After applying all eligibility criteria, 455 females with RTT were included in the study, of whom 412 (90.5%) had classic RTT and 43 (9.5%) had atypical RTT. Three hundred and sixty-three individuals (79.8%) were pediatric, while 92 (20.2%) were adults.
Demographic and clinical characteristics of the study population are presented in Table 1. Mean (SD) age at first visit was 11.8 (9.5) years in the overall RTT cohort, 7.9 (4.7) years among pediatric individuals, and 27.1 (8.1) years among adult individuals. Mean (SD) age of motor and communication regression was 2.3 (0.8) years overall. Individuals primarily identified as White (87.0%) and nearly all had an MECP2 mutation (98.2%).
Table 1 Demographics and clinical characteristics among females with RTT, overall and stratified by RTT type and ageCommon clinical manifestations of RTT included loss of language (95.8%), hand stereotypies (92.3%), respiratory dysfunction (75.8%), sleep disturbances (75.6%), and constipation (74.5%). Clinical manifestations were more prevalent in individuals with classic RTT than atypical RTT (loss of language: 99.5% vs. 60.5%, p < 0.001; hand stereotypies: 94.4% vs. 72.1%, p < 0.001; respiratory dysfunction: 79.1% vs. 44.2%, p < 0.001; sleep disturbances: 77.2% vs. 60.5%, p = 0.015; respectively). At first visit, scoliosis (73.9% vs. 45.7%, p < 0.001), constipation (83.7% vs. 72.2%, p = 0.024), and epilepsy (56.5% vs. 43.5%, p = 0.026) were more prevalent in adult individuals than pediatric individuals, respectively. There were no significant differences in ability to sit, stand, or walk independently between individuals with classic RTT and atypical RTT (classic: 47.3–74.0%; atypical: 58.1–79.1%).
Use of pharmacological and supportive therapies during the follow-up periodOverall, the most used pharmacological therapies were prokinetic agents (39.8%) and antiepileptic drugs (32.3%) (Table 2). Compared with adult individuals, pediatric individuals were more likely to use prokinetic agents (42.7% vs. 28.3%, p = 0.011), antiepileptics (35.0% vs. 21.7%, p = 0.015), sedatives/hypnotics (27.8% vs. 15.2%, p = 0.013), and nutritional supplements (25.1% vs. 15.2%, p = 0.045) (Table 2). Use of pharmacological therapies was similar between individuals with classic RTT and individuals with atypical RTT (Table 2).
Table 2 Pharmacological therapies used among females with RTT, overall and stratified by RTT type and ageThe most common reason for discontinuing prokinetic agents and sedatives/hypnotics among individuals who discontinued treatment was that the therapy was no longer needed (63.0% and 44.0%, respectively) (Table 2). Among individuals who discontinued antiepileptic drugs, nearly half (48.8%) stopped use due to ineffective treatment (Table 2).
The most used supportive therapies were physical therapy (77.8%), speech-language therapy (74.1%), and occupational therapy (70.5%) (Fig. 1). Pediatric individuals were more likely than adult individuals to use physical therapy (87.3% vs. 40.2%, p < 0.001), speech-language therapy (86.8% vs. 23.9%, p < 0.001), and occupational therapy (82.1% vs. 25.0%, p < 0.001) (Supplementary Table 1). Use of supportive therapies was similar between individuals with classic RTT and atypical RTT (classic: 1.9–78.4%; atypical: 0.0–72.1%) (Supplementary Table 1).
Fig. 1Supportive therapies used among females with RTT, overall and stratified by RTT type and age
Abbreviation: RTT: Rett syndrome
RTT-related outcomes during the follow-up periodOver a median follow-up period of 4 years, nearly half (44.6%) of all individuals had a hospital or emergency room visit (Fig. 2), with a significantly higher proportion of visits observed in individuals with classic RTT than atypical RTT (47.1% vs. 20.9%, p = 0.001), and pediatric individuals than adult individuals (48.5% vs. 29.3%, p = 0.001) (Supplementary Table 2). Incident g-tube surgeries were observed among 13.7% of individuals, and pediatric individuals had a significantly higher incidence of g-tube surgery than adult individuals (16.7% vs. 2.7%, p = 0.002) (Supplementary Table 2). Mortality was rare (0.7%) in the overall RTT cohort, and all observed deaths were due to natural causes, with no specific cause documented (Fig. 2).
Fig. 2RTT-related outcomes among females with RTT, overall and stratified by RTT type and age1,2
Abbreviations: G-tube: gastrostomy tube; RTT: Rett syndrome. 1. Proportions of individuals with incident g-tube surgery were evaluated among individuals without a g-tube surgery prior to the first visit (overall cohort: N = 350; classic RTT: N = 314; atypical RTT: N = 36; pediatric: N = 275; adult: N = 75). 2. G-tube surgeries included endoscopic gastrostomy, gastrostomy with fundoplication, and gastrostomy without fundoplication
Change in CSS and MBA scores from first visit to year 2 of follow-upIn the overall RTT cohort, mean CSS score (first visit: 22.7; year 1: 22.0; year 2: 23.2) (Fig. 3) and mean MBA score (first visit: 46.7; year 1: 46.0; year 2: 48.5) (Fig. 4) remained largely unchanged from first visit to year 2 of follow up. Mean CSS scores were significantly higher for individuals with classic RTT than individuals with atypical RTT across all timepoints assessed (classic: 22.5‒23.8; atypical: 16.8‒17.2, all p < 0.05) (Supplementary Table 3); a similar pattern was observed for mean MBA scores (classic: 47.2‒49.7; atypical: 34.9‒36.5, all p < 0.05) (Supplementary Table 4). Mean CSS score was significantly higher for adult individuals than pediatric individuals at year 1 of follow-up (adult: 26.6; pediatric: 21.7, p = 0.031) (Supplementary Table 3), while mean MBA scores were significantly higher for adult individuals than pediatric individuals at first visit (adult: 50.5; pediatric: 45.8, p = 0.009) and year 1 of follow-up (adult: 53.3; pediatric: 45.6, p = 0.046) (Supplementary Table 4).
Fig. 3Trends in CSS score among females with RTT, overall and stratified by RTT type and age
Abbreviations: CSS: Clinical Severity Scale; RTT: Rett syndrome. Note: 1. CSS score per year was calculated only among individuals with an available CSS measurement in the respective year
Fig. 4Trends in MBA score among females with RTT, overall and stratified by RTT type and age
Abbreviations: MBA: Motor Behavioral Assessment; RTT: Rett syndrome. Note: 1. MBA score per year was calculated only among individuals with an available MBA measurement in the respective year
There were no meaningful changes in clinical severity per year in the overall RTT cohort (mean change per year: 0.11; 95% CI: -0.08, 0.30), adult individuals (mean change per year: -0.39; 95% CI: -0.83, 0.05), individuals with classic RTT (mean change per year: 0.12; 95% CI: -0.07, 0.31), or individuals with atypical RTT (mean change per year: 0.00; 95% CI: -0.70, 0.69) (Table 3). Conversely, an increasing trend in clinical severity per year was observed in pediatric individuals (mean change per year: 0.24; 95% CI: 0.03, 0.44) (Table 3).
Table 3 Annual change in CSS and MBA scores among females with RTT, overall and stratified by RTT type and ageAn increasing trend in motor-behavioral dysfunction (as evaluated using the MBA scale) per year was observed in the overall RTT cohort (mean change per year: 0.92; 95% CI: 0.50, 1.35), pediatric individuals (mean change per year: 1.12; 95% CI: 0.63, 1.60), and individuals with classic RTT (mean change per year: 0.97; 95% CI: 0.53, 1.41) (Table 3). No meaningful changes in motor-behavioral dysfunction per year were observed in adult individuals (mean change per year: 0.17; 95% CI: -0.61, 0.94) or individuals with atypical RTT (mean change per year: 0.34; 95% CI: -1.06, 1.75) (Table 3).
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