Causes
Fragile X syndrome is a genetic disorder which occurs as a result of a mutation of the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene on the X chromosome, most commonly an increase in the number of CGG trinucleotide repeats in the 5 untranslated region of FMR1. Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 259 females. Incidence of the disorder itself is about 1 in every 3600 males and 1 in 4000–6000 females. Although this accounts for over 98% of cases, FXS can also occur as a result of point mutations affecting FMR1.In unaffected individuals, the FMR1 gene contains 5–44 repeats of the sequence CGG, most commonly 29 or 30 repeats. Between 45 and 54 repeats is considered a "grey zone", with a premutation allele generally considered to be between 55 and 200 repeats in length. Individuals with fragile X syndrome have a full mutation of the FMR1 allele, with over 200 CGG repeats. In these individuals with a repeat expansion greater than 200, there is methylation of the CGG repeat expansion and FMR1 promoter, leading to the silencing of the FMR1 gene and a lack of its product. This methylation of FMR1 in chromosome band Xq27.3 is believed to result in constriction of the X chromosome which appears fragile under the microscope at that point, a phenomenon that gave the syndrome its name. One study found that FMR1 silencing is mediated by the FMR1 mRNA.
Management
There is no cure for the underlying defects of FXS. Management of FXS may include speech therapy, behavioral therapy, occupational therapy, special education, or individualised educational plans, and, when necessary, treatment of physical abnormalities. Persons with fragile X syndrome in their family histories are advised to seek genetic counseling to assess the likelihood of having children who are affected, and how severe any impairments may be in affected descendants. Medication
Current trends in treating the disorder include medications for symptom-based treatments that aim to minimize the secondary characteristics associated with the disorder. If an individual is diagnosed with FXS, genetic counseling for testing family members at risk for carrying the full mutation or premutation is a critical first-step. Due to a higher prevalence of FXS in boys, the most commonly used medications are stimulants that target hyperactivity, impulsivity, and attentional problems. For co-morbid disorders with FXS, antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are utilized to treat the underlying anxiety, obsessive-compulsive behaviors, and mood disorders. Following antidepressants, antipsychotics such as risperidone and quetiapine are used to treat high rates of self-injurious, aggressive and aberrant behaviors in this population (Bailey Jr et al., 2012). Anticonvulsants are another set of pharmacological treatments used to control seizures as well as mood swings in 13%–18% of individuals with FXS. Drugs targeting the mGluR5 (metabotropic glutamate receptors) that are linked with synaptic plasticity are especially beneficial for targeted symptoms of FXS.