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

Abstract

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.

An analysis of challenging behavior, comorbid psychopathology, and Attention-Deficit/Hyperactivity Disorder in Fragile X Syndrome

“…Bailey et al, 2008). An explanation for the concurrence of these results with previous findings, despite the different age ranges assessed, may be due to the fact that symptoms of AD/HD are found to decrease as individuals with FRAX grow older (Tranfaglia, 2011).…”

“…Psychopathology is a further condition found to co-occur with FRAX with disorders such as anxiety and depression being prevalent (Tranfaglia, 2011). The behavioral expression of anxiety in FRAX may include poor eye-contact, gaze aversion, and shyness (Tranfaglia, 2011).…”

“…The behavioral expression of anxiety in FRAX may include poor eye-contact, gaze aversion, and shyness (Tranfaglia, 2011). Moreover, anxiety may manifest itself in the form of challenging behavior such as SIB and aggression towards others in this population (Boyle & Kaufmann, 2010).…”

“…The most commonly diagnosed comorbid condition in FRAX however is AD/HD (Tranfaglia, 2011). High levels of AD/HD are typically seen in early childhood.…”

“…High levels of AD/HD are typically seen in early childhood. As the individual matures, symptoms of AD/HD are found to decrease, although deficits in attention may persist (Tranfaglia, 2011). In a national parent survey, Bailey et al (2008) found that 66% of males and 30% of females with the FMR1 full mutation exhibited significant issues with hyperactivity.…”