Genetic and Physical Characteristics of Rett Syndrome

RTT is a brain disorder that causes problems with childhood development. It is usually
caused by an abnormality (mutation) in the gene MECP2. RTT can cause severe impairments in
movement and communication skills, including speech and social interaction. The first signs
of RTT include loss of acquired speech and loss of purposeful hand use for activities such
as eating or playing. Individuals may also develop abnormal walking, repetitive hand
movements, such as clapping or wringing, and abnormal breathing while awake.

Effective treatments for RTT are currently lacking. There is also inadequate information
about the link between RTT clinical features and its genetic basis. In order to prepare for
future clinical trials that may lead to effective therapies, it is important to collect
accurate information about the characteristics of RTT and the pattern of disease
progression. This study will gather historical and physical examination data to establish
phenotype-genotype correlations. Data on survival and quality of life in females with RTT
and males with MECP2 gene mutations will also be evaluated.

MECP2 Duplication disorder affects principally males who have one and rarely more than one
additional copy of MECP2 as well as a variable number of other duplicated genes. These males
have absent spoken language, shuffling gait, epilepsy, and, in some, frequent upper
respiratory infections or sinusitis. Mother of these males are generally normal due to
favorable skewing of X-chromosome inactivation, but in some instances may have
neurodevelop-mental delays. Effective treatments are lacking. It is critical to develop
phenotype-genotype correlations and longitudinal natural history data to assist the conduct
of clinical trials.

RTT-related disorders feature a variety of involvements either due to MECP2, CDKL5, and
FOXG1 as well as other potential causes of atypical RTT. Phenotype-genotype studies and
longitudinal natural history data are essential to the conduct of future clinical trials.

Participants in this observational study will be recruited from the four sites at which the
study is being conducted, as well as through the Rare Disease Clinical Research Network and
the International Rett Syndrome Association (IRSA). Prior to study entry, potential
participants are expected to be tested for a mutation in the MECP2 gene. No treatment will
be administered at any time during this study. Study visits will occur every 6 months until
the child is 6 years old and once a year thereafter. At each study visit, participants will
be examined to assess physical characteristics of the disorder, such as motor behavior and
disease severity. Additionally, participants will complete questionnaires about medical
history, contact information, and quality of life. The first visit will last approximately
1.5 hours, and every subsequent visit will last approximately 1 hour.

Inclusion Criteria:

- Meets clinical criteria for classic or variant RTT or tests positive for an MECP2
gene mutation or a MECP2 duplication or a mutation in CDKL5 or FOXG1.

Exclusion Criteria:

- Unwilling or unable to travel to study sites for annual or biannual evaluations