Fragile X Syndrome

Fragile X syndrome (FXS), also known as Martin–Bell syndrome or Escalante syndrome, is an X-linked dominant genetic disorder characterised by mild-to-moderate intellectual disability. The average IQ in males with FXS is below 55, while about two-thirds of affected females have intellectual disabilities. Physical features may include a long and narrow face, large ears, flexible fingers, and large testicles.

Approximately one-third of those affected display features of autism, such as problems with social interactions and delayed speech. Hyperactivity is common, and seizures occur in about 10% of cases. Males are generally more affected than females.

Overview

Most young children do not show physical signs of FXS until puberty when features such as an elongated face, large or protruding ears, flat feet, larger testes (macroorchidism), and low muscle tone become apparent. Recurrent otitis media and sinusitis are common in early childhood. Speech may be cluttered or nervous, and behavioural characteristics can include stereotypic movements like hand-flapping, shyness, limited eye contact, memory problems, and difficulty with face encoding.

Females with FXS generally have symptoms ranging from mild to severe, and they are typically less affected than males due to variability in X-inactivation.

Intellectual Development

Individuals with FXS may present anywhere on a continuum from learning disabilities within a normal IQ range to severe intellectual disability, with an average IQ of 40 in males with complete FMR1 gene silencing. Females, who tend to be less affected, generally have a normal or borderline IQ with learning difficulties. The main difficulties include working and short-term memory, executive function, visual memory, visual-spatial relationships, and mathematics, with verbal abilities being relatively unaffected.

Autism

FXS co-occurs with autism in many cases and is a suspected genetic cause of autism. Screening for FMR1 mutation is considered mandatory in children diagnosed with autism. Prevalence of concurrent autism spectrum disorder (ASD) in those with FXS is estimated to be between 15% and 60%. Social withdrawal behaviours, including avoidance and indifference, appear to be the best predictors of ASD in FXS. When both autism and FXS are present, a greater language deficit and lower IQ are observed.

Social Interaction

FXS is characterised by social anxiety, including poor eye contact, gaze aversion, prolonged time to commence social interaction, and challenges in forming peer relationships. Social anxiety is common, with up to 75% of males characterised as having excessive shyness and 50% experiencing panic attacks. Individuals with FXS display anxiety and withdrawal when placed in unfamiliar situations, ranging from mild social withdrawal to severe social withdrawal associated with co-existing ASD.

Mental Health

Attention deficit hyperactivity disorder (ADHD) is found in the majority of males with FXS and 30% of females. Children with FXS have very short attention spans, are hyperactive, and show hypersensitivity to visual, auditory, tactile, and olfactory stimuli.

Anxiety symptoms are commonly associated with FXS, spanning multiple psychiatric diagnoses but not fulfilling any criteria in full. Perseveration, cluttered speech, and self-talk are common communicative characteristics in FXS. Mood symptoms are typically transient and related to stressors, involving fluctuating mood, irritability, self-injury, and aggression.

Diagnosis

Clinical diagnosis relies on identifying a variant of FMR1 associated with decreased function alongside moderate to severe intellectual impairment. Diagnostic tests include PCR to analyse the number of CGG repeats, Southern blot analysis, and examination of AGG trinucleotides in the FMR1 gene region. Prenatal testing with chorionic villus sampling or amniocentesis allows diagnosis of FMR1 mutation while the foetus is in utero.

Management

There is no cure for FXS. Management may include speech therapy, behavioural therapy, occupational therapy, and special education. Medications are used to treat symptom-based conditions such as hyperactivity, anxiety, and seizures. Genetic counselling is important for families with a history of FXS to assess the likelihood of having affected children.

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Self-assessment MCQs (single best answer)

Fragile X Syndrome (FXS) is also known as:

The average IQ in males with Fragile X Syndrome is:

Approximately what percentage of individuals with Fragile X Syndrome display features of autism?

Which of the following physical features is NOT commonly associated with Fragile X Syndrome?

Females with Fragile X Syndrome are typically less affected than males due to:

Which of the following is a common behavioural characteristic in individuals with Fragile X Syndrome?

What is the estimated prevalence of concurrent autism spectrum disorder (ASD) in those with Fragile X Syndrome?

Which type of therapy is NOT commonly used in the management of Fragile X Syndrome?

What diagnostic test is used to analyse the number of CGG repeats in the FMR1 gene?

Which of the following is a common mental health issue in individuals with Fragile X Syndrome?