Rare Diseases Clinical Research Network: Neurophysiological Correlates

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.

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.