Clinical Features and Disease Progression in Older Individuals with Rett Syndrome
Abstract
:1. Introduction
2. Materials and Methods
2.1. Participants
2.2. Assessments
2.3. Statistical Analyses and Data Visualization
3. Results
3.1. Distributions of Mutations and Severity in under 30 yo vs. over 30 yo Cohorts
3.2. Differences in Clinical Features between under 30 yo vs. ≥30 yo Cohorts
3.3. Longitudinal Progression of Overall Severity in under 30 yo vs. ≥30 yo Cohorts
3.4. Longitudinal Progression of Clinical Features in under 30 yo vs. ≥30 yo Cohorts
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Classic RTT | Number |
---|---|
All Participants | 1253 |
Visits < 30 yo (all) | 1196 |
Only seen < 30 yo | 1143 |
Visits ≥ 30 yo (all) | 110 |
Baseline visits ≥ 30 yo | 56 |
Aged >30 yo during study | 52 |
Mutation | Age Group | n | CSS | MBA | Mutation Percentage | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Mean (SEM) | Change | p-Value | Mean (SEM) | Change | p-Value | Percentage | Change | p-Value | |||
All | <30 | 1195 | 24.5 (0.2) | 50.1 (0.4) | NA | NA | NA | ||||
≥30 yo | 110 | 24.5 (0.7) | 0 | 0.985 | 52.3 (1.2) | 2.2 | 0.100 | NA | NA | NA | |
R106W | <30 | 38 | 26.5 (1.1) | 53 (1.9) | 3.2 | ||||||
≥30 yo | 9 | 22 (2.3) | −4.5 | 0.080 | 50.8 (3.9) | −2.2 | 0.616 | 8.2 | 5.0 | 0.014 | |
R133C | <30 | 74 | 20.1 (0.8) | 46.8 (1.4) | 6.2 | ||||||
≥30 yo | 6 | 17.8 (2.8) | −2.3 | 0.433 | 42.8 (4.7) | −4 | 0.422 | 5.5 | −0.7 | 1.000 | |
R168X | <30 | 127 | 27.7 (0.6) | 52.9 (1.2) | 10.6 | ||||||
≥30 yo | 11 | 29.8 (2.1) | 2.1 | 0.335 | 59.5 (4.1) | 6.6 | 0.126 | 10.1 | −0.5 | 1.000 | |
T158M | <30 | 126 | 24.8 (0.7) | 50.5 (1.2) | 10.5 | ||||||
≥30 yo | 8 | 26.5 (2.6) | 1.7 | 0.537 | 54.6 (4.6) | 4.1 | 0.383 | 7.3 | −3.2 | 0.328 | |
R255X | <30 | 115 | 27.2 (0.6) | 51.7 (1) | 9.6 | ||||||
≥30 yo | 5 | 35.4 (3.1) | 8.2 | 0.010 | 64.2 (4.9) | 12.5 | 0.013 | 4.6 | −5.0 | 0.085 | |
R270X | <30 | 72 | 27.6 (0.9) | 53 (1.5) | 6.0 | ||||||
≥30 yo | 8 | 22.1 (2.6) | −5.5 | 0.049 | 49.1 (4.4) | −3.9 | 0.407 | 7.3 | 1.3 | 0.537 | |
R294X | <30 | 71 | 21 (0.8) | 48.8 (1.6) | 5.9 | ||||||
≥30 yo | 11 | 20.6 (1.9) | −0.4 | 0.878 | 45.5 (4.1) | −3.3 | 0.449 | 10.0 | 4.1 | 0.100 | |
R306C | <30 | 94 | 20.3 (0.7) | 46.3 (1.3) | 7.9 | ||||||
≥30 yo | 6 | 24.7 (2.9) | 4.4 | 0.146 | 57.8 (5.3) | 11.5 | 0.038 | 5.5 | −2.4 | 0.455 | |
CTT | <30 | 126 | 22.1 (0.7) | 48.8 (1.2) | 10.5 | ||||||
≥30 yo | 13 | 20.7 (2.1) | −1.4 | 0.513 | 49.8 (3.8) | 1 | 0.787 | 11.8 | 1.3 | 0.630 | |
LargeDel | <30 | 108 | 26.3 (0.8) | 52.8 (1.3) | 9.0 | ||||||
≥30 yo | 13 | 29.2 (2.2) | 2.9 | 0.225 | 55.4 (3.7) | 2.6 | 0.500 | 11.9 | 2.9 | 0.310 |
Scale | Item | Mean: <30, ≥30 | Median: <30, ≥30 | Test Statistic | p-Value |
---|---|---|---|---|---|
CSS | Somatic Growth | 1, 1.3 | 0, 1 | 2.947 | 0.086 |
Sitting | 1.3, 1.5 | 0, 0 | 0.079 | 0.779 | |
Ambulation | 2.7, 2.3 | 3, 3 | 4.908 | 0.027 | |
Hand Use | 2.3, 2.2 | 3, 3 | 0.694 | 0.405 | |
Scoliosis | 1.9, 2.8 | 1, 2 | 23.601 | 0.000 | |
Language | 3.2, 3.3 | 3, 3 | 1.795 | 0.180 | |
Nonverbal | 1.6, 1.9 | 2, 2 | 6.954 | 0.008 | |
Breathing | 1.5, 0.9 | 1, 1 | 24.919 | 0.000 | |
Autonomic | 1, 1 | 1, 1 | 0.001 | 0.976 | |
Seizures | 1.2, 1 | 0, 0 | 0.339 | 0.560 | |
MBA | Motor Skills | 2.9, 2.8 | 3, 3 | 0.681 | 0.409 |
Verbal Skills | 1.9, 2 | 2, 2 | 0.035 | 0.852 | |
Social Eye Contact | 1.4, 1.5 | 1, 2 | 2.283 | 0.131 | |
Lack of Sustained Interest | 1.2, 1.6 | 1, 1 | 8.136 | 0.004 | |
Irritability/Tantrums | 0.2, 0.1 | 0, 0 | 3.622 | 0.057 | |
Does Not Reach for Objects/People | 2.6, 2.6 | 3, 3 | 0 | 0.987 | |
Does Not Follow Verbal Commands | 1.5, 1.7 | 1, 2 | 4.428 | 0.035 | |
Feeding Difficulties | 1.7, 1.7 | 2, 1 | 0.09 | 0.764 | |
Chewing Difficulties | 2, 1.8 | 2, 2 | 1.783 | 0.182 | |
Aggressiveness | 0.1, 0.1 | 0, 0 | 0.003 | 0.959 | |
Seizures | 1.4, 1.3 | 1, 1 | 0.542 | 0.461 | |
Speech Disturbance | 3.2, 3.3 | 3, 3 | 1.323 | 0.250 | |
Bruxism | 0.8, 0.7 | 0, 0 | 1.897 | 0.168 | |
Breath Holding | 1.1, 0.9 | 1, 0.5 | 10.666 | 0.001 | |
Hyperventilation | 0.8, 0.3 | 0, 0 | 30.178 | 0.000 | |
Air/Saliva Expulsion | 1.3, 1.3 | 1, 1 | 0.106 | 0.744 | |
Mouthing Hands/Objects | 0.9, 0.5 | 0, 0 | 15.051 | 0.000 | |
Hand Clumsiness | 3.1, 3.1 | 4, 4 | 0.023 | 0.880 | |
Hand Stereotypies | 3.3, 2.9 | 4, 3.5 | 6.113 | 0.013 | |
Bradykinesia | 0.9, 1.8 | 0, 2 | 46.333 | 0.000 | |
Dystonia | 1.3, 1.4 | 1, 1 | 0.391 | 0.532 | |
Scoliosis | 1.7, 2.4 | 1, 2 | 22.913 | 0.000 | |
Dyskinesias | 0.4, 0.3 | 0, 0 | 3.006 | 0.083 | |
Hypertonia | 1.5, 2.2 | 1, 3 | 17.349 | 0.000 | |
Vasomotor Disturbance | 1.1, 1.2 | 1, 1 | 2.269 | 0.132 |
Age Mean (SD, Range) | ||
---|---|---|
<30 yo | ≥30 yo | |
First Visit | 8.3 (6.5, 1.1–29) | 34.1 (5.3, 30–57.1) |
Last Visit | 13.9 (7.3, 2.4–30) | 39.4 (7, 31.1–64.5) |
Age Change (First-Last) | 5.6 (3.7, 0.4–15.3) | 5.3 (3.4, 1–13.7) |
Age Group | Number | Visit | CSS | MBA | ||||
---|---|---|---|---|---|---|---|---|
Mean (SEM) | Change | p-Value | Mean (SEM) | Change | p-Value | |||
<30 | 985 | First | 22.2 (0.2) | 46.9 (0.4) | ||||
Last | 24.6 (0.2) | 2.5 | 0.000 | 50.7 (0.4) | 3.8 | 0.000 | ||
≥30 yo | 76 | First | 23.3 (0.9) | 51 (1.5) | ||||
Last | 23.5 (0.8) | 0.2 | 0.573 | 52.6 (1.4) | 1.6 | 0.151 |
Item | Age Group | Mean: First, Last | Median: First, Last | Test Statistic | p-Value | |
---|---|---|---|---|---|---|
CSS | Somatic Growth | <30 | 1, 0.9 | 0, 0 | −1.608 | 0.108 |
≥30 | 1.3, 1.1 | 0, 0.5 | −1.869 | 0.062 | ||
Sitting | <30 | 1, 1.3 | 0, 0 | 6.265 | 0.000 | |
≥30 | 1.1, 1.3 | 0, 0 | 1.252 | 0.210 | ||
Ambulation | <30 | 2.6, 2.7 | 3, 3 | 3.208 | 0.001 | |
≥30 | 1.9, 2.1 | 1, 1 | 1.701 | 0.089 | ||
Hand Use | <30 | 1.9, 2.3 | 2, 3 | 12.461 | 0.000 | |
≥30 | 2.2, 2.3 | 3, 3 | 2.265 | 0.024 | ||
Scoliosis | <30 | 1, 2 | 0, 1 | 18.891 | 0.000 | |
≥30 | 2.6, 2.7 | 2, 2 | 0.959 | 0.337 | ||
Language | <30 | 3, 3.3 | 3, 3 | 10.921 | 0.000 | |
≥30 | 3.3, 3.6 | 3, 4 | 3.162 | 0.002 | ||
Nonverbal Communication | <30 | 1.9, 1.6 | 2, 2 | −7.140 | 0.000 | |
≥30 | 2, 1.7 | 2, 2 | −2.211 | 0.027 | ||
Respiratory Dysfunction | <30 | 1.3, 1.5 | 1, 2 | 5.114 | 0.000 | |
≥30 | 1.1, 1 | 1, 1 | −0.887 | 0.375 | ||
Autonomic Symptoms | <30 | 0.9, 1 | 1, 1 | 4.388 | 0.000 | |
≥30 | 0.9, 0.9 | 1, 1 | −0.604 | 0.546 | ||
Seizures | <30 | 0.8, 1.2 | 0, 0 | 6.132 | 0.000 | |
≥30 | 0.9, 0.8 | 0, 0 | −1.249 | 0.212 | ||
MBA | Motor Skills | <30 | 2.6, 3 | 3, 3 | 12.940 | 0.000 |
≥30 | 2.7, 3 | 3, 3 | 2.966 | 0.003 | ||
Verbal Skills | <30 | 1.9, 2 | 1, 2 | 2.359 | 0.018 | |
≥30 | 2, 2.6 | 2, 3 | 3.344 | 0.001 | ||
Social Eye Contact | <30 | 1.1, 1.4 | 1, 1 | 5.124 | 0.000 | |
≥30 | 1.5, 1.6 | 2, 2 | 0.215 | 0.830 | ||
Lack Of Sustained Interest | <30 | 1.2, 1.2 | 1, 1 | −0.819 | 0.413 | |
≥30 | 1.7, 1.4 | 2, 1 | −1.813 | 0.070 | ||
Irritability or Tantrums | <30 | 0.4, 0.2 | 0, 0 | −7.609 | 0.000 | |
≥30 | 0.2, 0.1 | 0, 0 | −0.922 | 0.356 | ||
Does Not Reach for Objects/ People | <30 | 1.9, 2.6 | 2, 3 | 13.481 | 0.000 | |
≥30 | 2.5, 3 | 3, 4 | 2.967 | 0.003 | ||
Does Not Follow Verbal Commands | <30 | 1.8, 1.4 | 2, 1 | −8.256 | 0.000 | |
≥30 | 1.8, 1.5 | 2, 1 | −2.277 | 0.023 | ||
Feeding Difficulties | <30 | 1.4, 1.8 | 1, 2 | 9.066 | 0.000 | |
≥30 | 1.4, 1.7 | 1, 2 | 1.873 | 0.061 | ||
Chewing Difficulties | <30 | 1.6, 2.1 | 1, 2 | 11.301 | 0.000 | |
≥30 | 1.6, 2 | 1, 2 | 2.886 | 0.004 | ||
Aggressiveness | <30 | 0.2, 0.1 | 0, 0 | −3.243 | 0.001 | |
≥30 | 0.1, 0.1 | 0, 0 | −0.832 | 0.405 | ||
Seizures | <30 | 1, 1.4 | 0, 1 | 7.546 | 0.000 | |
≥30 | 1.2, 1.1 | 1, 1 | −1.062 | 0.288 | ||
Speech Disturbance | <30 | 2.9, 3.2 | 3, 3 | 13.835 | 0.000 | |
≥30 | 3.3, 3.5 | 3, 4 | 3.086 | 0.002 | ||
Bruxism | <30 | 1.1, 0.7 | 1, 0 | −7.951 | 0.000 | |
≥30 | 0.6, 0.5 | 0, 0 | −1.414 | 0.157 | ||
Breath Holding | <30 | 1.2, 1.1 | 1, 1 | −0.650 | 0.516 | |
≥30 | 1, 0.8 | 1, 0 | −1.719 | 0.086 | ||
Hyperventilation | <30 | 0.9, 0.7 | 0, 0 | −2.635 | 0.008 | |
≥30 | 0.3, 0.4 | 0, 0 | 1.296 | 0.195 | ||
Air/Saliva Expulsion | <30 | 1.4, 1.3 | 1, 1 | −2.343 | 0.019 | |
≥30 | 1.2, 1.1 | 1, 1 | −0.566 | 0.571 | ||
Mouthing Hands/Objects | <30 | 1.4, 0.9 | 1, 0 | −9.066 | 0.000 | |
≥30 | 0.4, 0.4 | 0, 0 | −0.083 | 0.934 | ||
Hand Clumsiness | <30 | 2.8, 3.1 | 3, 4 | 9.574 | 0.000 | |
≥30 | 3.1, 3.3 | 4, 4 | 1.947 | 0.052 | ||
Hand Stereotypies | <30 | 3.3, 3.3 | 4, 4 | −1.756 | 0.079 | |
≥30 | 3, 3.3 | 4, 4 | 2.012 | 0.044 | ||
Bradykinesia | <30 | 0.5, 0.9 | 0, 0 | 11.131 | 0.000 | |
≥30 | 1.6, 1.6 | 2, 1 | −0.545 | 0.586 | ||
Dystonia | <30 | 0.8, 1.4 | 0, 1 | 12.119 | 0.000 | |
≥30 | 1.4, 1.8 | 1, 2 | 2.260 | 0.024 | ||
Scoliosis | <30 | 0.9, 1.7 | 0, 1 | 18.300 | 0.000 | |
≥30 | 2.2, 2.3 | 2, 2 | 0.786 | 0.432 | ||
Dyskinesias | <30 | 0.3, 0.4 | 0, 0 | 2.679 | 0.007 | |
≥30 | 0.2, 0.5 | 0, 0 | 2.128 | 0.033 | ||
Hypertonia | <30 | 0.9, 1.6 | 0, 1 | 12.858 | 0.000 | |
≥30 | 2.1, 2.4 | 3, 3 | 1.637 | 0.102 | ||
Vasomotor Disturbance | <30 | 1, 1.1 | 1, 1 | 2.318 | 0.020 | |
≥30 | 1.1, 1 | 1, 1 | −1.139 | 0.255 |
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Neul, J.L.; Benke, T.A.; Marsh, E.D.; Suter, B.; Fu, C.; Ryther, R.C.; Skinner, S.A.; Lieberman, D.N.; Feyma, T.; Beisang, A.; et al. Clinical Features and Disease Progression in Older Individuals with Rett Syndrome. Genes 2024, 15, 1107. https://doi.org/10.3390/genes15081107
Neul JL, Benke TA, Marsh ED, Suter B, Fu C, Ryther RC, Skinner SA, Lieberman DN, Feyma T, Beisang A, et al. Clinical Features and Disease Progression in Older Individuals with Rett Syndrome. Genes. 2024; 15(8):1107. https://doi.org/10.3390/genes15081107
Chicago/Turabian StyleNeul, Jeffrey L., Timothy A. Benke, Eric D. Marsh, Bernhard Suter, Cary Fu, Robin C. Ryther, Steven A. Skinner, David N. Lieberman, Timothy Feyma, Arthur Beisang, and et al. 2024. "Clinical Features and Disease Progression in Older Individuals with Rett Syndrome" Genes 15, no. 8: 1107. https://doi.org/10.3390/genes15081107