Rare Diseases Clinical Research Network: Neurophysiological Correlates
Condition: Rett Syndrome, Preserved Speech Variant; Mecp2 Duplication Syndrome; Rett-related Disorders
MeSH terms: Rett Syndrome; Syndrome; Rare Diseases
Study type: Observational

Summary: 
      The overall purpose of this project is to advance understanding of the neurophysiological
      features of Rett syndrome (RTT), MECP2 Duplication (MECP2 Dup) and RTT-related disorders
      (CDKL5, FOXG1) to gain insight into disease pathogenesis, with an emphasis on identifying
      biomarkers of disease evolution and severity. This specific study is intertwined to the core
      study Natural History of Rett Syndrome and Related Disorders (RTT5211), which characterizes
      range of clinical involvement and genotype-phenotype correlations and will provide
      phenotypical data for determining the clinical relevance of the neurophysiologic parameters;
      study subjects here are co- and primarily enrolled in RTT5211. The proposed studies will
      serve as basis of future translational investigations, including further refinement of
      biomarkers, development of outcome measures, and clinical trials per se.
    

Detailed description: 
      Individuals with RTT, MECP2 Dup and RTT-related disorders have significant abnormalities on a
      number of neurophysiological measures such as EEG and Evoked Potentials (EP). Studies in
      representative animal models reproduce many of these abnormalities. Little is known about the
      relationship between these neurophysiological findings to disease evolution, severity and
      specific clinical features. Therefore, it is considered likely that detailed understanding of
      such neurophysiological features would provide additional insight into disease pathogenesis
      and will lead to biomarkers of disease state and severity of different features.
      Consequently, specialized neurophysiological assessments will be acquired, without sedation
      or any other type of pharmacological manipulation, on a subset of 170 subjects: 60 RTT, 18
      MECP2 Dup, 32 RTT-related disorders, and 60 age-matched typically developing controls (30
      females, 30 males). Primary evaluations will include auditory ERP (AEP) and visual ERP (VEP),
      as well as secondary analyses of specific rhythms/band activities obtained during the ERP
      acquisitions (gamma band changes and frontal alpha band asymmetry). Individuals will be
      recruited across the spectra of ages and severity. The main goal of the project is to
      identify potential biomarkers that can become measures for intervention and other
      translational studies and, at the same time, provide insight into abnormal synaptic activity
      and pathogenesis of RTT, MECP2 Dup, and RTT-related disorders. Therefore, the proposed
      assessments will be performed in all three groups of subjects enrolled in this consortium
      (RTT5211): RTT, MECP2 Dup, and RTT-related disorders. Findings in each set of disorders will
      be linked to the objectives of the the longitudinal clinical and neurobehavioral data
      (RTT5211) as well as to biological factors and genotyping that may be linked to clinical
      severity (RTT5213). The neurophysiological parameters for RTT, MECP2 Dup, and RTT-related
      disorders will not only be correlated with each other but also to disease staging, overall
      clinical severity scores and through exploratory analyses with specific clinical features;
      these will be repeated up to 3 times (i.e., annual [every 10-14 month] evaluations, in the
      context of visits for the RTT5211 protocol) during the course of study. For this purpose,
      linear regression and linear mixed models will be used. Preliminary and published data
      indicate that RTT and MECP2 Dup have distinct patterns of cortical processing on AEP, VEP
      demonstrates disorder and age/disease-stage dependent changes. Phenotypic severity may be
      related to specific ERP parameters, as some modest effects of (severity) category of
      mutations were observed. In addition, the secondary analyses of specific EEG rhythms/band
      activities will expand our preliminary studies demonstrating alpha band asymmetry as a marker
      of an anxiety-like response in RTT.
    

Intervention name(s): Auditory and Visual Event-related Potentials and EEG
Intervention type(s): Procedure
Intervention description(s): Specifically, through up to three standardized sessions (i.e., annual [every 10-14 months]), we will assess AEP and VEP. ERP recordings will also provide data for specific rhythms/band (gamma and alpha) pattern analyses as secondary measures as well as technical control data, which will help to exclude those with co-current seizures.
Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Individuals with RTT, MECP2 Dup, and RTT-related disorders (mutations or deletions in CDKL5
        and FOXG1 genes) who are also enrolled in the RTT5211 Protocol, which collects longitudinal
        clinical and neurobehavioral data in the above mentioned disorders. Participants will be
        linked to the RTT5211 Protocol by their RDCRN identification numbers. All participants will
        be tested for MECP2, CDKL5, and/or FOXG1 mutations; those with RTT phenotype will be
        assessed in terms of diagnostic criteria for classic or atypical RTT. No phenotypic
        selection will be performed; the cohort will be representative of each disorder.

        60 typically developing girls and boys (30 each) will be enrolled to serve as controls for
        all three cohorts with age matching to the RTT/CDKL5 girls and MECP2 Dup/FOXG1 boy cohorts.
      
Keywords: Auditory ERP, Visual ERP, EEG