Specific Aims: Rett syndrome (RTT, MIM 312750) is a severe neurodevelopmental disorder characterized by loss of spoken language and hand use, development of characteristic repetitive hand movements, and difficulty walking. Most individuals with RTT have mutations in Methyl-CpG-binding Protein 2 (MECP2), whose protein product MeCP2 functions as an epigenetic gene regulator by recognizing methylated DNA. Recently, a number of promising advances have been reported that modify the disease course, most importantly the evidence that restoring gene function in a mouse model rescues phenotypic abnormalities. The emergence of potential disease modifying therapies highlights the critical importance of carefully conducted longitudinal assessments documenting the natural history of disease, allowing future investigations to ascertain the efficacy of evolving therapies. In the previous funding period we established the genotype/phenotype relationship in RTT, characterized a number of important clinical features such as quality of life, growth, acquisition of developmental skills, epilepsy, and scoliosis,, and described survival and cause of death in RTT. This knowledge has been critical in the initiation of clinical treatment trials at three of the four sites. Although we have achieved all the aims set out in the previous application, in doing so we uncovered aspects of RTT not fully understood. Moreover, the onset of clinical trials has raised additional critical issues that demand attention. For example, we now know that the phenotypic spectrum of RTT is broader than initially understood, and the currently utilized longitudinal metrics do not completely capture this, variation. Furthermore, the currently used clinical rating scales, while good at capturing overall severity, lack the dynamic range needed to be useful as outcome measures. Genotype/phenotype analysis demonstrates group properties of common mutations;however, additional factors must contribute to the intra-mutation group variation in clinical severity observed. Although basic research provides insight into the pathophysiological processes involved in RTT, such as the role of alterations in excitatory/inhibitory (E/l) balance, we currently do not know how this relates to disease progression or severity in people. Finally, we have no biomarkers to aid in clinical trials. To address these issues, we propose to continue the ongoing research with a set of revised Aims and new goals:
Aim 1 : Perform longitudinal and neurobehavioral assessments in people with RTT. Clinical features in RTT are dynamic and the phenotypic spectrum is wider than previously believed. Understanding this progression and inherent variation is critical for the design and implementation of clinical trials. In order to address these issues, we will use knowledge obtained from the current study to develop new, expanded longitudinal assessment tools to evaluate a large cohort of people with RTT over time. These data will be used to develop new clinical rating scales with qualities suitable for outcome measures in clinical trials.
Aim 2 : Identify additional biological factors that contribute to disease severity in RTT: Specific MECP2 mutations contribute to disease severity;however, significant variation exists. Factors such as X-chromosome inactivation (XCI) skewing and Brain derived neurotrophic factor (BDNF) polymorphisms appear to modulate disease severity, but the exact contribution of any factor is currently unknown. Furthermore, unrecognized factors likely modify clinical severity. Therefore, we will systematically collect DNA, RNA, and plasma from all enrollees, and skin biopsies from select enrollees, for planned and future analysis. All samples will be characterized fpr XCI and BDNF polymorphism,analysis, and a model incorporating these data with genotype information will be developed to determine the overall contribution of these factors. Additionally, this biological material will be banked in a manner linked to the longitudinal clinical information obtained in Aim 1 for future analyses, and used for a pilot proposal exploring metabolic profiles in RTT. Ultimately, this work will contribute to identification of biomarkers, genetic modifiers, and provide banked material for future studies.
Aim 3 : Identify and characterize neurophysiological and neuroimaging correlates of disease severity in RTT. Individuals with RTT show marked abnormalities on a number of neurophysiological measures such as EEG and Evoked Potentials (EP), and animal models reproduce many of these abnormalities. Standard structural MRI in RTT is generally unremarkable;however, imaging changes are seen with specialized studies. Preliminarily, these data suggest an imbalance between excitatory and inhibitory function in cortical circuits, but the relationship between these neurophysiological and neuroimaging findings to disease severity and specific clinical features are unknown. To address this, we will prospectively collect non-invasive measures of E/l function on a subset of enrollees. Specifically, we will assess neurophysiological parameters using auditory evoked potential (AEP) and clinical EEG. We will also measure in these individuals Glutamate (Glu) and GABA concentrations in the auditory cortex of these individuals using Magnetic Resonance Spectroscopy (MRS). We will correlate AEP induced gamma frequencies and Glu and GABA concentrations to clinical severity, age, and mutation. This will identify relationships between neurophysiological and MRS data and test the hypothesis that E/l imbalance is a characteristic feature of RTT that correlates with key clinically-relevant parameters.
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