title: The challenges of clinical trials in fragile X syndrome.
abstract: BACKGROUND
  Advances in understanding the underlying mechanisms of conditions such as fragile X syndrome (FXS) and autism spectrum disorders have revealed heterogeneous populations. Recent trials of novel FXS therapies have highlighted several challenges including subpopulations with possibly differential therapeutic responses, the lack of specific outcome measures capturing the full range of improvements of patients with FXS, and a lack of biomarkers that can track whether a specific mechanism is responsive to a new drug and whether the response correlates with clinical improvement.
  
  
  OBJECTIVE
  We review the phenotypic heterogeneity of FXS and the implications for clinical research in FXS and other neurodevelopmental disorders.
  
  
  RESULTS
  Residual levels of fragile X mental retardation protein (FMRP) expression explain in part the heterogeneity in the FXS phenotype; studies indicate a correlation with both cognitive and behavioral deficits. However, this does not fully explain the extent of phenotypic variance observed or the variability of drug response. Post hoc analyses of studies involving the selective mGluR5 antagonist mavoglurant and the GABAB agonist arbaclofen have uncovered significant therapeutic responses following patient stratification according to FMR1 promoter methylation patterns or baseline severity of social withdrawal, respectively. Future studies designed to quantify disease modification will need to develop new strategies to track changes effectively over time and in multiple symptom domains.
  
  
  CONCLUSIONS
  Appropriate selection of patients and outcome measures is central to optimizing future clinical investigations of these complex disorders.
authors.affiliation: Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois, 1011, Lausanne, Switzerland.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jacquemont
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Berry-Kravis
authors.forename: Randi
authors.initials: R
authors.lastname: Hagerman
authors.forename: Florian
authors.initials: F
authors.lastname: von Raison
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gasparini
authors.forename: George
authors.initials: G
authors.lastname: Apostol
authors.forename: Mike
authors.initials: M
authors.lastname: Ufer
authors.forename: Vincent
authors.initials: V
authors.lastname: Des Portes
authors.forename: Baltazar
authors.initials: B
authors.lastname: Gomez-Mancilla
mesh_terms: D000818:Animals; D002659:Child Development Disorders, Pervasive / Q000188:drug therapy / Q000503:physiopathology; D002986:Clinical Trials as Topic / Q000379:methods*; D005600:Fragile X Syndrome / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D006801:Humans; D010641:Phenotype