Rett Disorder: The Pre-Regression Period

The proposed study will be an extension and continuation of our detailed research project, which provided compelling evidence of deviation from normal development in 1- to 6-month-old infants with Rett disorder. The aim of the proposed study is to shed light on the development of Rett girls from 6 months to the onset of regression (12 to 18 months) as a contribution to the early diagnosis of this neurodisability. Rett disorder is a neurodevelopmental condition resulting from mutations in the gene MECP2 for methyl-CpG- binding protein 2. However, in the light of the presence of Rett syndrome without MECP2 mutations, and the description of mutations in individuals without Rett features, the clinical criteria for the delineation of the disorder are of utmost importance. After some development during the first year of life (Stage I), children with classical Rett syndrome enter a period of rapid regression (Stage II) during which speech and purposeful hand use diminishes and cranial growth slows. The characteristical hand movements begin to emerge and include wringing, washing, clapping, or tapping, as well as repeatedly moving the hand(s) to the mouth. Breathing irregularities, autistic-like symptoms, unsteady gait patterns, apraxia, motor problems, and seizures are prominent during Stage III. The subsequent Stage IV is characterized by reduced mobility, muscle weakness, rigidity, spasticity, dystonia, and scoliosis. The proposed study is in the tradition of the observation of infant behaviour that has been recently stressed again to be fundamental to the understanding of developmental neurology and ontogenetic adaptation. We propose to address questions concerning individual developmental trajectories of gross and fine motor performance, hand preference, (hand) stereotypies, facial expression, interaction with the environment, and communication. Furthermore we shall relate the early behavioural phenotypes to later severity and various genotypes. In addition, findings obtained in girls with Rett syndrome will be compared with data obtained from video analyses of children developing normally, or with minor neurological dysfunctions, or with cerebral palsy and/or intellectual disabilities, Fragile-X syndrome, autism spectrum disorder, and Angelman syndrome. Methods applied will be the following: systematic video analyses of family videos of sufficient length and quality, extensive parental questionnaires and checklists, and direct observation. Both, the early history of Rett disorder and the association between genotype and phenotype are two of the three topics of interest defined by the International RettSearch Consortium. Hence, our study will provide substantial contribution to these efforts facilitating early diagnosis as a basis for early intervention.

FWF Project P19581-B02 (Rett Disorder: The Pre-Regression Period) was part of our comprehensive long-term research project (Developmental Physiology and Developmental Neuroscience) on normal and impaired child development. The aim of the FWF project was to shed light on the first two years of life of individuals with Rett syndrome, focussing on the development of gross and fine motor proficiencies, as well as the speech-language, socio- communicative and cognitive domains. In addition, by delineating atypical developmental pathways, we aimed at contributing to reduce the mean age of diagnosis for this devastating progressive neurodevelopmental disorder. To reach these goals we conducted detailed analyses on the above-mentioned developmental domains throughout the first two years of life (i.e. the pre-regression period) in 43 children with Rett syndrome. Our findings contributed to a new view of the pre-regression period of Rett syndrome, for we provided a profound body of evidence of early atypicalities / abnormalities and deviant developmental pathways in the above-mentioned domains. Also, our results on the Preserved Speech Variant of Rett suggested that this syndrome variant should be relabelled, as the speech- language domain is restricted from the very beginning and follows an atypical pathway. The aim of the project to delineate neurophysiological and behavioural peculiarities (e.g. abnormal motor development, early socio-communicative and speech-language deficiencies) and thus contribute to our understanding of MECP2 mutations on the developing brain was largely accomplished. Yet our results also made it clear that further research is needed in order to (A) define a critical threshold of abnormal early signs and gain a better understanding of the crucial first years of development of Rett; and (B) to allow for an earlier diagnosis in affected children (i.e. before they reach toddler age).