Rare Diseases Clinical Research Network: Neurophysiological Correlates

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.

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.

Eligibility Criteria:
Inclusion Criteria: 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 will be linked to the RTT5211 Protocol by their RDCRN identification numbers. No phenotypical selection of subjects will be performed; we expect the cohort will be representative of each disorder.

A cohort of 60 typically developing girls and boys (30 each) will be enrolled to serve as controls. Typical development in the control group will be confirmed by normal intelligence quotient scores or equivalent scores on developmental tests using standardized measures and negative psychiatric diagnoses on a standardized diagnostic interview administered to their mothers, fathers or guardians (Diagnostic Interview for Children and Adolescents, Revised: Parents' Version). All control subjects must have a negative history of neurologic impairment or neuropsychiatric conditions and show no clinical evidence of a genetic disorder.

Exclusion Criteria: Individuals who do not meet the above criteria will be excluded.