The Psychiatric Presentation of Fragile X: Evolution of the Diagnosis and Treatment of the Psychiatric Comorbidities of Fragile X Syndrome

Fragile X syndrome (FXS) is the leading inherited cause of mental retardation and autism spectrum disorders worldwide. It presents with a distinct behavioral phenotype which overlaps significantly with that of autism. Unlike autism and most common psychiatric disorders, the neurobiology of fragile X is relatively well understood. Lack of the fragile X mental retardation protein causes dysregulation of synaptically driven protein synthesis, which in turn causes global disruption of synaptic plasticity. Thus, FXS can be considered a disorder of synaptic plasticity, and a developmental disorder in the purest sense: mutation of the FMR1 (fragile X mental retardation 1) gene results in abnormal synaptic development in response to experience. Accumulation of this abnormal synaptic development, over time, leads to a characteristic and surprisingly consistent behavioral phenotype of attention deficit, hyperactivity, impulsivity, multiple anxiety symptoms, repetitive/perseverative/stereotypic behaviors, unstable affect, aggression, and self-injurious behavior. Many features of the behavioral and psychiatric phenotype of FXS follow a developmental course, waxing and waning over the life span. In most cases, symptoms present as a mixed clinical picture, not fitting established diagnostic categories. There have been many clinical trials in fragile X subjects, but no placebo-controlled trials of adequate size or methodology utilizing the most commonly prescribed psychiatric medications. However, large and well-designed trials of investigational agents which target the underlying pathology of FXS have recently been completed or are under way. While the literature offers little guidance to the clinician treating patients with FXS today, potentially disease-modifying treatments may be available in the near future.