Fragile X-associated conditions: implications for the whole family

Abstract

Fragile X syndrome (FXS) is a triplet-repeat expansion disorder of the X chromosome, with repeats of more than 200 (sometimes referred to as the full mutation) causing FXS and ∼59–200 repeats (the so-called premutation) being responsible for a variety of clinical presentations. Clinicians in primary care should be aware of these conditions and in particular be vigilant for common comorbidities to allow for early treatment. This article summarises the common issues for individuals with FXS and carriers of the premutation. FXS is the most common inherited cause of intellectual disability, occurring in approximately 1 in 3000–4000 males and 1 in 6000–8000 females. Although the genetic underpinnings of FXS are similar across individuals, the manifestations vary widely and in some ways there is no ‘typical’ presentation. Nonetheless, males with the syndrome generally have an intellectual disability ranging from mild to severe, whereas females are much more variably affected (due to random X-inactivation) and can range from being essentially asymptomatic to having a severe intellectual disability. There are a number of common physical comorbidities associated with the syndrome including epilepsy (∼25%), mitral valve prolapse (≤80%), hyperextensible joints, and an increased risk of inguinal hernias. Anxiety, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorders (ASDs) are also significantly more common. Hyperarousal and sensory hypersensitivity are frequent symptoms, which may occur across a range of diagnoses. It is worth noting that, although one-third to two-thirds of individuals with FXS may meet criteria for an ASD, the presentation often varies subtly from that seen in idiopathic ASDs. In particular, some traits such as social difficulties and atypical eye contact may have very different underpinnings in FXS as compared with ASDs. …