Aim of the present work was to expand the survey of Weber and colleagues [9], exploring the main areas of concern and treatment priorities among Italian individuals with FXS. Furthermore, we added a new section specifically designated for people with PM in order to investigate the main symptoms, associated clinical disorders and treatment needs also in this condition.

Taking into account the section on FXS, while our initial goal was to understand if different subcategories of respondents would have provided statistically different answers, the inhomogeneous numerousness of sub-groups did not allow us to perform comparative analyses. Nevertheless, we conducted qualitative analyses highlighting the most frequently selected items by different subgroups of respondents. Before discussing these results, it must be said that, as in Weber and coll. [9], there were very few individuals with FXS answering to the survey, which could be due to the difficulty for people with ID in responding to a questionnaire with a lot of questions and options. Furthermore, most of respondents compiled the questionnaire for males with FXS aged 6–12. Therefore, it is essential to interpret findings cautiously and avoid generalizing them to the entire Fragile X population.

Additionally, despite our decision to translate Weber's survey into Italian language, it's important to note that we couldn't directly juxtapose our results with those of Weber and colleagues [9]. This discrepancy arose because our respondents encountered challenges in ranking only five items per question on a scale from 1 to 5. Consequently, we had to employ a different methodology from the one utilized by the authors; indeed, we asked to the compilers to assign to each item a score from 1 to 5, subsequently selecting the highest mean scores for each question and presenting them in the paper. Moreover, in contrast to Weber and colleagues [9], who divided respondents into only three categories (self, family members/caretakers, professionals), we made a more detailed distinction. Specifically, we separated the responses of mothers with PM from those of other family members with PM, as well as from other relatives without PM. Nevertheless, while a direct comparison was not possible, our results are in some way consistent with the ones of Weber; specifically, anxiety emerged as the most concerning symptom of FXS among individuals with FXS and their family members, ranking within the top three answers across all respondent groups except for mothers with PM. Intriguingly, while mothers with PM identified ID as the primary challenge, anxiety did not averagely rank within their top three concerns. The explanation of this result could be twofold: firstly, one conceivable speculation is that mothers, identifying anxiety within themselves as a significant symptom (Table 5), viewed it as less worrisome in their children; secondly, it is also viable to consider that mothers deemed factors such as IQ, academic skills, and expressive language to be more pressing concerns. This perspective aligns with existing literature highlighting the influential role of IQ, learning capabilities, and speech in adaptive functioning and QoL, both within FXS and broader neurodevelopmental disorders (NDs) [1, 12, 23]. In all instances, mothers with PM agreed with other Italian subgroups of respondents and with the American compilers [9] in considering anxiety a treatment priority.

Expressive language was advised as another significant problematic symptom, which is in line with previous works reporting that language difficulties represent one of the greatest challenges and a primary concern of FXS ([i.e., [2, 12, 9]). This is to be expected considering the strong correlation between expressive language skills of children with FXS and their capacity for independence in adulthood [1]. Therefore, it is in some way surprising that Italian respondents, while pointing out the ability to communicate as one of the daily living skills most affected, did not rate language as a treatment priority. Nonetheless, it's plausible that this result is partially influenced by the extensive utilization of speech therapy in the clinical management of NDs, especially among children aged 0–7 years. Consequently, respondents may have perceived this issue as less urgent in terms of treatment needs.

Our results are also consistent with Bailey [3, 4], since we found that learning disabilities, overall thinking and planning as well as the difficulties in attending events where there are lots of people/noise, were strongly associated to FXS phenotype. Furthermore, in line with Cross and colleagues [12], challenging behaviors were reported as primary concerns, which is consistent with data in literature showing that individuals with FXS exhibit elevated rates of behavioral problems ([i.e., [9]) that are considered to have, together with psychiatric issues, the greatest impact (more than ID) to the QoL of individuals with FXS and their families [12]. Effectively, in accordance with those premises, Italian respondents considered anxiety followed by behavioral issues, a priority for intervention, with 11 out of 47 mothers responding that their answers referred to a behavioral treatment and not to medication. One possible explanation to the higher choice of anxiety as the main focus of treatment, could be that non-pharmacological early interventions like Applied Behavior Analysis (ABA) are commonly recommended and have proven effective in managing challenging behaviors in children with FXS [27, 27]. In contrast, treatments for anxiety, such as cognitive behavioral therapy (CBT), have received less attention despite some initial evidence supporting their efficacy [9]. As a result, there remains a high demand for interventions tailored specifically to addressing anxiety in this population. Furthermore, it must be said that, contrastively to the robust data on the FXS phenotype, to date there are still not systematic guidelines for non-pharmacological treatment in FXS [23], reason for which respondents could consider behavioral interventions as more urgent.

These findings are valuable both for research and clinical purpose; indeed, on one hand they direct toward the development of novel research lines (i.e., to testing novel behavioral interventions) and on the other hand they guide clinicians in identifying treatment goals.

Considering data on FXS section as a whole, it can be concluded that, exactly as in Weber and colleagues [9], Italian respondents considered anxiety, learning abilities and behavior the main concerning problems in people with FXS, with the relevance of each of these areas varying based on the focus of the question and the category of respondents. More specifically, while mothers with PM seem to be more worried about the impact of ID/academic problems in the future of their children with PM, other respondent categories express greater concern about anxiety, behavior and language skills. Interestingly, motor stereotypies were reported as a main symptom from almost all the categories of compilers and a treatment priority from professionals’ perspective. As stereotypies in FXS and more in general in NDs can be interpreted as a manifestation of anxiety [6], it cannot be excluded that the underlying symptomatology for which respondents declared to be worried was the same. In this regard, future diagnostic manuals should aim to provide clearer explanations of anxiety and other psychiatric disorders in individuals with ID. This would enable patients, caregivers, and clinicians to better understand the clinical manifestations associated with NDs.

Considering the PM section, our initial goal was to directly compare responses from females and males. However, due to only 9 males completing the online questionnaire, quantitative analysis was not feasible. Before delving into qualitative findings, it's crucial to highlight that although PM appears to be more prevalent among women [9, 12], this doesn't justify the significant gap between female and male respondents; one explanation could be that women are in general more likely to answer questionnaires/surveys than men [5]; another possible interpretation is that a man with PM does not pass on a full mutation to any of his children, therefore remaining unaware of the condition unless other family members do not present FXS; consequently, it's plausible that various Italian male carriers are still unaware of their diagnosis [12]. The reason for which we decided to include PM in our survey is because the condition has long been considered asymptomatic, with males with PM called nonpenetrant and transmitting males. With time, it has been shown that individuals with PM are at increased risk for several health concerns, often ignored not only by carriers themselves but also by clinicians. Those concerns include FXTAS, FXPOI and other multiple medical conditions [9], but also anxiety, ADHD, social deficits, depression, and cognitive problems that fall under the category of FXAND [9]. Our results are consistent with previous data, indeed females with PM of all ages reported short and long memory problems together with social anxiety as main problematic symptoms. To note, the daily life skills considered to be the most affected by all the women with PM were the inability to attend places where there are a lot of people/noise, a symptom that can also be considered a sign of social anxiety [9] and that has already frequently depicted in women with PM [i.e., [9]). Other main concerns that emerged as consistently problematic were academic problems and difficulties to cope with anger. These results are in some ways in line with the survey of Bailey and colleagues [3, 4] in which learning disabilities and autistic traits were strongly associated with PM and in line with previous studies on the neurobehavioral phenotype associated to PM [23]. Additionally, the worry for the future, the inability to relax and overthinking that represent a core symptomatology in the cognitive model of anxiety and depression [9], were considered by Italian respondents to be the most challenging aspects of PM. This result aligns with the literature showing that anxiety and depression are commonly experienced by people with PM and that this is not due only to raising up a child with FXS [9, 9]. To note, while reporting anxiety as a major concern, none of the compilers declared to suffer of FXAND. This result could be due to a dual interpretation: on one hand, it is possible that Italian compilers are not aware about the meaning of FXAND; on the other hand, we cannot exclude the possibility that they dislike the terminology therefore deciding not to use it in the survey. This second interpretation is supported by previous studies underlying that carries find the term FXAND as stigmatizing ([i.e., [12]) and by the fact that, when asked to specify if they suffered of any comorbidity, Italian respondents did not hide to exhibit anxiety, mood disorders, sleep difficulties and cognitive deficits which all fall under the umbrella term of FXAND. Furthermore, anxiety and mood disorders were considered the top treatment priorities, which confirm that our respondents show insight about their daily life difficulties. This data is important and raises areas for discussion. Indeed, in a future work it should be investigated if carriers are aware that psychiatric in PM are not due only to having a child with ID, but also to specific genetic factors (elevated FMR1 mRNA, mitochondrial dysfunction and calcium dysregulation underline the pathophysiological changes seen in PM) [27, 27]. Further studies aiming to investigate the effectiveness of behavioral interventions (i.e., psychoeducation) in this population should be pursued, too.

Interestingly, Italian respondents with PM identified memory and attention problems as primary concerns, yet they did not prioritize cognitive intervention. This could be attributed to a lack of awareness about the availability of neuropsychological treatments or, alternatively, the perception that anxiety/mood disorders have a greater impact on daily life when compared to other symptoms. It is also possible that subjective memory complaints may be indicative of anxiety, particularly among younger respondents, and that addressing psychiatric issues could also benefit cognitive deficits. Future research on treatment strategies among carriers is needed to address these important, still unanswered questions.

In summary, Italian data emerging from this survey, totally align with previous findings on PM, suggesting that some people with PM may exhibit health problems that are different from FXTAS and FXPOI and that should receive more attention by clinicians. Genetic screenings are now more accessible than ever before and should maybe be considered from both preventive and early treatment perspectives.

In summary, this work represents the first Italian survey to provide information about FXS and PM phenotyping and treatment priorities assuming a patient/caregiver first perspective. Our results, consistently with the ones of Weber [9], encourage clinicians to carry out cognitive-behavioral and neuropsychological interventions in the treatment of the symptomatology associated with both FXS and PM and researchers to develop novel targeted interventions. This need becomes even more critical given the significant lack of research on psychological interventions for mental health issues in individuals with NDs. The limited understanding of effective therapeutic approaches for this population underscores the urgency for more comprehensive studies and targeted treatment strategies. Addressing this gap is essential for improving the mental health outcomes and overall well-being of individuals with NDs [23].

The study presents the following main limitation: 1) as the survey was anonymous and conducted online, we did not have the possibility to confirm the correctness of the information provided; on the other hand, the aim of the study was to replicate the work of Weber and colleagues [9] giving voice also to Italian respondents; for this reason, we translated the American survey rather than validating it into Italian language, which could represent another limitation; 2) the structure of the survey, which included different questions and options, could be difficult to be compiled by some people (mostly by the ones with ID or cognitive difficulties); therefore, future surveys should use a design more appropriate and accessible by everyone (i.e., with less options); 3) finally, the sample-size among subcategories was inhomogeneous not allowing us to perform direct comparison. Future research should provide more homogeneous sample-sizes to allow direct comparisons and perform proper statistical analysis.