An interdisciplinary View: The Early Phenotype of Fragile X Syndrome

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and the most common genetic cause of autism spectrum disorders. It results from the silencing of the FMR1 gene and the consequent deficit or absence of the fragile X mental retardation protein (FMRP). As FMRP regulates a number of proteins important for synaptic plasticity, FXS is associated with a wide range of physical, neurological and neurobehavioral abnormalities (fine and gross motor performance, speech-language and socio-communicative functions). As FXS has, in contrast to other genetic disorders like Down syndrome, no apparent dysmorphic features peri- or even postnatally, these functional abnormalities must reach a clinical "threshold" to justify genetic testing. While the average family of individuals with FXS has concerns about the child`s development during the early-mid infancy period, the average age of FXS diagnosis for boys is around 3 years of age and for girls even later around 3,6 years. This certainly delays access to services, frustrates parents, and may also lead to the birth of a second child with FXS before the diagnosis of the first one. As knowledge about the early FXS phenotype is still limited, the proposed project intends to delineate early signs of deviation from typical development in individuals with FXS during their first two years of life. It will be based on the retrospective analysis of family audio-video recordings, a method with proven value to the delineation of early phenotypical peculiarities, for example in Rett syndrome and autism spectrum disorders. The aim of the proposed project is to test the hypotheses that individuals with FXS will have abnormal gross- and fine-motor development and performance; age-inadequate and abnormal postural patterns; deviations in speech- language development, socio-communicative skills and play behavior during their first two years of life. Furthermore, we will focus on the first appearance of stereotypies such as hand flapping and biting, the first signs of tactile defensiveness, and the issue if any of the observed signs are specific for FXS. By identifying and delineating the early signs of deviation from typical development in individuals with FXS this study has as its long term aim to facilitate timely genetic diagnosis of FXS, which will enable affected individuals to access early intervention services and alert their families to timely genetic counselling.

The FWF Project P25241 An Interdisciplinary View: The Early Phenotype of Fragile X Syndrome. Delineating First Signs of Deviation for Timely Detection was part of our comprehensive long-term research initiative and research group iDN (interdisciplinary Developmental Neuroscience) focusing on typical and atypical child development. The aim of the FWF project was to shed light on the first two years of life of individuals with fragile X syndrome (FXS) 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 earlier identifying this developmental disorder in the future. To reach these goals we conducted detailed analyses of home videos and parental questionnaires studying the above-mentioned developmental domains throughout the first two years of life in a group of individuals later diagnosed with FXS. In addition, we initiated a cross-syndrome comparison approach to compare early development of infants later diagnosed with FXS, Rett syndrome (RTT), and autism spectrum disorder (ASD). Our findings contributed to a better understanding of the prodrome of these disorders and we provided a profound body of evidence of early atypicalities and deviant developmental pathways in the above-mentioned domains. In particular, our results are among the first to describe the early onset of hand stereotypies in FXS, and to demonstrate different developmental profiles over time comparing FXS, RTT and ASD, for example, by assessing a single behavioural marker response to name calling. 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, to contribute to our understanding of the developing brain has been accomplished. Our results made it clear that further research is needed in order to (A) identify an FXS specific symptom constellation and gain a better understanding of the pre-diagnostic development of FXS that will (B) enable earlier diagnosis in affected children in order to enable earlier intervention.