fXs

Fragile X syndrome (FXS) is a genetic condition and the most common inherited cause of intellectual disability and autism spectrum disorder. It is caused by an expansion of CGG trinucleotide repeats in the FMR1 gene on the X chromosome, leading to decreased or absent production of the FMRP protein.

Genetics: FXS is inherited in an X-linked manner. Full mutation (>200 CGG repeats) in the FMR1 gene leads to hypermethylation and silencing of FMR1, reducing FMRP production. Premutation carriers (55–200 repeats) can transmit the condition to offspring and have a risk of expansion in transmission, particularly when the mother is a carrier. Males are typically more severely affected; females may have milder symptoms due to X-inactivation and mosaic expression.

Clinical features: In males, intellectual disability and developmental delays with language impairments are common. Behavioral features include autism spectrum traits, anxiety, and attention-deficit symptoms. Physical features can include a relatively long face, large ears, high-arched palate, and flat feet; macroorchidism can appear after puberty. Seizures and connective tissue features occur in a subset of individuals.

Diagnosis: Molecular testing confirms FXS by CGG repeat sizing and FMR1 methylation analysis. Prenatal testing is available for at-risk pregnancies; mosaic cases may complicate results and interpretation.

Management: There is no cure. Management is multidisciplinary and individualized, emphasizing early intervention, speech and language therapy, occupational therapy, and educational supports. Behavioral therapies, treatment of ADHD, anxiety, and seizures as needed, and monitoring for associated medical issues such as cardiac and orthopedic problems are part of care.

Epidemiology and prognosis: FXS occurs in about 1 in 4,000 males and 1 in 8,000 females. Intelligence and daily functioning vary widely; with supportive care, many individuals achieve meaningful independence and quality of life, though challenges often persist.