Fragile X syndrome

Fragile X syndrome (FXS), also known as Martin-Bell syndrome, is the most common inherited cause of intellectual disability and the leading single-gene cause of autism spectrum disorder. It is caused by a CGG trinucleotide repeat expansion in the FMR1 gene located on the X chromosome (Xq27.3). When the CGG repeat exceeds approximately 200 copies (full mutation), the FMR1 gene becomes hypermethylated and silenced, resulting in absent or markedly reduced production of the fragile X messenger ribonucleoprotein (FMRP), a protein essential for normal neuronal development and synaptic plasticity. The syndrome primarily affects the nervous system, leading to mild to severe intellectual disability, developmental delays (particularly in speech and language), attention deficit, hyperactivity, anxiety, and autistic-like behaviors including poor eye contact, hand flapping, and social avoidance. Physical features become more apparent with age and may include a long face, prominent ears, a prominent jaw (macrognathia), macroorchidism (enlarged testes after puberty in males), joint hypermobility, flat feet, and soft skin. Males are generally more severely affected than females, as females have a second X chromosome that may partially compensate. Some individuals also experience seizures, recurrent otitis media, strabismus, and mitral valve prolapse. There is currently no cure for Fragile X syndrome. Management is multidisciplinary and supportive, involving speech and language therapy, occupational therapy, behavioral interventions, and special education services. Pharmacological treatments target specific symptoms: stimulants or alpha-2 adrenergic agonists for attention problems, selective serotonin reuptake inhibitors (SSRIs) for anxiety, and anticonvulsants for seizures. Research into targeted therapies, including mGluR5 antagonists and other agents aimed at correcting downstream molecular consequences of FMRP deficiency, has been ongoing, though no targeted therapy has yet received regulatory approval. Genetic counseling is essential for affected families, particularly regarding the risk of premutation carriers developing fragile X-associated tremor/ataxia syndrome (FXTAS) or fragile X-associated primary ovarian insufficiency (FXPOI).

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

Common questions about Fragile X syndrome