• MECP2
• rett

The topic of this PhD thesis is the Rett syndrome (RTT, OMIM 312750), an X-linked neurodevelopmental condition characterized by loss of spoken language and hand use with the development of distinctive hand stereotypies, originally described in the 1960s by Andreas Rett [Rett1966].
The interest for RTT stems from the consideration that, although a rare disease, it is responsible for a high percentage of cases of mental retardation in children.
The clinical diagnosis has been based on consensus clinical criteria [Hagberg et al 2002], which have been slightly modified over time to reflect increased understanding of the disease features. More than 95% of individuals with RTT have mutations in methyl-CpG-binding protein 2 gene (MECP2), whose protein product modulates gene transcription.
Currently, no effective treatment is available for this disorder although many trials were conducted on RTT patients and animal studies have suggested that RTT symptoms are potentially revers¬ible.
The aim of this research project, supported by TELETHON (Application GGP09196), is to identify specific biomarkers of RTT using neurophysiological and neuroimaging techniques on a group of 16 RTT girls with proven MECP2 mutation. The identification of potential biomarkers of RTT syndrome could be relevant to monitoring both the progression of disease and the response to experimental treatment.

The first part of this PhD thesis including the first two chapters describing the introduction to the RTT syndrome focused mainly on clinical and genetic aspects of the disease.
From the chapter 3 starts the second part of the work representing the main core of the research project: firstly, an introduction and overall aims and methodological approaches to the study; secondly, a detailed description of the neurophysiological and imaging studies, each organized in subsections.
The multimodal neurophysiological approach allowed us to evaluate the amount of impairment of central motor and sensory pathways in this disorder and, to our knowledge, this type of study is the first reported on RTT after the identification of MECP2 as causative gene of the syndrome.
The neuroimaging including Voxel Based Morphometry (VBM), Diffusion Tensor Imaging (DTI) and Arterial Spin Labeling (ASL) studies. VBM findings seemed to further confirm the global hypoplasia of RTT brain, already reported in literature, with preferential involvement of GM, rather than a progressive reduction of brain tissue. In DTI study our sample showed a reduction of Fractional Anisotropy in the same areas (corpus callosum, centrum semiovale..) reported in literature but only in younger RTT girls.
Finally, the application of ASL technique to RTT was the first report in literature toward an analysis performed on case-control study, also in relation to the different RTT clinical characteristics (epilepsy, cardiorespiratory phenotype, disease severity). Almost all patients showed elevated cerebral perfusion values in comparison with controls of same age and we discussed the hypothesis of a brain immaturity in RTT more than a neurodegenerative process.
The thesis concludes with a general discussion of the topic and the future perspectives on the importance to corroborate the potential role of the multimodal neurophysiological approach and of the ASL as markers of RTT disease.