Rett syndrome diagnostic criteria: lessons from the Natural History Study.
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ABSTRACT:
SUBMITTER: Percy AK
PROVIDER: S-EPMC3021984 | biostudies-literature | 2010 Dec
REPOSITORIES: biostudies-literature
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Rett syndrome diagnostic criteria: lessons from the Natural History Study.
Percy Alan K AK Neul Jeffrey L JL Glaze Daniel G DG Motil Kathleen J KJ Skinner Steven A SA Khwaja Omar O Lee Hye-Seung HS Lane Jane B JB Barrish Judy O JO Annese Fran F McNair Lauren L Graham Joy J Barnes Katherine K
Annals of neurology 20101201 6
Analysis of 819 participants enrolled in the Rett syndrome (RTT) Natural History Study validates recently revised diagnostic criteria. 765 females fulfilled 2002 consensus criteria for classic (653/85.4%) or variant (112/14.6%) RTT. All participants classified as classic RTT fulfilled each revised main criterion; supportive criteria were not uniformly present. All variant RTT participants met at least 3 of 6 main criteria in the 2002, 2 of 4 main criteria in the current format, and 5 of 11 suppo ...[more]
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Project description:ObjectiveTo characterize hand stereotypies (HS) in a large cohort of participants with Rett syndrome (RTT).MethodsData from 1,123 girls and women enrolled in the RTT Natural History Study were gathered. Standard tests for continuous and categorical variables were used at baseline. For longitudinal data, we used repeated-measures linear and logistic regression models and nonparametric tests.ResultsHS were reported in 922 participants with classic RTT (100%), 73 with atypical severe RTT (97.3%), 74 with atypical mild RTT (96.1%), and 17 females with MECP2 mutations without RTT (34.7%). Individuals with RTT who had classic presentation or severe MECP2 mutations had higher frequency and earlier onset of HS. Heterogeneity of HS types was confirmed, but variety decreased over time. At baseline, almost half of the participants with RTT had hand mouthing, which like clapping/tapping, decreased over time. These 2 HS types were more frequently reported than wringing/washing. Increased HS severity (prevalence and frequency) was associated with worsened measures of hand function. Number and type of HS were not related to hand function. Overall clinical severity was worse with decreased hand function but only weakly related to any HS characteristic. While hand function decreased over time, prevalence and frequency of HS remained relatively unchanged and high.ConclusionsNearly all individuals with RTT have severe and multiple types of HS, with mouthing and clapping/tapping decreasing over time. Interaction between HS frequency and hand function is complex. Understanding the natural history of HS in RTT could assist in clinical care and evaluation of new interventions.
| S-EPMC6556084 | biostudies-literature
Project description:Rett syndrome (RTT) is a severe neurodevelopmental disease that affects approximately 1 in 10,000 live female births and is often caused by mutations in Methyl-CpG-binding protein 2 (MECP2). Despite distinct clinical features, the accumulation of clinical and molecular information in recent years has generated considerable confusion regarding the diagnosis of RTT. The purpose of this work was to revise and clarify 2002 consensus criteria for the diagnosis of RTT in anticipation of treatment trials.RettSearch members, representing the majority of the international clinical RTT specialists, participated in an iterative process to come to a consensus on a revised and simplified clinical diagnostic criteria for RTT.The clinical criteria required for the diagnosis of classic and atypical RTT were clarified and simplified. Guidelines for the diagnosis and molecular evaluation of specific variant forms of RTT were developed.These revised criteria provide clarity regarding the key features required for the diagnosis of RTT and reinforce the concept that RTT is a clinical diagnosis based on distinct clinical criteria, independent of molecular findings. We recommend that these criteria and guidelines be utilized in any proposed clinical research.
| S-EPMC3058521 | biostudies-literature
Project description:Early development appears normal in Rett syndrome (OMIM #312750) and may be more apparent than real. A major purpose of the Rett Syndrome (RTT) Natural History Study (NHS) was to examine achievement of developmental skills or abilities in classic and atypical RTT and assess phenotype-genotype relations in classic RTT.Developmental skills in four realms, gross and fine motor, and receptive and expressive communication from initial enrollment and longitudinal assessments for up to 7 years, were assessed from 542 females meeting criteria for classic RTT and 96 females with atypical RTT divided into two groups: 50 with better and 46 with poorer functional scores. Data were analyzed for age at acquisition and loss of developmental features and for phenotype-genotype effects. Acquired, lost, and retained skills were compared between classic RTT and atypical RTT with better or poorer functional scores using Fisher's Exact test. To examine if the mean total score from the Motor Behavioral Assessment during follow-up differed for acquiring a skill, we used a generalized estimating equation assuming compound symmetry correlation structure within a subject. A general linear model was used to examine whether the mean age of acquisition or loss of a developmental skill differed by mutation type. P values <0.05 were considered significant and were two-sided without adjustment for multiple testing. Statistical analyses utilized SAS 9.3 (SAS Institute, Cary, NC, USA).Early developmental skills or abilities were often acquired albeit later than normal. More complex motor and communication acquisitions were delayed or absent. Clinical severity was less in those achieving the respective skill. Individuals with R133C, R294X, and R306C point mutations and 3' truncations tended to have better developmental outcomes.Early developmental skills were acquired by many, but clear differences from normal emerged, particularly in skills expected after age 6 months. When comparing clinical severity, greater acquisition of specific skills was associated with specific mutations, confirming the impression that these mutations confer milder developmental abnormalities. These data may serve for planning and interpretation of early intervention studies in RTT.This NHS study, clinicaltrials.gov (NCT00296764), represents the largest group of RTT participants assessed repeatedly by direct examination.
| S-EPMC4112822 | biostudies-literature
Project description:IntroductionRett syndrome (RTT) is a complex neurodevelopmental disorder with known behavioral abnormalities, both internalizing (e.g., anxiety, social withdrawal) and externalizing (e.g., aggression, self-abuse). However, a broad evaluation of behavioral abnormalities in a large cohort is lacking.ObjectiveIn this report, we describe profiles of internalizing and externalizing behaviors in individuals evaluated in the multi-center U.S. Rett Natural History Study.MethodsCross-sectional and longitudinal data were collected from 861 females with RTT and from 48 females who have MECP2 mutations without meeting criteria for RTT. Standard statistical methods including linear regression evaluated internalizing behavioral components from the Child Health Questionnaire (CHQ-PF50) and externalizing components from the Motor Behavioral Assessment (MBA).ResultsWe found mildly to moderately severe internalizing behaviors in nearly all individuals with RTT, while externalizing behaviors were mild and uncommon. Internalizing behavior in RTT was comparable to groups with psychiatric disorders. Participants with mixed (internalizing and externalizing) behaviors were younger and less affected overall, but showed prominent self-injury and worsening internalizing behaviors over time.ConclusionsThis study revealed that internalizing behaviors are common at a clinically significant level in RTT. Understanding clinical features associated with behavioral profiles could guide treatment strategies.
| S-EPMC6392009 | biostudies-literature
Project description:BackgroundRett syndrome (RTT) is a neurodevelopmental disorder primarily seen in females, most with a mutation in MECP2. Epilepsy has been reported in 50%-80%. Previous reports were based on small sample sizes or parent-completed questionnaires, or failed to consider the impact of specific MECP2 mutations.MethodsThe Rare Disease Consortium Research Network for RTT is an NIH-funded project to characterize the clinical spectrum and natural history of RTT in advance of clinical trials. Evaluations include clinical status (classic vs atypical RTT), MECP2 mutations, clinical severity, and presence, frequency, and treatment of seizures.ResultsEnrollment as of June 2008 is 602; 528 (88%) meet clinical criteria for classic RTT. Of these, 493 (93%) have MECP2 mutations. Age range was 8 months to 64 years. A total of 360 (60%) were reported to have seizures, including 315 (60%) classic and 45 (61%) atypical RTT. Physician assessment of the 602 indicated that 48% had seizures. There was no significant difference in seizure occurrence by race/ethnicity. A significant age impact for seizures was seen and seizures were infrequent before age 2 years. MECP2 mutations most frequently associated with epilepsy were T158M (74%) and R106W (78%), and less frequently R255X and R306C (both 49%). Individuals with seizures had greater overall clinical severity, and greater impairment of ambulation, hand use, and communication.DiscussionSeizures are common in Rett syndrome, have an age-related onset and occurrence, vary by mutation, and are associated with greater clinical severity. This information represents a key consideration for designing clinical trials.
| S-EPMC2836870 | biostudies-literature
Project description:BackgroundRett syndrome (RTT) is a neurodevelopmental disorder most often related to a pathogenic variant in the X-linked MECP2 gene. Internalizing behaviors appear to be common, but standard methods of diagnosing anxiety are not readily applied in this population which typically has cognitive impairment and limited expressive language. This study aims to describe the frequency of anxiety-like behavior and anxiolytic treatments along with associated clinical features in individuals with RTT.MethodsParental reports and medication logs provided data from 1380 females with RTT participating in two iterations of the multicenter U.S. RTT Natural History Study (RNHS) from 2006 to 2019.ResultsMost participants with RTT (77.5%) had at least occasional anxious or nervous behavior. Anxiety was reported to be the most troublesome concern for 2.6%, and within the top 3 concerns for 10.0%, of participants in the second iteration. Parents directly reported treatment for anxious or nervous behavior in 16.6% of participants in the second iteration with most reporting good control of the behavior (71.6%). In the medication logs of both RNHS iterations, the indication of anxiety was listed for a similar number of participants (15% and 14.5%, respectively). Increased use of anxiolytics and selective serotonin reuptake inhibitors (SSRIs) was related to more frequent anxiety-like behaviors (P < 0.001), older age (P < 0.001), and mild MECP2 variants (P = 0.002).ConclusionAnxiety-like behavior is frequent at all ages and is a significant parental concern in RTT. Older individuals and those with mild MECP2 variants are more likely to be treated with medications. Better diagnosis and treatment of anxiety in RTT should be a goal of both future studies and clinical care.Trial registrationNCT00299312 and NCT02738281.
| S-EPMC9107202 | biostudies-literature
Project description:During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations.
| S-EPMC6417794 | biostudies-literature
Project description:OBJECTIVES:Rett syndrome (RTT) is an X-linked autism spectrum disorder caused by mutations in the MeCP2 gene in the great majority of cases. Evidence suggests a potential role of oxidative stress (OS) in its pathogenesis. Here, we investigated the potential value of OS markers (non-protein-bound iron (NPBI) and F2-isoprostanes (F2-IsoPs)) in explaining natural history, genotype-phenotype correlation, and clinical heterogeneity of RTT, and gauging the response to omega-3 polyunsaturated fatty acids (?-3 PUFAs). METHODS:RTT patients (n=113) and healthy controls were assayed for plasma NPBI and F2-IsoPs, and intraerythrocyte NPBI. Forty-two patients with typical RTT were randomly assigned to ?-3 PUFAs supplementation for 12 months. NPBI was measured by HPLC and F2-IsoPs using a gas chromatography/negative ion chemical ionization tandem mass spectrometry (GC/NICI-MS/MS) technique. RESULTS:F2-IsoPs were significantly higher in the early stages as compared with the late natural progression of classic RTT. MeCP2 mutations related to more severe phenotypes exhibited higher OS marker levels than those of milder phenotypes. Higher OS markers were observed in typical RTT and early seizure variant as compared with the preserved speech and congenital variants. Significant reduction in OS markers levels and improvement of severity scores were observed after ?-3 PUFAs supplementation. DISCUSSION:OS is a key modulator of disease expression in RTT.
| S-EPMC6837451 | biostudies-literature
Project description:Rett Syndrome Natural History Clinical Protocol - ARP 5201
| PRJNA184913 | ENA
Project description:ObjectiveRecent advances in the understanding of neurodevelopmental disorders such as Rett syndrome (RTT) has enabled development of novel therapeutic approaches that are currently undergoing clinical evaluation or are proposed to move into clinical development. 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 clinical concerns in order to gain information to guide the development and selection of outcome measures for future clinical trials.MethodsCaregivers of participants enrolled in the US Natural History Study of RTT and related disorders 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.ResultsThe top caregiver concerns for Classic RTT were effective communication, seizures, walking/balance issues, lack of hand use, and constipation. The rank order of 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. The frequency of caregiver concern for seizures, hand use, and spoken language increased in relation to clinician assessed severity in these clinical domains, showing consistency between clinician assessments and caregiver concerns. 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.ConclusionThe top caregiver concerns for individuals with RTT and the 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.
| S-EPMC10055548 | biostudies-literature