Targeted treatments for fragile X syndrome

Abstract

Fragile X syndrome (FXS) is the most common identifiable genetic cause of intellectual disability and autistic spectrum disorders (ASD), with up to 50% of males and some females with FXS meeting criteria for ASD. Autistic features are present in a very high percent of individuals with FXS, even those who do not meet full criteria for ASD. Recent major advances have been made in the understanding of the neurobiology and functions of FMRP, the FMR1 (fragile X mental retardation 1) gene product, which is absent or reduced in FXS, largely based on work in the fmr1 knockout mouse model. FXS has emerged as a disorder of synaptic plasticity associated with abnormalities of long-term depression and long-term potentiation and immature dendritic spine architecture, related to the dysregulation of dendritic translation typically activated by group I mGluR and other receptors. This work has led to efforts to develop treatments for FXS with neuroactive molecules targeted to the dysregulated translational pathway. These agents have been shown to rescue molecular, spine, and behavioral phenotypes in the FXS mouse model at multiple stages of development. Clinical trials are underway to translate findings in animal models of FXS to humans, raising complex issues about trial design and outcome measures to assess cognitive change that might be associated with treatment. Genes known to be causes of ASD interact with the translational pathway defective in FXS, and it has been hypothesized that there will be substantial overlap in molecular pathways and mechanisms of synaptic dysfunction between FXS and ASD. Therefore, targeted treatments developed for FXS may also target subgroups of ASD, and clinical trials in FXS may serve as a model for the development of clinical trial strategies for ASD and other cognitive disorders.

The neurobiology of the Prader-Willi phenotype of fragile X syndrome

“…A previous study by Jennings et al demonstrated that GABAergic (Vgat-expressing) neurons in the LH are responsible for producing appetitive and consummatory behaviors (14). FXS animal models have lowered GABA subunit receptors, synthesis of GABA, GABAergic input to many regions of the brain, and increased catabolism of GABA (15,16). Similarly, cerebral GABAA receptor expression is reduced in several brain regions of subjects with PWS (17).…”

Fragile X Syndrome: A Review of Associated Medical Problems

“…Previous studies recruiting from programs focused on epilepsy and neurology clinics reported a broad range of 14% to 44% prevalence, [30][31][32][33][34][35][36][37][38] and genetics clinics reported an intermediate range of 9% to 27%. [39][40][41][42] Larger studies focused on people with FXS in the community or FXS clinics reported lower prevalence rates overall, ranging from 12% to 18%, 29,[43][44][45] and with higher prevalence for male than for female patients. In the FXCRC Database, seizures had occurred in 10% of patients, with a higher prevalence in male patients than in female patients (Table 1).…”

“…48,49 Seizures are easily controlled 29,31,36,38,42,45,47 and resolve during childhood in the majority of people with FXS. 43,47 Routine EEG screening of people with FXS is not recommended unless the patient presents with behaviors or episodes that might represent seizures.…”

“…A study of a small cohort showed a trend toward an elevated rate of seizures in people with FXS and autism (28%, compared with 12% with FXS alone). 50 Two studies from a large cohort of the National Fragile X Survey showed a higher frequency of ASD in people with FXS and seizures, as compared with an age-and gender-matched FXS group without seizures, 43 and a greater prevalence of seizures in male patients with FXS and ASD when compared with their counterparts without ASD. 51 Both studies suggest a shared neurobiology resulting in seizure and ASD propensity.…”

The Link between Genetic Abnormalities in the Monogenic Disorders and the Behavioral Phenotype of Polygenic Disorders Has Yet To Be Addressed in Research

“…Genes known to be causes of ASD interact with the translational *Corresponding author: Nagwa A Meguid, Professor of Human Genetics, National Research Centre, Cairo, Egypt, E-mail: meguidna@yahoo.com pathway defective in FXS, and it has been hypothesized that there will be substantial overlap in molecular pathways and mechanisms of synaptic dysfunction between FXS and ASD [13]. It was suggested that the difference between the 2 groups in the medial prefrontal and anterior cingulated cortices thickness may entail an altered social cognitive style [14].…”