Natural History of Rett Syndrome & Related Disorders

At the present time, effective treatments for RTT, MECP2 Dup, or Rett-related disorders are
lacking. Substantial progress has been made in RTT over the past eleven years such that this
study represents a narrowing of focus to mutations or duplications of the MECP2 gene and
related disorders, including those with phenotypic overlap. Understanding of RTT has advanced
remarkably well through the Rett Syndrome Natural History Clinical Protocol (NHS) and
correspondingly advancement in the basic science realm has moved forward with equivalent
success. Thus, progress in clinical and basic science has led to the establishment of
clinical trials and other translational studies that hold promise for additional clinical
trials in future. In the process, however, additional MECP2- and RTT-related disorders that
were unknown at the time the original proposal have been identified. In addition, substantial
clinical variability in individuals with RTT that cannot be explained by differences in
mutations alone must be explored further. In fact, variability among individuals with
identical mutations has led to the search for additional explanations. At the time of the
initial application (2002), just three years after the identification of the gene, MECP2, as
the molecular link to RTT, the variation in clinical disorders related to MECP2 mutations or
to the related but quite different MECP2 Dup were unknown. Each disorder is characterized by
significant neurodevelopmental features related either to alterations in the MECP2 gene or
related to phenotypes closely resembling those seen in individuals with RTT. Further, the
phenotypic overlap with RTT due to mutations in CDKL5 and FOXG1 was also unexplored. This new
study will build on the substantial progress made in understanding both classic and variant
RTT and to add these related disorders, MECP2 Dup and the Rett-related disorders including
CDKL5, FOXG1, and individuals with MECP2 mutations who do not have RTT. A comprehensive
clinical research program will be performed including clinical, neurophysiologic, and
molecular and biochemical markers across these different, but related disorders. This
protocol will address the natural history components only and will serve as the basis for
other study protocols including the neurophysiologic and biomarker studies. Thereby, these
studies will represent a continuing pathway to focus and inform not only the ongoing but also
the emerging clinical trials.

Inclusion Criteria:

- Individuals of both genders and of all ages, with RTT, MECP2 Dup, and, RTT-related
disorders including those with mutations or deletions in CDKL5 and FOXG1 genes, or
those with RTT (atypical or typical) who are mutation negative.

Exclusion Criteria:

- Individuals who do not meet the above criteria will be excluded.