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Fragile X syndrome
Fragile X syndrome (FXS) is a rare genetic disease associated with mild to severe intellectual deficit that may be associated with behavioral disorders and characteristic physical features.
Prevalence is estimated at approximately 1/4000-1/5000 although the prevalence may vary, depending on where the screening is carried out in the world.
FXS presents with a variable clinical phenotype. In males, the disease presents during childhood with delayed developmental milestones. Intellectual deficit can be of variable severity and may include problems with working and short-term memory, executive function, language, mathematics and visuospatial abilities. Behavioral anomalies can be mild (e.g. anxiety, mood instability) to severe (e.g. aggressive behavior, autism). Autistic-like behavior can include hand flapping, poor eye contact, hand biting, gaze avoidance, social phobia and tactile defensiveness. In females, intellectual and behavioral disorders are typically mild and usually consist of shyness, social anxiety, and mild learning problems with a normal IQ, although 25% of girls have an IQ less than 70. Attention deficit hyperactivity disorder (ADHD) is present in over 89% of males and 30% of females and behavioral disinhibition is very common. Recurrent otitis (60%) and seizures (20%) can also be observed. Physical features are subtle and may include a narrow and elongated face, prominent ears and forehead, hyperextensible finger joints, pes planus, and macroorchidism in postpubertal males.
FXS is caused by the transcriptional silencing of the FMR1 gene (Xq27.3) due to the progressive expansion and subsequent methylation of (CGG)n trinuleotide repeats in the 5'-untranslated region of the gene. These full mutations originate from unstable alleles called premutations (55-200 CGG repeats), also associated with other phenotypes, including a risk of primary ovarian insufficiency in women and the fragile X-associated tremor/ataxia syndrome (FXTAS; see this term). In some rare cases, FXS was shown to result from intragenic FMR1 point mutations or deletions. FMR1 codes for the FMRP, an RNA-binding protein that regulates protein synthesis and other signaling pathways in neuronal dendrites. FMR1 silencing is thought to reduce synaptic plasticity and modulation throughout the brain including the hippocampus.
Diagnosis cannot be based on the clinical picture as physical features may be mild or absent and is therefore based on genetic testing of FMR1, performed for all patients with an intellectual deficiency or autism.
The differential diagnosis includes other X-linked intellectual deficiencies, Sotos syndrome, microdeletion syndromes (e.g. 22q11.2 deletion syndrome), fetal alcohol syndrome (see these terms) or idiopathic autism.
Prenatal diagnosis is based on Southern blot hybridization and PCR on samples of chorionic villi or amniotic fluid.
FXS is an X-linked dominant disorder with reduced penetrance in females. Genetic counseling should be offered to families of an affected individual or of carriers of the premutation.
Management and treatment
Management is symptom-based and requires a multidisciplinary approach. Treatment with drugs, such as stimulants and selective serotonin reuptake inhibitors (SSRIs; for anxiety, obsessive-compulsive behaviors) and atypical antipsychotic agents (for self-injury, aggressive behaviors, and autism), should be combined with speech therapy, sensory integration occupational therapy, individualized educational plans, and behavioral interventions. New targeted treatments for FXS (mGluR5 antagonists, GABA A and B agonists, minocycline) are now being studied. Early reports are promising for minocycline. These new treatments are likely to modify the lifetime course of FXS and to improve the prognosis.
Currently most boys and approximately 30% of girls with FXS will have significant intellectual deficiency in adulthood.
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