FXS is the most common cause of inherited intellectual disability, affecting up to 1 in 2,500 males and 1 in 4,000 females. Triplet-repeat expansion in the FMR1 gene leads to a loss of function in FMRP, a regulatory protein linked to neuronal development and plasticity. Clinical features of FXS are rather unspecific and genomic testing is mandatory to confirm the diagnosis. FXS may present itself in many shapes from mild learning difficulties to severe mental retardation and the extent of disability correlates with expression levels of FMRP. For its X-linked nature, female patients with a normal allele can present a very mild phenotype. Muscular hypotonia and speech delay usually allow for an early diagnosis before the age of three. However, due to the uncharacteristic nature of associated symptoms diagnosis may be delayed until later childhood or adolescence.
Besides cognitive dysfunction, the full clinical picture of FXS is often characterized by severe behavioural abnormalities such as anxiety, autism, attention-deficit, hyperactivity, and (auto-) aggression. Up to 20% of FXS-patients may develop – mostly benign forms of sleep - epilepsias. Physical features may comprise a long and slim face, prognathism and rather prominent ears. Macroorchidism is very common in males and may be associated with infertility. Weak connective tissue can lead to hyper-extensible joints, and some reports claim a higher incidence of mitral valve prolapse and aortic dilatation in FXS. There is a high prevalence of obstructive sleep apnoea in FXS.