Top caregiver concerns in classic RTT

The top 5 weighted concerns reported by caregivers for people with classic RTT (Fig. 1) are (1) lack of effective communication; (2) seizures; (3) lack of hand use; (4) abnormal walking/balance; and (5) constipation. Notably, these top 5 weighted concerns were identified as one of the top 3 listed concerns (meaning the caregiver selected the concern as either the 1st, 2nd, or 3rd concern) by > 25% of caregivers (communication 60.2%; seizures 27.9%; hand use 27.8%; walking balance 25.6%; constipation 25.3%), whereas the subsequent top weighted concerns were identified by < 17% of caregivers as one of the top 3 listed concerns. Figure 1 displays the weighted concerns whose 95% CI are above zero on the left, with the pairwise differences between concerns shown on the right. The concerns can be placed into “groups” of concerns that are not statistically different from each other but different from other concern groups. Lack of effective communication (communication) stands out as significantly different than all other concerns and is considered group 1 (dark green in Fig. 1). Group 2 (seizures, hand use, walking/balance, and constipation, light green in Fig. 1), represents important caregiver concerns with percentages ranging from 7.5 to 10.5%, and different from subsequent groups. Group 3 contains concerns meaningful in classic RTT (repetitive hand movements, sleep problems, breathing abnormalities, etc.) with percentages ranging from ~ 3 to 5% (yellow in Fig. 1). Group 4 consists of concerns with percentages between 2 and 2.5%, and group 5 represents concerns that overall are relatively low frequency in classic RTT (~ 1%, white in Fig. 1). Overall, the top 3 groups of caregiver concerns likely represent the most relevant concerns in classic RTT (overall frequency between ~ 3% and 25%) and align well with known clinical problems observed in RTT [3].

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)

Variation in top caregiver concerns in classic RTT between age groups

While assessment of the weighted caregiver concerns across all participants with classic RTT identified the most relevant issues in classic RTT, there was variation in top caregiver concerns in different age groups, especially those concerns identified with frequency above 2.5% (groups 1–3) in the overall classic RTT cohort (Fig. 2). Effective communication remained a high-level concern across all age groups; however, within the oldest age group, concern about ambulation became more frequent. Seizures, the second-most overall concern across the classic RTT group (with a percentage of 10.5%), was a minor concern under age 5 (1.6–1.9%), climbed in frequency after 5 years old, peaked in the 15–20-year-old group, and declined in the over 20 years old age bins while remaining a high-level concern (> 8%). This pattern of caregiver concern is consistent with clinical observation of the peak period of seizure onset and severity [35]. Lack of hand use was a frequent concern across all age groups but declined in frequency with age despite the lack of notable improvement in hand function in older age groups [36]. Caregiver concern about constipation, a common problem [37], generally increased in importance with age, especially in the older age groups. Repetitive hand movements [36] were a frequent concern throughout most of the age groups, with a peak during the first 5 years, but declined to lower frequency (< 2.5%) between 15 and 25 years old with a subsequent progressive increase in older age groups. Rapid breathing or breathholding was non-existent as a concern until age 3, increased through age 15 and then declined to non-existent in the oldest group, following expected trends observed for the incidence of breathing abnormalities [38]. Similarly, air swallowing/bloating only became a major concern after 5 years old. Concern about scoliosis remained low in younger ages, peaked in the 10–15-year-old group, and then declined, consistent with the timing of marked progression of scoliosis in classic RTT [5]. Notably, concerns that in the overall group fell into the ~ 2% range (group 4 in Fig. 1), such as anxiety, teeth grinding, and gastroesophageal reflux, increased in frequency of concern in various age groups; however, they remained below 5% throughout the age groups. Thus, while the overall caregiver concerns for classic RTT from the entire cohort are useful, especially the high-frequency caregiver concern groups (groups 1–3), consideration for the age-related differences in the relative frequency of caregiver concerns is important.

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

Caregiver concerns in classic RTT based on MECP2 mutation

Based on known genotype–phenotype relationships [6, 7], we compared variation in caregiver concerns for Classic RTT across the common, recurrent MECP2 mutations (R168X, R255X, R270X, R106W, T158M, R133C, R294X, R306C) as well as mutation groupings that cause similar molecular disruption of the MECP2 gene (early truncations, large deletions, C-terminal truncations [CTT]) compared to the combined caregiver concerns for people with Classic RTT (Fig. 3). The top 5 concerns (groups 1–2 in Fig. 1) remained frequent concerns (> 3%) across the mutation groups. Within the overall group 3 concerns (2.5–5%), some notable changes were observed, with repetitive hand movements dropping significantly in R924X, air swallowing dropping in R270X and CTT, screaming episodes dropping in R270X and R294X, and scoliosis dropping in R106W and R294X. In contrast, some of the caregiver concerns identified in the lower range within the overall Classic RTT cohort (between 1 and 2.5%), were increased in frequency within specific mutation groups. For example, behavioral problems such as anxiety and self-abusive behaviors were more frequently raised as caregiver concerns in milder mutations such as R133C, R294X, and R306C, concordant with the clinically observed increased rates of behavioral problems in less severely affected individuals with classic RTT [39], whereas frequent infections were more common concerns in severe mutations such as large deletions and R106W.

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

Caregiver concerns in classic RTT vary by clinical severity

To assess whether caregiver concerns varied by clinical severity, we evaluated top caregiver concerns in different severity groups as determined by clinician-assessed severity using the Clinical Global Impression–Severity (CGI-S) and RTT Clinical Severity Score (CSS). Within the severity categories defined by the CGI-S, lack of effective communication remained the top concerns across all severity groups (Fig. 4). Within the group 2 concerns (seizures, hand use, walking/balance, and constipation), it is notable that seizures and constipation were low-frequency concerns in the mildest severity group (CGI-S = 3), but became progressively higher frequency concerns with increasing severity. Lack of hand use was a constant high-frequency concern throughout most of the severity range (CGI-S = 3–6), but unexpectedly dropped to only 2.5% in the most impaired group (CGI-S = 7), despite the fact that people within this severity group have the most overall impaired hand function. Abnormal walking/balance issues were a high-frequency concern across the severity range, with a peak in the markedly impaired group (CGI-S = 5) and decline in the more severely affected groups (CGI-S = 6–7). Concern about repetitive hand movements was greatest in the mildest severity groups (CGI-S = 3–4) and declined in the more severely affected groups (CGI-S = 5–7). In contrast, rapid breathing or breath holding and Air swallowing/bloating were more frequent in the middle severity groups (CGI-S = 4–6), which represent the bulk of people with classic RTT, and lower in the mildest (CGI-S = 3) and most severe (CGI-S = 7) groups. Behavioral features (screaming episodes, anxiety, self-abusive behaviors, aggressiveness) and bruxism concerns were increased in the mildest group (CGI-S = 3), but were very low in the most severe group (CGI-S = 7), consistent with the observation that behavioral issues are more prominent in less severely affected individuals [39]. On the other hand, concerns such as scoliosis, gastroesophageal reflux, poor weight gain, and frequent infections were low-frequency concerns in the milder severity groups (CGI-S = 3–4), but were meaningful concerns (percentage > 2.5%) in more severely affected groups (CGI-S = 6–7).

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

The comparison of caregiver concerns with severity assessed using the CSS broadly showed similar results as with severity assessed with the CGI-S, but there are some notable differences (Fig. 5). Effective communication remained a high-frequency concern across all CSS groups; however, the percentage in the mildest group (CSS 6–10) was double that for the overall classic RTT cohort (49.7% vs 24.8%) and in the most severe group (CSS > 40), the percentage of Communication concern dropped to 16.5%, below that for seizures in this group. Concern about seizures showed the same pattern in CSS severity groups as in CGI-S groups, with seizures not being a concern in the mildest group (CSS 6–10), but progressively became more frequent with increasing CSS severity. Similarly, concern about walking/balance was highest in the middle CSS severity groups (CSS 16–30), low in the mildest (CSS 6–10), and non-existent in the most severe (CSS > 40), consistent with the pattern observed in the CGI-S severity groups. Repetitive hand movement concerns also showed the same pattern in the CSS severity groups as observed in CGI-S severity groups, being most prominent in the less severe CSS groups and dropping in the most severe CSS groups (CSS 36–40 and CSS > 40). In contrast, the decline in concern for Hand Use in the most severe CGI-S group was not observed in the CSS severity groups, with the frequency of concern related to hand use remaining high in the most severe CSS group (CSS > 40). While behavioral concerns such as screaming episodes, anxiety, and aggressiveness were high in mild CSS severity groups and low in the most severe CSS severity groups, unexpectedly concern for self-abusive behaviors was low in all CSS severity groups except the second most severe group (CSS 36–40). As seen in the analysis based on CGI-S severity, medical concerns such as scoliosis, frequent infections, and genitourinary (GU) issues increased with CSS severity.

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

Comparison of caregiver concerns to assessments of clinical features

To evaluate the relationship of the First Caregiver Concern (not weighted) for an individual to clinical features, we compared the First (number 1) listed caregiver concern to individual CSS item scores related to language, seizures, and hand use. Overall, 35.3% (n = 226) caregivers reported effective communication (communication) as the First Concern, 12.6% (n = 81) listed Seizures as the First Caregiver Concern, and 5.5% (n = 35) listed lack of hand use (hand use) as the First Caregiver Concern (Table 4). Within each of these three First Caregiver Concerns, we calculated the number (and percentage) that were given CSS scores on the CSS items Language, Seizure, and Hand Use (Table 4).

Table 4 Comparison of individual CSS item scores to number one caregiver concern

When communication was indicated as the First Caregiver Concern, a large percentage of participants had a CSS Language score = 3 (vocalization, babbling), but the percentage dropped at the most severe CSS Language score = 4 (screaming, no utterances). However, this pattern was also observed in the CSS Language score distribution when hand use was indicated as the First Caregiver Concern. In contrast, when the First Caregiver Concern was seizures, a similar percentage of participants had CSS Language scores of 3 or 4. Interestingly, the percentage of participants with more preserved language function (CSS Language scores of 0, 1, or 2) in the group with the First Caregiver Concern was 12.4%, compared to 0% in the group that indicated hand use as the First Caregiver Concern, suggesting that communication is a larger concern for caregivers when their child has more language skills.

A similar pattern is observed when the First Caregiver Concern was Hand use, with a large percentage of participants having a CSS Hand Use score = 3 (acquired and lost), but a significant decline in the percentage of participants having a CSS Hand Use score = 4 (never acquired). Again, this pattern of change in the percentage of individuals in the two most severe CSS Hand Use was not unique to the group that had the First Caregiver Concern of Hand Use but was also present in the groups that had the First Caregiver Concern of Communication or Seizures. The percentage of participants with some level of hand function (CSS Hand Use scores of 0, 1, or 2) were similar when the First Caregiver Concern was hand use or communication (34.3% and 40.3% respectively), but interestingly was lower when the First Caregiver Concern was Seizures (20.9%).

The most dramatic difference between the First Caregiver Concern groups was observed in the percentage of participants who did not have seizures (CSS Seizure score = 0, absent). When the First Caregiver Concern was Communication or Hand Use, a large percentage of participants had a CSS Seizure score of 0 (55.8% and 65.7% respectively). In contrast, when the First Caregiver Concern was Seizures, only 1.2% had a CSS Seizure score of 0. Similarly, 46.9% of participants in the Seizures First Caregiver Concern group had severe CSS Seizure scores (CSS Seizure score of 4 or 5), whereas the percentage of participants with severe CSS Seizure scores was much lower in the communication (9.7%) or the hand use (5.8%) First Caregiver Concern group. Thus, the presence of seizures drives caregivers to list seizures as the First Concern, despite the overall poor skills in this group in language or hand use.

Caregiver concerns in atypical RTT

The top concerns for caregivers of individuals with Atypical RTT were generally similar to those reported in classic RTT, especially in the highest frequency concerns (Fig. 6), but some lower frequency concerns for classic RTT, such as rapid breathing or breath holding, Air swallowing/bloating, scoliosis, and anxiety were different between classic RTT and the entire atypical RTT group. However, atypical RTT is composed of individuals who are milder and more severely affected than classic RTT, as shown by the bimodal distribution of total CSS scores in atypical RTT, mild atypical RTT having a total CSS score < 18 and Severe Atypical RTT having a total CSS score > 18 [34]. The pattern of caregiver concerns is markedly different between these groups of Atypical RTT, with Mild Atypical RTT having a decreased frequency of Caregiver Concerns for a number of items such as seizures, rapid breathing/breath holding, and scoliosis, but increased frequency for behavioral issues such as anxiety and other behavioral issues. For people with severe atypical RTT, caregivers indicated increased concerns in areas such as seizures, abnormal movements, and GI issues (lack of effective chewing/swallowing, gastroesophageal reflux, poor weight gain).

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

Comparison of caregiver concerns between Classic RTT and RTT-related disorders

Top concerns were compared across RTT-related disorders including MDS, CDD, and FS (Fig. 6). Lack of effective communication remained the top-weighted concern for both MDS and FS, but for CDD seizures become the top-weighted concern, with more than 20% higher than for Classic RTT. This reiterates the known increase in overall seizure burden in people with CDD [22, 40]. Lack of hand use remained a frequent concern in CDD and FS but dropped markedly for MDS. In contrast, Walking/balance concerns increased in MDS. Caregivers did not endorse Repetitive hand movements as a frequent concern in FS. Some concerns in group 3 for classic RTT such as rapid breathing/breath holding, air swallowing/bloating, scoliosis, and screaming episodes were found at low frequency in MDS, CDD, and FS, whereas lack of effective/chewing had a higher frequency in MDS and FS than classic RTT. Other low-frequency concerns in classic RTT (~ 1%) were more frequently endorsed in other disorders, consistent with known issues in these disorders. For example, in MDS there was a higher frequency of caregiver concern for frequent infections, a noted problem in MDS [41,42,43], and in FS there is an increase in caregiver concern for abnormal movements [44]. Concerns about vision were present in people with CDD and FS, both of which have reported issues with cortical visual impairment [22, 45, 46].

Caregiver impression of change: reasons and top concern

At each visit, caregivers provided a global impression of whether they felt that their child had improved, worsened, or remained unchanged, to identify the main reason for their overall global impression for improvement or worsening. For all visits, a significant number of caregivers felt that there was no change for their child, although this varied across disorders (Table 5). The most frequent caregiver reason provided for improvement for all disorders (classic RTT, MDS, CDD, FS) was communication (Table 5), although variation was noted between the disorders. When caregivers reported improvement, the first listed top concern for classic RTT, MDS, and FS was lack of effective communication; however, for CDD Seizures was most frequent first concern (47%) with lack of effective communication still being a frequent first concern (33%). The top caregiver-reported reason for worsening in all disorders was seizures, ranging from 19% for classic RTT to 63% for CDD (Table 5). When caregivers reported worsening, the first listed caregiver concern for all disorders was seizures. The concern of lack of effective communication remained a high-frequency caregiver concern in classic RTT but dropped dramatically in the other disorders. Overall, the top caregiver reason for improvement was communication and for worsening was seizures. The number one (first listed) caregiver concern aligned with the caregiver impression of change, with the notable exceptions that when improvement was noted, caregivers of participants with CDD listed seizures as their first concern although identified communication as the reason for improvement, and when caregivers of participants with classic RTT felt their child was worse the frequency of first concern was very similar for seizures and lack of communication although the top reason for worsening was seizures.

Table 5 Caregiver impression of change