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Study Description

This observational study will involve the comprehensive assessment of the clinical features of Rett syndrome with this Rare Diseases Clinical Research Network. A clinical database of 1350 individuals with Rett syndrome including MECP2 mutation status for the purpose of elaborating phenotype-genotype correlations will be established. Eligible participants will be enrolled in the natural history study for 11 years from the 4 clinic sites currently involved with Rett syndrome (BCM, GGC, and UAB, CHB) as well as from the several thousand registrants in the International Rett Syndrome Foundation registry who will be invited to the nearest consortium site involved in Rett syndrome.

Potential participants are expected to have had determination of their MECP2 mutation status, but will not be excluded should no mutation be present. All individuals who meet criteria and are currently receiving care from study sites will be invited to participate (N>600). Additional participants will be invited through the assistance of the International Rett Syndrome Foundation (IRSF). All individuals with RS registered with IRSF will be invited to participate in this study via the IRSF website and the IRSF newsletter. Potential participants will be apprised of the participating study sites and invited to contact one of the sites based on feasibility of travel. Inasmuch as the enrollment goal of 1350 participants is 40% of the current IRSF registry, we believe this will be a representative sampling. Bias can certainly occur based on travel requirements, level of interest, and other factors. However, inclusion of such a large sample should minimize sampling bias. No travel expenses will be covered, so it is likely that participants will be those with geographic proximity to Houston, Greenwood, Birmingham, or Boston.

From the sample pool described above, the aim is to conduct the observational longitudinal (natural history) study on up to 1350 participants with classic Rett syndrome and variant forms of Rett syndrome, that is, participants who fully meet the established clinical criteria for Rett syndrome and those who meet some but not all of these criteria. All participants expressing MECP2 mutations irrespective of phenotype will be eligible for enrollment.

For each of the eight common genetic mutations as well as those with large scale deletions, the prevalence of the following RS characteristics will be estimated for each age category and overall: seizure presence and frequency, ambulation status, scoliosis, ECG abnormality, breathing irregularities while awake, feeding difficulties, growth as measured in percentiles from NCHS standards curves, the presence of osteopenia as evidenced by bone fracture, and the presence of gallbladder disease. Both incidence and prevalence estimates will be made using a combination of data obtained at the regularly scheduled clinical visits and that obtained from the medical history. Incidence estimates will be calculated using time-to-event analyses (e.g., Kaplan-Meier survival curves) with appropriate calculations of standard errors and 95% confidence intervals. Cox proportional hazard regression models will be used to allow control for other factors, and t-tests will be calculated on the coefficients themselves. Appropriate transformations on explanatory variables will be used as deemed necessary in Cox models. Prevalence estimates will be calculated from estimates of proportions with exact confidence intervals. For a sample size of 275, the standard error of the estimate will not exceed 0.03 (3%) and for a sample size of 60, the standard error of the estimate will not exceed 0.06 (6%).

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Study Inclusion/Exclusion Criteria

Inclusion Criteria:

Individuals fulfilling consensus clinical criteria for Classic or Variant Rett Syndrome (Appendix C. and D.) or individuals with MECP2 mutations who do not meet the clinical criteria. All ages will be eligible. Patients must be able to travel to study sites for annual evaluations (for those 6 years or older) or bi-annual evaluation (for those through age 5).

Exclusion criteria:

Individuals who do not fulfill the consensus clinical criteria for classic or variant RS or otherwise lack a mutation in MECP2 will be excluded

Study History

Rett syndrome (RS) is a neurodevelopmental disorder that develops almost exclusively in females following apparently normal psychomotor development for the first six months of life. The characteristic features include loss of speech and purposeful hand use, occurrence of stereotypic hand movements, gait dyspraxia, and deceleration of head growth [14, 17, 33-35]. These individuals frequently develop severe motor problems including an abnormal gait or the loss of ability to ambulate. They may develop seizures, abnormal breathing consisting of periods of apnea and hyperventilation occurring only during wakefulness, symptoms suggesting autonomic nervous system dysfunction, and growth failure [4]. Increases in occurrence of prolonged QTc (>0.45 secs) and abnormal heart rate variability consistent with clinical signs (e.g. cold, blue extremities) indicating autonomic dysfunction have been previously reported in Rett syndrome [31, 32]. RS occurs in all ethnic groups worldwide.

In 1999, the gene for RS was discovered. Amir et al. [1] reported the presence of several mutations in MECP2 in individuals with RS. MECP2 encodes methyl-CpG-binding protein 2 (MeCP2). MeCP2 is a member of a family of proteins known to bind specifically to methylated-CpGs and to be capable of repressing transcription. Although MeCP2 is expressed in all tissues, it is more abundant in the brain than any other tissue, and the brain may be more sensitive to abnormal MECP2 than other tissues [2, 6, 18, 25, 30, 36]. The binding site of MECP2 requires only a single methylated CpG dinucleotide to bind [22]. It has been proposed that MECP2 acts as a global transcriptional repressor that prevents unscheduled transcription throughout the genome and has been implicated as a key player in assembling transcriptional silencing complexes [7, 11, 21, 24, 26, 37, 41]. Approximately 80% of females meeting the clinical criteria for Rett syndrome will have a mutation in MECP2 [27]. More recently, additional mutation types have been identified including large scale deletions[10,23,39] and a splice variant beginning in exon 1 [28]. Hence, we expect to enroll a higher number of participants from among those who have MECP2 mutations, perhaps 95% of the total, or greater. More recently, MECP2 duplications have been identified in a number of males. In up to 70%, their mothers carry the same duplication, but due to favorable X chromosome inactivation skewing, the mothers generally function quite well although depression and obsessive-compulsive behaviors may be noted. We will enroll these males and their mothers as well.

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Study Attribution
  • Principal Investigator
    • Alan Percy, MD. University of Alabama at Birmingham, AL, USA.
  • Funding Source
    • HD061222. National Institutes of Health, Bethesda, MD, USA.