Fragile X-associated disorders (FXD) are a group of disorders caused by expansion of non-coding CGG repeat elements in the fragile X (gene. FXPM disorders although to a lesser degree [3-6]. This review will focus primarily on carriers and the neuropsychiatric consequences of premutation status. We will discuss the various neurodevelopmental phenotypes that commonly present in carriers such as ASD ADHD and seizures. We also discuss the burden of mood and anxiety disorders that affect many adult and some female child carriers. These are sometimes accompanied by cognitive decline that may precede FXTAS and an associated cortical-subcortical dementia the details of which continue to be fully elucidated. We highlight some of the clinical neuroimaging findings in these disorders to emphasize both the clinical and endophenotypic overlap with other neuropsychiatric disorders. Suggestions for appropriate genetic testing are provided taking into consideration both psychiatric and neurological symptoms with a strong emphasis on family history. Lastly we provide treatment suggestions for psychiatric symptoms based on reported clinical experience AZD6140 and offer our thoughts on the most fruitful areas of future research to AZD6140 improve our understanding and treatment of FXPM disorders. Neurodevelopmental AZD6140 Disorders in Carriers Initial studies comparing psychiatric phenotypes of carriers with related non-carriers suggested that there were few if any differences [7]. However with expanded study it became clear that some carriers were clinically affected presenting with intellectual disability learning difficulty or ASD Rabbit polyclonal to ARHGAP15. [8-11]. There has since been significant investigation into the frequency of ASD in the carrier population. Many studies use a design that compares the phenotype of probands carriers that are identified by presenting to clinicians for medical purposes to related non-probands carriers that are identified secondary to genetic testing of family members of a proband. In an early case series Aziz et al described 10 proband boys with high rates of social impairment hyperactivity delayed receptive and expressive vocabulary and impaired social use of language [12]. The rate of ASD in carrier probands has since been found to be significantly higher than both AZD6140 non-probands and related non-carriers [10 11 Farzin et al compared 14 male probands 13 non-probands and 16 related controls [10]. They found that 79% of probands met the criteria for an ASD; 29% for autistic disorder and 50% for pervasive developmental disorder-not otherwise specified. In contrast only 8% of non-probands met criteria for ASD. In a study of 50 boys (25 probands 25 non-probands) with the premutation Chonchaiya et al observed similar trends in the relative frequency of ASD [11]. Compared with non-carriers ASD was significantly more frequent in both probands and non-probands [11]. In studies of young adult male carriers social deficits consistent with ASD have also been observed [13]. Compared with unrelated noncarriers carriers had poorer social cognition with the most notable impairment on interpersonal skills that require accurate social perception such as recognizing complex emotions from photographs of eyes [13]. Additional epidemiological data comes from a national survey that asked parents to report neuropsychiatric symptoms such as attention problems hyperactivity aggressiveness self-injury autism seizures anxiety or depression along with the mutational status of all of their children [14]. They identified 211 female and 65 male carriers and compared them to sex-matched controls. In male carriers 33 were reported to have developmental delays (DD) 41 attention problems 19.3% aggressiveness 19.3% autism 11.3% seizures and 33.3% anxiety [14]. All conditions AZD6140 were significantly more common in carriers than in controls. In contrast only 8.6% of females were reported to have DD 1.1% autism 18.5% attention problems 35.6% anxiety and 34.2% depression suggesting that mood disorders may be the AZD6140 most predominant psychiatric disorder in female children with the premutation [14]. The main limitation to this study was that all data was ascertained from parent report and was not verified for accuracy. Additionally there was a low response rate from low socioeconomic status and ethnic minority groups. Therefore these results may not be broadly generalizable to all carriers. However Clifford et al observed similar trends in autism frequency in a study of 7 male and 43 female carriers who ranged in age from 5 to 80 years with 14.3% of males and 7% of females meeting.