Department of Molecular Medicine, National Public Health Institute

........................................................................................................9 INTRODUCTION.............................................................................................10 REVIEW OF THE LITERATURE ................................................................11 1. AUTISM SPECTRUM DISORDERS AND DEVELOPMENTAL DYSPHASIA ..11 1.1. History ................................................................................................................................... 11 1.2. Clinical characteristics and classification .............................................................................. 12 1.2.1. Infantile autism ..................................................................................................12 1.2.2. Asperger Syndrome............................................................................................14 1.2.3. Developmental dysphasia ..................................................................................14 1.3. Epidemiological studies......................................................................................................... 16 1.4. Neuropathological, brain imaging and metabolic studies...................................................... 17 1.5. Molecular genetic studies ...................................................................................................... 19 1.5.1. Chromosomal aberrations .................................................................................19 1.5.2. Candidate gene studies ......................................................................................19 1.5.3. Genome-wide scans ...........................................................................................20 2. RETT SYNDROME ......................................................................................................24 2.1. Clinical characteristics and classification .............................................................................. 24 2.1.1. Classical Rett syndrome.....................................................................................24 2.1.2 Rett syndrome variants .......................................................................................25 2.2 Neuropathological and metabolic studies ............................................................................... 27 2.3. Molecular genetic studies ...................................................................................................... 28 2.3.1 Identification of the MECP2 gene underlying RTT syndrome............................28 2.3.2. Structure and function of the Mecp2 protein .....................................................28 2.3.3. Mutation spectrum and clinical phenotype of the patients ................................29 2.3.4. Mouse models for RTT.......................................................................................33 3. STATISTICAL APPROACHES ..................................................................................35 3.1. Background............................................................................................................................ 35 3.2. Linkage analyses.................................................................................................................... 36 3.3. Association studies ................................................................................................................ 37 4. STRATEGIES IN COMPLEX DISEASE MAPPING...............................................38 AIMS OF THE PRESENT STUDY................................................................40 MATERIALS AND METHODS .....................................................................41 5. PATIENT MATERIAL.................................................................................................41 5.1. Autism spectrum disorders and developmental dysphasia .................................................... 41 5.2. Rett syndrome........................................................................................................................ 44 6. METHODS .....................................................................................................................45 6.1. Genealogical studies .............................................................................................................. 45 6.2. DNA isolation and genotyping .............................................................................................. 45 6.3. Linkage and association analyses .......................................................................................... 45 6.4. Sequencing of the MECP2 gene ............................................................................................ 46 6.5. X chromosome inactivation studies....................................................................................... 47