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. 2023 Oct 13;15(1):33.
doi: 10.1186/s11689-023-09502-z.

Top caregiver concerns in Rett syndrome and related disorders: data from the US natural history study

Jeffrey L Neul  1 , Timothy A Benke  2 , Eric D Marsh  3 , Bernhard Suter  4 , Lori Silveira  2 , Cary Fu  5 , Sarika U Peters  5 , Alan K Percy  6 ; Rett syndrome Natural History Study Group
Collaborators, Affiliations

Top caregiver concerns in Rett syndrome and related disorders: data from the US natural history study

Jeffrey L Neul et al. J Neurodev Disord. .

Abstract

Objective: Recent advances in the understanding of neurodevelopmental disorders such as Rett syndrome (RTT) have enabled the discovery of novel therapeutic approaches that require formal clinical evaluation of efficacy. Clinical trial success depends on outcome measures that assess clinical features that are most impactful for affected individuals. To determine the top concerns in RTT and RTT-related disorders we asked caregivers to list the top caregiver concerns to guide the development and selection of appropriate clinical trial outcome measures for these disorders.

Methods: Caregivers of participants enrolled in the US Natural History Study of RTT and RTT-related disorders (n = 925) were asked to identify the top 3 concerning problems impacting the affected participant. We generated a weighted list of top caregiver concerns for each of the diagnostic categories and compared results between the disorders. Further, for classic RTT, caregiver concerns were analyzed by age, clinical severity, and common RTT-causing mutations in MECP2.

Results: The top caregiver concerns for classic RTT were effective communication, seizures, walking/balance issues, lack of hand use, and constipation. The frequency of the top caregiver concerns for classic RTT varied by age, clinical severity, and specific mutations, consistent with known variation in the frequency of clinical features across these domains. Caregivers of participants with increased seizure severity often ranked seizures as the first concern, whereas caregivers of participants without active seizures often ranked hand use or communication as the top concern. Comparison across disorders found commonalities in the top caregiver concerns between classic RTT, atypical RTT, MECP2 duplication syndrome, CDKL5 deficiency disorder, and FOXG1 syndrome; however, distinct differences in caregiver concerns between these disorders are consistent with the relative prevalence and impact of specific clinical features.

Conclusion: The top caregiver concerns for individuals with RTT and RTT-related disorders reflect the impact of the primary clinical symptoms of these disorders. This work is critical in the development of meaningful therapies, as optimal therapy should address these concerns. Further, outcome measures to be utilized in clinical trials should assess these clinical issues identified as most concerning by caregivers.

Trial registration: ClinicalTrials.gov NCT02738281.

Keywords: CDKL5; Caregiver concerns; FOXG1; MECP2 duplication; Neurodevelopmental disorders; Rett syndrome.

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Conflict of interest statement

JLN received research funding from the National Institutes of Health, the International Rett Syndrome Foundation, and Rett Syndrome Research Trust; clinical trials with Acadia Pharmaceuticals Inc., GW Pharmaceuticals; personal consultancy for Acadia Pharmaceuticals Inc., Analysis Group, AveXis, GW Pharmaceuticals, Hoffmann-La Roche, Myrtelle, Neurogene, Newron Pharmaceuticals, Signant Health, Taysha Gene Therapies, and the preparation of CME activities for PeerView Institute, MedEdicus, and Medscape; serves on the scientific advisory board of Alcyone Lifesciences; is a scientific cofounder of LizarBio Therapeutics; and was a member of a data safety monitoring board for clinical trials conducted by Ovid Therapeutics.

TAB received research funding from GRIN2B Foundation, International Rett Syndrome Foundation, the International Foundation for CDKL5 Research, Loulou Foundation, the National Institutes of Health, and Simons Foundation; consultancy for Alcyone, AveXis, GRIN Therapeutics, GW Pharmaceuticals, the International Rett Syndrome Foundation, Marinus Pharmaceuticals, Neurogene, Ovid Therapeutics, and Takeda Pharmaceutical Company Limited; clinical trials with Acadia Pharmaceuticals Inc., GW Pharmaceuticals, Marinus Pharmaceuticals, Ovid Therapeutics, and Rett Syndrome Research Trust; all remuneration has been made to his department.

EDM received research support from the National Institutes of Health, Penn Orphan Disease Center, the International Rett Syndrome Foundation, Rett Syndrome Research Trust, International CDKL5 Research Foundation, and the Loulou Foundation. He has been a site principal investigator for trials from Stoke Therapeutics, Zogenix, Acadia Pharmaceuticals Inc., Takeda Pharmaceuticals, Epygenix Pharmaceuticals, and Marinus Pharmaceuticals. He has received personal compensation for consulting from Acadia Pharmaceuticals Inc. and the preparation of CME activities for Medscape.

BS has been a site investigator for clinical trials with Acadia, Marinus, and Newron; consultancy for Neurogene and Taysha; all remuneration has been paid to his department.

LS declares no competing interests.

CF has been a site investigator for clinical trials with Acadia.

SUP received research funding from the National Institutes of Health, the MECP2 Duplication Foundation, and the ActiGraph Corporation.

AKP received research funding from the National Institutes of Health, International Rett Syndrome Foundation, Rett Syndrome Research Trust; clinical trials with Acadia Pharmaceuticals Inc. and Anavex Life Sciences Corp.; and personal consultancy for Acadia Pharmaceuticals Inc. and Anavex Life Sciences Corp.

Figures

Fig. 1
Fig. 1
Weighted top caregiver concerns for classic RTT. The percentage of each weighted top caregiver concern is presented on the left with 95% CI, with groupings shaded as described in the text. The right side of the figure shows significant differences between weighted concerns as shaded cells (dark gray, p < 0.05; light gray p < 0.10)
Fig. 2
Fig. 2
Weighted top caregiver concerns for classic RTT vary by age. Top weighted concerns are listed on the left, with the order presented representing the rank order for all people with Classic RTT. Age bins are shown in subsequent columns. The heatmap color shows the highest ranked concerns as dark green (as in group 1 in Fig. 1), with intermediate ranked concerns as light green (as in group 2 in Fig. 2), and lower frequency concerns as yellow (as in group 3 in Fig. 1, with a lower cutoff of 2.5%). Concerns with weighted rank percentages below 2.5% are in white. Concerns are included only if at least one cell for concern had a percentage above 2.5% within any of the age bins. Abbreviations: GI = gastrointestinal
Fig. 3
Fig. 3
Weighted top caregiver concerns for classic RTT across MECP2 genotypes. Top weighted concerns are listed on the left, with the order presented representing the rank order for all people with classic RTT. MECP2 mutation groups are shown in subsequent columns, arranged with more severe mutations on the left. Abbreviations: EarlyTrunc = Early Truncations; LgDel = Large Deletions; CTT = C-terminal truncations. Heatmap color, concern presentation (> 2.5% in at least one cell), and other abbreviations are as in Fig. 2
Fig. 4
Fig. 4
Weighted top caregiver concerns for classic RTT across CGI-S scores. Top weighted concerns are listed on the left, with the order presented representing the rank order for all people with Classic RTT. CGI-S are shown in subsequent columns. Percentages of people in each CGI-S group are shown in the header. Heatmap color, concern presentation (> 2.5% in at least one cell), and abbreviations are as in Fig. 2
Fig. 5
Fig. 5
Weighted top caregiver concerns for classic RTT across CSS scores. Top weighted concerns are listed on the left, with the order presented representing the rank order for all people with classic RTT. CSS are shown in subsequent columns, arranged in groups from least to most severe. Percentages of people in each CSS group are shown in the header. Heatmap color, concern presentation (> 2.5% in at least one cell), and abbreviations are as in Fig. 2, with additional abbreviation: GU = Genitourinary
Fig. 6
Fig. 6
Weighted top caregiver concerns for atypical RTT, MDS, CDD, and FS. Top weighted concerns are listed on the left, with the order presented representing the rank order for all people with classic RTT. For atypical RTT, total results for all people with atypical RTT are shown, as well as those considered “mild” (CSS < 18) and those considered “severe” (CSS > 18). Heatmap color, concern presentation (> 2.5% in at least one cell), and abbreviations are as in Fig. 2
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