The FMR1 mutations can cause a variety of disabilities, including cognitive deficits, attention-deficit/ hyperactivity disorder, autism, and other socioemotional problems, in individuals with the full mutation form (fragile X syndrome) and distinct difficulties, including primary ovarian insufficiency, neuropathy and the fragile X-associated tremor/ataxia syndrome, in some older premutation carriers. Therefore, multigenerational family involvement is commonly encountered when a proband is identified with a FMR1 mutation. Studies of metabotropic glutamate receptor 5 pathway antagonists in animal models of fragile X syndrome have demonstrated benefits in reducing seizures, improving behavior, and enhancing cognition. Trials of metabotropic glutamate receptor 5 antagonists are beginning with individuals with fragile X syndrome. Targeted treatments, medical and behavioral interventions, genetic counseling, and family supports are reviewed here. NIH Public Access Author ManuscriptPediatrics. Author manuscript; available in PMC 2010 June 21. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptKeywords fragile X syndrome; autism; behavioral interventions; fragile X mental retardation protein; targeted treatments; fenobam FRAGILE X SYNDROME (FXS) is associated with an array of intellectual and emotional disabilities, ranging from mental retardation (hereafter referred to as intellectual disability) to learning problems, autism, and anxiety. The cause of FXS is decreased or absent levels of fragile X mental retardation protein (FMRP). Decreased levels of FMRP typically are caused by the full mutation (>200 CGG repeats), which usually is methylated, in the proximal regulatory region of FMR1 (fragile X mental retardation 1 gene). 1-3 FXS occasionally occurs because of a point mutation or deletion in FMR1 4,5 or even a smaller expansion in the CGG repeat, which leads to lower levels of FMRP and intellectual disability. 6 Intellectual disability linked to FXS occurs in ~1 per 3600 individuals in the general population, 7,8 whereas milder cognitive and behavioral problems (eg, math and language deficits, social phobia, and attention-deficit/ hyperactivity disorder [ADHD]) associated with FXS may be more common. A more-frequent (1 of 130-250 female individuals and 1 of 250-800 male individuals) but smaller expansion (55-200 CGG repeats) of FMR1 is termed a premutation. [9][10][11][12] In contrast to the full mutation, the premutation usually does not cause decreased FMRP levels but leads to enhanced production of FMR1 mRNA (2-8 times normal levels) 13,14 (Fig 1). The enhanced mRNA production can lead to clinical features in premutation carriers that do not occur in full mutation carriers, including primary ovarian insufficiency and the fragile X-associated tremor/ataxia syndrome (FXTAS).In general terms, the severity of the FXS physical phenotype and intellectual impairment is correlated with the magnitude of the FMRP deficit. 1,2,15 Male individuals with incomplete methylation of a full mutation...

Fragile X syndrome (FXS) is the most common known genetic cause of inherited intellectual disability and the most common known singlegene cause of autism spectrum disorder. It has been reported that a spectrum of medical problems are commonly experienced by people with FXS, such as otitis media, seizures, and gastrointestinal problems. Previous studies examining the prevalence of medical problems related to FXS have been challenging to interpret because of their marked differences in population, setting, and sampling. Through this comprehensive review, we update the literature by reviewing studies that have reported on prominent medical problems associated with FXS. We then compare prevalence results from those studies with results from a large cross-sectional database consisting of data collected by fragile X clinics that specialize in the care of children with FXS and are part of the Fragile X Clinical and Research Consortium. It is vital for pediatricians and other clinicians to be familiar with the medical problems related to FXS so that affected patients may receive proper diagnosis and treatment; improved care may lead to better quality of life for these patients and their families. Pediatrics 2014;134:995-1005