409), as did “Self-control” (+6.67, p = 0.0086), “Social” interactions (+8.69, p = 0.0246), and “Society” (+4.55, p = 0.0255). For other domains such as “Performance” (−4.35, p = 0.0138) statistically significant decline.

4. General and age-dependent improvements by category

   For the majority of participants, improvements of 62 to 69% in seven out of nine categories ([Fig. 3A]) were reported. The greatest changes were stated in “Performance” (69%) and “Social” (65.5%). Significant improvements were also mentioned in “At home” (65.5%) and “Self-control” (62.1%). Concerning age, for school-age children, the most beneficial overall responses were described, with 80% improvement across categories ([Fig. 3B]) and positive values of 60 to 100% in all the nine categories ([Fig. 3C], middle). For the youngest group, 62.2% overall positive changes ([Fig. 3B]) were reported as well as positive values between 60 and 80% in seven out of nine categories but without significant gains ([Fig. 3C], left). In contrast, for adult participants, 54.4% positive changes were mentioned ([Fig. 3B]). Regarding the different categories, positive gains between 52.6 and 63.2% were stated in seven out of nine categories ([Fig. 3C], right).

5. Age-independent improvements by severity of condition

   By further break down the data concerning age and severity, for the severely affected group (L) ([Fig. 4], top; [Supplementary Table S2] [available in online version only]) significant improvements in leisure activities (p = 0.02997), suggesting better engagement in recreational tasks, and in self-control (p = 0.03461), indicating potential behavioral regulation benefits were reported. For the moderately affected group (M) ([Fig. 4], middle; [Supplementary Table S2] [available in online version only]), the most pronounced improvement was reported for home functioning (p = 0.0068), followed by health status (p = 0.0329) and performance-related tasks (p = 0.0392). In the mildly affected group (S) ([Fig. 4], bottom; [Supplementary Table S2] [available in online version only]), no significant improvements were reported.

   Of note, the number of participants per age group and severity level was not sufficient to draw statistically sound conclusions about which combination of age and severity level would benefit most from biotin administration ([Supplementary Fig. S2], [Supplementary Table S3] [available in online version only]).

6. Participants' own observations while taking biotin

   Beyond the ABAS-II questionnaires, we inquired about additional changes observed by patients or caregivers ([Supplementary Fig. S3] [available in online version only]). The most frequently reported improvement was cognitive function, noted in 19/29 (66%) of participants, including enhanced memory, concentration, attention, and overall activity levels, possibly reflecting increased cognitive engagement and energy. Speech and language improvements, such as better vocabulary and grammar, were reported in 7/29 (24%). General health benefits, including reduced skin inflammation, hair regrowth, and fewer inflammatory bowel disease flare-ups, were observed in 6/29 (21%). Similarly, 6/29 (21%) noted enhanced motor skills, such as improved coordination and fluidity of movement. Mood and behavior improved in 5/29 (17%), with reduced irritability and greater engagement in activities. Tremor and ataxia reduction, indicating better motor control, was reported in 4/29 (14%), as were improved sleep patterns and reduced fatigue. Additionally, 3/29 (10%) experienced better ocular function with less squinting. Notably, most improvements emerged within the first 2 to 12 weeks of biotin intake.

7. Participants with CDG defects other than PMM2-CDG

   Although this study focused on individuals with PMM2-CDG, we also aim to demonstrate that biotin supplementation was administered to fourteen non-PMM2-CDG patients, with seven cases each of CDG-I and CDG-II ([Supplementary Fig. S4], left [available in online version only]). The treatment resulted in a positive outcome in six out of the nine tested categories of the ABAS-II questionnaire, reaching or exceeding a 50% improvement threshold ([Supplementary Fig. S4], right [available in online version only]).

8. Adverse effects

   The inquiry regarding adverse events or side effects did not reveal any abnormalities in any of the participants.

Fig. 2 Impact of biotin supplementation on functional domains of PMM2-CDG patients in and across the different age groups (0–5, 6–15, 16–89 years). (A) Shown are the changes under biotin administration of various functional domains investigated for the three age groups. Although enhancements in different categories were observed in the age groups 0–5 and 6–15 years, significant improvements could only be shown in the adult group in “At home” (p = 0.05), “Self-control” (p = 0.0353), and “Social” (p = 0.0230). (B) Horizontal summary of all investigated functional domains within each age group. The data demonstrate consistent enhancements across multiple domains for the 6 to 15 years and 16 to 89 years age groups with values of p = 0.0447 and 0.0526, respectively, reflecting the overall efficacy of biotin treatment in improving patient outcomes in a range of functional areas. (C) Vertical summary of each investigated functional domain across all age groups. Significant improvements were present in six out of nine categories: “At home” p = 0.0034, “Leisure” p = 0.0335), “Health” p = 0.0409, “Self-control” p = 0.0086, “Social” interactions p = 0.0246, and “Society” p = 0.0255, reinforcing the broad-spectrum efficacy of biotin in enhancing various aspects of patient functionality regardless of age. Please note that a scale may have a different number of questions for each age group. The sum of the maximum achievable points on a scale varies depending on the age group. To ensure comparability, all scales were subjected to min-max normalization. The achievable points hereby vary between 0 and 100. t1: before biotin treatment, t2: after 12 months biotin treatment. Blue triangle: mean value.

Fig. 3 Percentage change in participants independent of severity. (A) Shown are the percentage changes in the different categories of biotin taking persons, independent of age attesting enhancements in seven out of nine categories. (B) Summary of changes in all scales within the three different age groups. Although all age groups presented with a general enhancement after biotin administration, the middle age group (6–15 years) profited most. (C) Percentage changes in the individual categories depending on the respective age group. While there is a clear indication of improvement in the three age groups in a majority of the categories, the school-aged children presented the most benefit over all categories. Green: positive change, gray: no change, orange: negative change.

Fig. 4 Impact of biotin supplementation on functional categories of PMM2-CDG patients based on their age-independent severity level. Shown are the changes under biotin administration of various functional categories investigated for the three severity levels (L: 9 cases, M: 14 cases, and S: 6 cases). The L group showed significant improvements in leisure activities (p = 0.02997) and in self-control (p = 0.03461). In the M group, home functioning (p = 0.0068), health (p = 0.0329), and performance (p = 0.0392) improved significantly, whereas the S group no category was altered significantly. Please note that due to the low number of participants in some of the age groups, an age-independent summary is given here. See [Supplementary Fig. S2] (available in online version only) and [Supplementary Table S3] (available in online version only) for change of participants per scale depending on age and severity. Please also note that a scale may have a different number of questions for each age group, so the sum of the maximum achievable points on a scale varies depending on the age group. To ensure comparability, all scales were subjected to min–max normalization. The achievable points hereby vary between 0 and 100. t1: before biotin treatment, t2: after 12 months' biotin treatment. Blue triangle: mean value.

Discussion

Therapeutic options for CDG remain scarce and are currently available for only a limited number of CDG subtypes. In our initial observations, we found that patients with PMM2-CDG exhibit generally reduced activity of the glycoprotein biotinidase (BTD), which carries up to six N-glycans and two core-1 mucin-type O-glycans.[18] Although not the primary focus of this manuscript, we emphasize that the expression of human BTD with mutated N- and O-glycosylation sites in HEK293 cells led to significantly reduced protein levels and enzymatic activity (unpublished laboratory data, Thiel group), indicating that hypoglycosylation has a secondary effect on BTD function in PMM2-CDG. Given that BTDD shares clinical features with CDG,[12] [19] we explored whether oral biotin supplementation could alleviate symptoms in PMM2-CDG patients.

Biotin supplementation has been associated with improvements in seven out of nine functional categories, with positive changes observed in 62 to 69% of participants. The most pronounced benefits were noted in school-aged children (6–15 years), where 80% of participants demonstrated improvements across multiple domains, particularly in social interactions and leisure activities. Adults also experienced significant gains, particularly in self-control and social functioning, whereas the youngest age group (0–5 years) exhibited mixed effects, with some improvements but also a decline in health scores. Regarding symptom severity, patients with moderate symptoms showed the most substantial benefits, particularly in-home functioning, health, and performance. Severely affected individuals experienced the greatest improvements in leisure activities and self-control, whereas those with mild symptoms exhibited no significant changes. These findings indicate that the response to biotin varies by age and symptom severity. However, given the limited number of participants in certain subgroups, further studies are required to refine the understanding of age- and severity-specific treatment effects. Patients also reported several subjective improvements beyond those captured in structured questionnaires, with the majority noticing benefits within the first 2 to 12 weeks of biotin therapy. A significantly increased cognitive engagement in daily activities was particularly noticeable, alongside improvements in various health parameters, such as enhanced skin and hair condition and a reduction in gastrointestinal issues. Additionally, some patients exhibited a reduction in tremors, with one patient even experiencing a complete disappearance of symptoms under biotin supplementation. Nevertheless, it is essential to interpret the observed effects of biotin supplementation in the context of the natural course of PMM2-CDG in which slow, heterogeneous, and often modest clinical progression can be observed. In addition to spontaneous biochemical improvements in blood markers such as CDT, aPTT, Factor XI, antithrombin III, protein C, AST, and ALT, which were not the focus of this study, longitudinal investigations have demonstrated that some patients may experience spontaneous improvements in mobility, communication, and other functional domains,[20] [21] as well as gradual developmental gains more generally.[22] However, these gains usually manifest over extended timeframes—often beyond one to two years—and vary substantially between individuals. In most cases, it remains unclear whether changes in diet, medication, or individualized therapy occurred during the observation period, which may have contributed to the reported improvements. Our study was specifically designed to minimize such confounding factors. These findings emphasize the generally limited and slow nature of spontaneous clinical improvement in PMM2-CDG. By contrast, the rapid and multidimensional benefits seen within 2 to 12 weeks of biotin supplementation—including enhanced cognitive engagement, motor function, gastrointestinal stability, and social interaction—suggest a response beyond the expected course of natural progression.

While these results are promising, it is important to acknowledge the limitations of this study. The open-label design and lack of a control group introduced potential bias and make it difficult to definitively attribute the observed improvements to biotin supplementation. This is particularly relevant for the youngest age group (0–5 years), where developmental changes occur rapidly and may be difficult to distinguish from treatment effects.

We also like to point out that this study was initiated closely before and conducted despite the coronavirus disease 2019 pandemic and associated lockdowns, which presented significant operational challenges. These included prohibition on studies with external participants, limiting our ability to conduct more rigorous assessments and follow-ups by treating physicians and using validated scores during a longer time period. To proceed with the study and avoid postponement to an undetermined future date due the ongoing pandemic, we opted to utilize ABAS-II questionnaires that could be completed remotely. The reliance on self-reported measures and questionnaires completed by patients, parents, or caregivers, rather than physicians, may have introduced variability in the assessment of outcomes. These discrepancies became evident through the negative scores reported on the ABAS-II questionnaires, which averaged between 20 and 38% across various scales, despite families describing noticeably more positive developments in interviews or reporting no change at all. When participants were asked about this inconsistency, two main reasons emerged. First, different parents or caregivers completed the assessments before and after treatment, which may have led to gender-related differences in perception.[23] Second, participants filled out the second survey without referring to their initial responses from before biotin supplementation, likely contributing to the discrepancy. Despite this, the relatively large number of participants for whom >60% positive responses across multiple domains were reported, provide a strong rationale for further investigation. Future studies then should address the named limitations by incorporating randomized, double-blind, placebo-controlled designs with larger sample sizes and more objective outcome measures.

Our explorative study identifies biotin as a promising candidate substance for supportive treatment in PMM2-CDG. Of note, we also explored biotin use in 14 non-PMM2-CDG cases as well in which a 50% positive gain or more was reported in 6 out of 9 categories. These findings suggest that biotin could hold potential for supportive treatment in all N-glycosylation deficiencies (>108 defects).[1] The safety, and low cost along with its capability to target multiple aspects of CDG pathophysiology, make biotin an attractive option for further explorations how and if biotin could improve the quality of life of CDG patients.

Declaration of Generative Artificial Intelligence and Artificial Intelligence-Assisted Technologies in the Writing Process

During the preparation of this work, the authors used ChatGPT 4o to improve language and readability. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Contributors' Statement

N.H.: Planned and conducted experiments, summarized clinical data, contributed to the writing of the manuscript. R.B., J.M., S.B.W.: collected and summarized clinical data, contributed to the writing of the manuscript. S.H., V.G., J.G.O.: collected biochemical data. S.G.: statistically summarized the data. C.T.: Planning of experiments, data analyses, and writing of the manuscript. All authors contributed to the interpretation of the results, revised, and approved the manuscript for submission.

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgments

We thank all patients and families for participating. Special thanks go to the German “Bundesverein CDG-Syndrom “GlycoKids” e.V.” for their consistent support. Further thanks go to Karolin Schaefer for excellent technical support and Nenad Blau for fruitful discussions.

Data Availability Statement

The data that support the findings of this study are available upon reasonable request.

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Publication History

Received: 16 May 2025

Accepted: 23 September 2025

Article published online:
06 October 2025