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-associated tremor/ataxia syndrome (FXTAS) is generally considered to be uncommon in older female carriers of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene; however, neither prevalence, nor the nature of the clinical phenotype, has been well characterized in female carriers. In this study, we evaluated 146 female carriers (mean, 42.3 years; range, 20-75 years) with and without core features of FXTAS (tremor; gait ataxia), and 69 age-matched controls (mean, 45.8 years; range, 21-78 years). Compared with controls, carriers with definite or probable FXTAS had greater medical co-morbidity, with increased prevalence of thyroid disease (P ¼ 0.0096), hypertension (P ¼ 0.0020), seizures (P ¼ 0.0077), peripheral neuropathy (P ¼ 0.0040), and fibromyalgia (P ¼ 0.0097), in addition to the typical symptoms of FXTAS-tremor (P < 0.0001) and ataxia (P < 0.0001). The non-FXTAS premutation group had more complaints of chronic muscle pain (P ¼ 0.0097), persistent paraesthesias in extremities (P < 0.0001), and history of tremor (P < 0.0123) than controls. The spectrum of clinical involvement in female carriers with FXTAS is quite broad, encompassing a number of medical co-morbidities as well as the core movement disorder. The remarkable degree of thyroid dysfunction (17% in the non-FXTAS group and 50% in the FXTAS group) warrants consideration of thyroid function studies in all female premutation carriers, particularly those with core features of FXTAS. ß

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Trisomy X is a sex chromosome anomaly with a variable phenotype caused by the presence of an extra X chromosome in females (47,XXX instead of 46,XX). It is the most common female chromosomal abnormality, occurring in approximately 1 in 1,000 female births. As some individuals are only mildly affected or asymptomatic, it is estimated that only 10% of individuals with trisomy X are actually diagnosed. The most common physical features include tall stature, epicanthal folds, hypotonia and clinodactyly. Seizures, renal and genitourinary abnormalities, and premature ovarian failure (POF) can also be associated findings. Children with trisomy X have higher rates of motor and speech delays, with an increased risk of cognitive deficits and learning disabilities in the school-age years. Psychological features including attention deficits, mood disorders (anxiety and depression), and other psychological disorders are also more common than in the general population. Trisomy X most commonly occurs as a result of nondisjunction during meiosis, although postzygotic nondisjunction occurs in approximately 20% of cases. The risk of trisomy X increases with advanced maternal age. The phenotype in trisomy X is hypothesized to result from overexpression of genes that escape X-inactivation, but genotype-phenotype relationships remain to be defined. Diagnosis during the prenatal period by amniocentesis or chorionic villi sampling is common. Indications for postnatal diagnoses most commonly include developmental delays or hypotonia, learning disabilities, emotional or behavioral difficulties, or POF. Differential diagnosis prior to definitive karyotype results includes fragile X, tetrasomy X, pentasomy X, and Turner syndrome mosaicism. Genetic counseling is recommended. Patients diagnosed in the prenatal period should be followed closely for developmental delays so that early intervention therapies can be implemented as needed. School-age children and adolescents benefit from a psychological evaluation with an emphasis on identifying and developing an intervention plan for problems in cognitive/academic skills, language, and/or social-emotional development. Adolescents and adult women presenting with late menarche, menstrual irregularities, or fertility problems should be evaluated for POF. Patients should be referred to support organizations to receive individual and family support. The prognosis is variable, depending on the severity of the manifestations and on the quality and timing of treatment.