Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is an ultrarare genetic condition, with an estimated incidence of 2.36 per 100,000 live births [1]. It is a developmental epileptic encephalopathy condition and was first described in 2004 [2]. Initially, CDD was believed to be an early-onset variant of Rett syndrome, another rare neurological disorder, due to the similarity in symptoms (seizures, developmental delay, gastrointestinal dysfunction, scoliosis, etc). However, CDD has a distinct genetic cause and symptom profile, as severe developmental delay is exhibited from birth and seizure onset occurs earlier, and it was thus established as a separate clinical condition in 2013 [3-5]. CDD is caused by pathogenic variants in the X-linked gene CDKL5, which plays a key role in normal brain development and function [6]. The disorder is estimated to be 4 times more prevalent in females than in males, but male patients often experience more severe symptoms than their female counterparts [7].

CDD is characterized by a broad range of clinical features, including early-onset refractory epilepsy; hypotonia; developmental, motor, and intellectual disabilities; cerebral (cortical) visual impairment; and microcephaly [3]. Epileptic seizures are usually the first symptom to occur, with a median age of onset of 6 weeks (by the age of 3 months in 90% of cases) [3,8,9]. Psychomotor impairments, hypotonia, and significant intellectual disability in children with CDD result in difficulties with gross motor skills, such as sitting, standing, or walking, and communication skills, which are often limited to body language, facial expressions, and vocalizations [5,10-12]. Other common comorbidities of CDD include sleep disturbances, movement disorders, respiratory issues, and gastrointestinal disorders [13,14].

CDD can be suspected through clinical examination, but genetic testing is required to confirm the diagnosis [3]. Phenotypic variability exists between individuals in terms of symptom range and severity [3,7,15]. Management of CDD typically starts with pharmacological interventions to alleviate seizures and other comorbid symptoms, as no disease-modifying therapies are currently available [3,16,17]. Antiseizure medications (ASMs) are prescribed based on seizure types and patterns, with polypharmacy often necessary due to seizure refractoriness [3,18]. The most commonly used ASMs for CDD include levetiracetam, topiramate, sodium valproate, vigabatrin, phenobarbital, and clobazam [18]. Ganaxolone, a neuroactive steroid, demonstrated long-term reduction of CDD-associated seizure frequency in clinical trials and became the first ASM approved by US and European regulatory agencies for the treatment of seizures associated with CDD in patients aged 2 years or older [19-22]. In addition to medications, a ketogenic diet and vagus nerve stimulation (VNS; for patients over 4 years old) may also help to reduce the frequency and intensity of seizures [17,23,24]. For developmental and social issues, a multidisciplinary approach is considered essential, including speech therapy, physiotherapy, psychosocial support, and occupational therapy, to address the broader needs of patients [17]. Given the symptom load and the necessary care, the burden of CDD is considered substantial for patients and their family members. Families caring for children with CDD experience significant emotional and financial burdens, with primary caregivers, particularly mothers, reporting lower mental well-being. The severity of the child’s sleep disturbances and the financial hardships further exacerbate stress levels, while the significant care needs likely contribute to a higher caregiving burden and reduced family quality of life [25]. Emotional well-being appears to be more impacted in the parents of children with CDD than in those caring for children with other genetic disorders associated with intellectual disability, such as Down syndrome or Rett syndrome [26]. Although recent studies have provided major insights on the clinical features and disease management of CDD, research quantifying and qualifying this burden remains limited, given the scarcity of the disorder and its recent identification [14,25-29].

The aim was to better understand the burden of CDD on both patients and their family caregivers and identify unmet needs by analyzing the perspectives of family caregivers in an international cross-sectional survey.

This study included a descriptive, cross-sectional, web-based, self-administered survey completed by the caregivers of patients with CDD. The survey was designed and approved by a multidisciplinary steering committee of CDD specialists and caregivers.

Participants were recruited through CDD patient advocacy organizations, including CDKL5 UK (United Kingdom), CDKL5 Alliance Francophone (France), CDKL5 Deutschland (Germany), Asociacion de Afectados CDKL5 (Spain), CDKL5 Ireland, CDKL5 Italy, CDKL5 Alliance (World), Finnish Epilepsy Association (Finland), Svenska Epilepsiförbundet - Swedish association from the International Bureau for Epilepsy (IBE), and EpiCare-network (Europe), as well as through Carenity, a web-based community in which both patients and caregivers can share their experiences, provide support, and receive information. CDD caregivers were recruited via digital communication and invited by patient organizations via email to voluntarily complete an online survey about the burden of this disease and its impact on the quality of life of patients with CDD and their caregivers. Eligible participants included adult legal representatives or guardians (18 years or older at the time of inclusion) of individuals with genetically confirmed CDD. While the study initially targeted caregivers living in western parts of Europe, no respondents were excluded based on their country of residence. All participants provided electronic informed consent prior to participating in the survey.

The questionnaire consisted of 3 sections with a total of 40 questions: sociodemographic and medical characteristics (25 questions); quality of life, disease burden, and unmet needs (10 questions); and treatment and support received (5 questions) (Multimedia Appendix 1). There were various question formats, such as single- and multiple-choice questions, numerical questions, slider-scale questions, and open-ended questions, and there was an adapted version of the self-administered EQ-5D-5L instrument, developed by the EuroQol Research Foundation to measure patients’ health-related quality of life [30,31]. The estimated completion time for the survey was 25 minutes, and the average completion time was 24.5 minutes.

The EQ-5D-5L proxy version 1 questionnaire was modified for caregivers to describe patients’ health state. The adapted version was validated by EuroQol [31]. Using a 5-level scale (no problems, slight problems, moderate problems, severe problems, and extreme problems), caregivers reported the severity of issues patients faced across 5 dimensions: mobility, self-care, everyday activities, pain/discomfort, and anxiety/depression. These levels are combined to obtain a single index value, reflecting the preferences of the general population in the caregiver’s country, with each dimension weighted accordingly (Multimedia Appendix 2) [32,33]. Additionally, using a visual analog scale (VAS), caregivers rated the patient’s health on the day the questionnaire was completed, ranging from 0 (worst health imaginable) to 100 (best health imaginable).

The impacts of CDD on the caregiver’s family, social, and work life; financial resources; quality of sleep; level of stress; and general quality of life were self-rated using a slider scale, with responses ranging from “no impact at all” (value=0) to “very high impact” (value=10).

The data collection occurred from May 25, 2023, to December 31, 2023.

Data management and analysis were performed using R (version 4.1.2; R Core Team).

A comprehensive quality check was performed prior to analysis on fully completed questionnaires in order to exclude respondents with inconsistent answers (eg, conflicting responses between similar questions, unrealistic values in numerical fields, or incoherent open-ended responses), response times shorter than the calculated minimum for the shortest completion path (2.6 minutes or less than 5 seconds per question), and suspected duplicate entries.

We conducted descriptive analyses to characterize our study population and summarize responses to the survey. The data have been presented as median and IQR or frequency and percentage values as appropriate. Responses to open-ended questions were translated into English when necessary and manually analyzed to identify categories and subcategories. Where relevant, subgroup analyses were conducted based on caregivers’ sociodemographic characteristics and patients’ medical characteristics.

This study was conducted in accordance with the current version of the Declaration of Helsinki, the ICH Good Epidemiological Practice guidelines, any local regulations, and the General Data Protection Regulation (GDPR). The study did not undergo an ethical review as it was considered as “a satisfaction survey” with a focus to better understand the impact of a disease (CDD) on patients and caregivers [34].

All patients provided electronic informed consent (translated to the language of the questionnaire) before any patient data collection. Participation was voluntary, and participants received no incentives to participate in the study.

Of 245 participants who started the survey, 132 (53.9% response rate) completed a valid questionnaire (Figure 1). Most participants were from Europe (106/132, 80.3%), more specifically western Europe (France and Benelux; 32/132, 24.2%), southern Europe (Spain, Italy, and Portugal; 30/132, 22.7%), central Europe (Germany, Austria, and Switzerland; 21/132, 15.9%), and northern Europe (United Kingdom, Ireland, and Sweden; 20/132, 15.2%). A few responses were gathered from eastern Europe (Poland, Slovakia, and Montenegro; 4/132, 3.0%). Respondents outside Europe (26/132, 19.7%) were from Latin America (Argentina, Bolivia, Chile, Colombia, Peru, Mexico, and Uruguay; 15/132, 11.4%), Turkey (8/132, 6.1%), Australia (2/132, 1.5%), and the United States (1/132, 0.8%).

When completing the adapted version of the EQ-5D-5L, most of the caregivers declared that patients’ mobility (88/132, 66.7%), self-care (120/132, 90.9%), and everyday activities (103/132, 78.0%) were severely affected by CDD (level 5 “extreme problems/unable to do”) on the day of completion (Figure 6). For most of the patients, there was little to no pain or discomfort (77/132, 58.3%) and depression or anxiety (97/132, 73.5%) reported that day.

Caregivers mentioned consistent levels of severity for mobility, pain or discomfort, and depression or anxiety across all countries, but more European caregivers reported that patients with CDD were not able to wash or dress themselves (99/106, 93.4%) or perform usual activities (86/106, 81.1%) that day compared to non-European caregivers (21/26, 81% and 17/26, 65%, respectively) (Figure S7 in Multimedia Appendix 3).

Overall, severity appeared to be similar across most age groups, with the exception of mobility, which seemed to be less affected among older patients in this study. Among patients aged ≥18 years, only 35% (7/20) had a rating of level 5, indicating “extreme problems/unable to do” compared to 65% (15/23) of patients aged 10-17 years, 74% (29/39) of patients aged 5-9 years, and 76% (37/49) of patients aged <5 years.

The survey population showed a notably low health-related quality of life for patients with CDD, with an overall median EQ-5D-5L index value of 0.18 (IQR 0.11-0.32) on a scale ranging from 0 (a state comparable to being dead) to 1 (representing full health). The VAS results were different, with an overall median score of 56 out of 100 (IQR 39.0-71.0), suggesting a neutral stance on the health status of patients.

Median index values were slightly higher for patients aged <5 years (0.21, IQR 0.13-0.31) and patients aged ≥18 years (0.25, IQR 0.16-0.36) that for patients aged 5-17 years (patients aged 5-9 years: 0.13, IQR –0.09 to 0.27; patients aged 10-17 years: 0.17, IQR 0.08-0.35). Patients aged <10 years had lower VAS scores (patients aged <5 years: 52/100, IQR 35.0-75.0; patients aged 5-9 years: 50/100, IQR 39.0-62.5) compared to older patients (patients aged 10-17 years: 59/100, IQR 41.5-70.5), and patients aged ≥18 years had the highest median score (70/100, IQR 50.5-80.25), indicating a better health status as perceived by family caregivers.

In this study, we found that the perceived burden of CDD was substantial for patients and their caregivers. Using a tailored version of the EQ-5D-5L for this condition for the first time, we were able to better assess patients’ health-related quality of life. Caregiver burden was also reported to be significant, with CDD affecting multiple life aspects. Unmet needs were identified and appeared to be population-dependent, as variations between age groups and world regions were observed.

As previously reported for CDD, patients in this study had an early onset of seizures (median of 2.0 months), and most experienced daily seizures (66%), often of multiple types [4,9,14,27]. Variations regarding the proportion of patients experiencing different types of seizures, especially absence seizures, can be observed between this work and previous ones [14]. Identification of seizure types can be challenging for caregivers, as CDD seizures can present mixed motor and sometimes nonmotor features [14]. It is notably possible for caregivers to mistake epileptic spasms for hypermotor-tonic-spasm sequence seizures. Symptom load was high, with 57% of caregivers reporting eight or more symptoms. Over two-thirds of patients were hospitalized for CDD-related symptoms over the past year, and the proportion of hospitalized patients increased with the frequency of seizures. This aligns with previous findings that most hospitalizations of patients with CDD are related to seizures [29]. Almost all patients with seizures were on one or more ASMs (97%), and 82% of them discontinued at least one ASM. In previous work, the number of seizure-related hospital admissions increased with the number of ASMs used during the lifetime of patients [29]. All these findings may be an indication of the refractoriness of seizures, which is characteristic of CDD epilepsy [6,9,18,23,35].

The steady decline in caregiver satisfaction with the effectiveness of treatments in reducing seizures as time passed could be a further indication of potential treatment fatigue or habituation. Dissatisfaction with side effects, which usually consist of increased fatigue, irritability, and behavior disturbance, was also reported [18]. Polypharmacy, which was common in our study population, was previously associated with a higher likelihood of experiencing side effects and a lower quality of life for patients [18,28]. A ketogenic diet previously showed promising results for a short-term decrease in seizure frequency but poor long-term efficacy, which might explain the decrease in patients treated with this approach as they age [24].

The EQ-5D-5L is a standardized instrument used to quantitatively measure health-related quality of life, and it involves questions on health status [30,36]. In this study, most caregivers reported the highest severity in 3 out of the 5 dimensions measured: mobility, self-care, and everyday activities. Moreover, index values were low, with a median of 0.18, and were even negative for 17 respondents, indicating a perceived health state worse than death. This is consistent with previous research indicating that children with intellectual disabilities had lower EQ-5D scores than other populations [37]. Overall, these findings highlight the poor health-related quality of life of patients with CDD as perceived by their caregivers. The findings align with previous work using the Quality of Life Inventory Disability (QI-Disability), an instrument developed for children and adolescents with intellectual disability, which showed an association between more limited functional abilities and a poorer quality of life in patients with CDD [28,38]. These results provide some baseline data for comparison when using EQ-5D-5L as a standardized method for quantitatively assessing health-related quality of life in patients of all ages, enabling the analysis of various conditions and contributing factors. Furthermore, it may serve as a valuable complement to the QI-Disability scores in studies involving children and adolescents with CDD.

Family caregiver burden was reported as substantial in several aspects, both in this study and in previous work [25,26]. Most caregivers (64%) reported that their employment status was impacted by CDD. CDD care involved a wide range of health care professionals and was demanding and time-consuming, with the majority of patients requiring at least one appointment per week. Caregivers whose employment was impacted by CDD reported attending more appointments compared to those whose employment was not affected, highlighting the time-intensive nature of multidisciplinary care. Additionally, these caregivers faced greater financial challenges in covering costs related to the disease. This is a crucial issue, as a previous study has shown that financial strain is closely linked to a decline in parental well-being for CDD caregivers, emphasizing the importance of financial support for families [25].

Overall, caregivers reported substantial impacts of CDD on their family, social, and professional lives, as well as on their quality of sleep and stress levels. The burden of seizures was particularly significant for caregivers, with 73% identifying seizures as one of the most challenging symptoms to manage and reporting a greater impact on their own quality of life. This is consistent with findings that epilepsy, even in the absence of CDD or developmental delay, is associated with poorer family functioning [39].

These burdens and resulting unmet needs should be considered in the context of the profiles of both caregivers and patients, as noticeable differences were highlighted between world regions and age groups.

Caregivers outside Europe seemed to have more difficulties with access to resources and support, with only 19% of them reporting having access to a specialized CDD center compared to 51% of European respondents. Delay between the first seizure and diagnosis was also longer outside Europe than in Europe (26.5 months vs 11 months). This difference may be attributed to several factors, including varying levels of awareness of CDD, access to specialized medical centers, and the availability or reimbursement of genetic testing across different countries. CDD care varied by geographic location, with differences in the types of health care professionals consulted between European countries and countries outside Europe. The proportion of patients on ASMs and a ketogenic diet were similar across world regions. VNS was however reported exclusively among patients living in central, western, northern, and eastern Europe and was not reported among patients living outside Europe or in southern Europe. Major disparities in the availability of resources for neurological disorders exist across countries, with low-income countries being most severely disadvantaged [40]. These disparities could impact the level of care available for patients with CDD, potentially adversely impacting their quality of life [28].

Financial strain was also more severe for caregivers outside Europe, with a median rating of CDD impact on financial resources of 10 out of 10 compared to 6 out of 10 for European caregivers. Non-European caregivers reported greater difficulties in covering out-of-pocket fees related to medical treatments, medical appointments, or work-up evaluations, which were less frequently reported by Europeans. This may further highlight differences in health care systems and may suggest that European families benefit from better coverage and financial support, reducing the financial burden of CDD compared to families in other countries. Caregivers outside Europe were also more impacted in their professional life. All these difficulties had an impact on their quality of life, as caregivers outside Europe had higher median ratings of CDD impact on stress levels, social life, and general quality of life. All these findings are aligned with previous ones regarding the impacts of a family’s residential location and especially the presence of universal health care on financial well-being, which is often closely linked to overall well-being [25,41].

Many CDD symptoms are age-dependent [7,10,14]. In our survey, patients aged 5-9 years exhibited a higher number of symptoms, had more varied and frequent seizures, and were on more medications. This may be due to the course of the disease or individual variability, or because symptoms become more detectable by parents from the age of 5 years [10]. These patients also had poorer functional ability, as reflected by their EQ-5D-5L index values and VAS results. Adult patients in this study were reported to be notably less severely affected than children, exhibiting less frequent seizures, reduced visual impairment, and fewer walking difficulties. Moreover, they were reported to receive less comprehensive care, with fewer appointments and fewer different types of health care professionals involved. This suggests that the transition to adult care may pose challenges for patients with CDD, resulting in poorer care. Further evidence would be needed to better understand the biological and nonbiological factors that could impact the life and care of adult patients, as well as the rationale behind them being reported to be less affected than younger patients.

This highlights the need for an evolving, age-specific multidisciplinary care approach, as supported by previous work by Amin et al [3]. Finally, the age at diagnosis was reported to be higher for older patients, which may be explained by the relatively recent discovery of the disease in 2004 and the growing accessibility of genetic testing [2,14]. At present, patients are diagnosed at a younger age, and this trend is expected to continue, with the age at diagnosis anticipated to decrease and stabilize in the coming years.

This study is one of the few studies illustrating the burden and impact of CDD on patients and caregivers with 132 respondents, mainly from western parts of Europe, Latin America, and Turkey. Clinical features of patients reported by caregivers were consistent with the epidemiological and clinical characteristics reported in the literature, including female predominance, early onset of seizures, impaired development, limited communication and gross motor skills, high seizure frequency, and multiple seizure types [5,10,14,42,43]. Treatments reported aligned with those commonly described in the literature [18,23,24]. Despite self-reporting by caregivers, the consistency of reported medical data with the literature verifies the representativeness of our study’s sample.

To measure health-related quality of life, we used an adapted and validated version of a standardized tool, the EQ-5D-5L, as described in the methods. This tool has been used in several studies and demonstrated excellent psychometric properties across a broad range of populations [44]. However, dimension scores for conditions associated with intellectual disability are usually much lower than for other chronic health conditions but map to other measures of the dimension (eg, mobility and self-care), highlighting that scores reflect relevant impairments and functions [28,36,37]. Different value sets were used to obtain the EQ-5D-5L index values of countries, complicating cross-country comparisons, as differences may result from the value sets rather than from the respondents’ answers [45] (Multimedia Appendix 2).

In this study, comparisons between European respondents (n=106) and those from outside Europe (n=26; mostly from Southern America and Turkey) were unbalanced, with a higher number of participants from Europe and especially from Western Europe. Patients’ medical characteristics varied between countries, and these disparities may have influenced the cross-country analysis, limiting the generalizability of the results. Participation in the survey was voluntary, with most participants recruited via support organizations and the Carenity platform. This may have led to an overrepresentation of caregivers for patients with severe symptoms, while isolated caregivers or those without internet access were underrepresented. This also may have impacted the geographic distribution of the respondents, as they were recruited from locations where active support organizations exist. Additionally, women and younger adults are often overrepresented in online communities, potentially influencing the sample composition [46].

If a respondent stopped and closed the questionnaire during completion, it was technically not possible for them to resume where they left off and they had to start over. This limitation may have contributed to a reduction in the number of fully completed and analyzable surveys.

The same team member conducted both the quality check and analysis, which may have introduced slight bias. However, another analyst, independent of the project, reviewed both the quality check and analysis results.

Our findings highlight the critical need for new effective ASMs as part of CDD treatment, benefiting not only patients but also their families, whose well-being is closely tied to the management of the condition. The use of a tailored version of the EQ-5D-5L to quantify health status in this survey generated values that could potentially serve as reference points for future studies to evaluate the impact of treatments, other therapies, practices, or other factors. As the EQ-5D-5L is a measure of health-related quality of life and is therefore influenced by impairments, it could benefit from being complemented by a measure of quality of life such as the QI-Disability score.

Solutions regarding support and access to resources must be adjusted depending on the family location, as considerable geographical discrepancies exist. The care provided for patients with CDD should evolve as they age, be multidisciplinary, and be adapted to the clinical features exhibited by the patient, as significant individual variations exist for this disorder [10].

Our results reveal the significant burden of CDD on both patients and caregivers, affecting caregivers’ quality of life, including financial resources, sleep, stress levels, and professional and social aspects. Seizures in particular have a profound impact on caregivers’ quality of life, underscoring the need to develop efficient and long-lasting ASMs. Furthermore, the study highlights geographical discrepancies regarding access to specialized medical centers, diagnosis delays, health-related cost coverage, and financial resources. These findings suggest that disease management and support should be tailored to the specific needs and health care systems of each region.

For the first time, the health-related quality of life of patients with CDD was measured by caregivers using a tailored version of the standardized and validated EQ-5D-5L tool, which provides a valuable baseline for future research.

The observed differences between age groups emphasize the need for multidisciplinary care for all patients, including adult patients with CDD, who appear to receive less comprehensive care. Further research is needed on caregivers outside Europe, children aged 5-9 years, and adult patients.