Introduction

Fragile X syndrome (FXS) is a rare genetic disorder characterised by intellectual disability and behavioural challenges that affect males to a higher proportion than females.¹ FXS is the most common inherited cause of intellectual disability that affects approximately 1 in 4,000 to 1 in 7,000 males and 1 in 6,000 to 1 in 11,000 females, respectively.² It is caused by a mutation in a gene called the fragile X messenger ribonucleoprotein 1 gene (FMR1) located on the X chromosome, which leads to a deficiency or complete absence of the fragile X mental retardation protein (FMRP), which is needed for normal brain development.¹

Males typically experience more severe symptoms than females because they only have one X chromosome. In contrast,  the other X chromosome in females provides some degree of compensation for the mutated X chromosome, thereby lessening their symptom severity.

Symptomatology of fragile X syndrome (FXS)

In males

The following symptoms will present differently between individuals. However, some features, such as a long face and macroorchidism, may be more prevalent in the post-pubertal stage.²

Physical characteristics

• Long face
• Large ears
• Hyperextensive joints – particularly fingers
• Low muscle tone
• Flat feet
• Large testicles (i.e., macroorchidism) in males after puberty

Behavioural characteristics

• Aggressive-like tendencies
• Hand flapping
• Anxiety
• Poor eye contact
• Sensory processing difficulties
• Sleep disorders
• Autism spectrum disorders
• Attention deficit hyperactivity disorder (ADHD)

Cognitive features

• Range widely from mild learning disabilities to severe intellectual disabilities
• Speech and language disturbances
• Motor delay (e.g., walking, crawling)

Other symptoms may include seizures and strabismus (i.e., crossed eyes).²

In females

Behavioural characteristics observed in males may also appear in females, but females often have a milder presentation of the features of FXS than their male counterparts.²

Pharmacological interventions

There is currently no cure for FXS.³ People with FXS may exhibit developmental delays and behaviour that requires additional support. Medications are used to manage symptoms such as anxiety and aggression, and improve the overall standard of living.

Disclaimer: the following list of medications (as well as the subsequent treatment strategies) mentioned below are stated for educational purposes only, and are not intended as medical advice. The therapeutic interventions for FXS should be discussed with a qualified healthcare professional who can tailor recommendations to individual needs. Please remember to consult a healthcare provider before starting, stopping or modifying any treatment plan.

The medications listed below are in the format of their generic name listed, followed by the most common brand name in parenthesis. 

Antipsychotic medications

Antipsychotic medications are often prescribed to manage symptoms of aggression and anxiety in people with FXS. Behavioural challenges such as aggression may interfere with daily activities and pose a significant threat to the affected person and those around them. The following medications have been approved by the FDA for treating aggressive behaviour, commonly observed in those with autism spectrum disorder (ASD) aged 5 and up:⁴

• Aripiprazole (Abilify)
• Risperidone (Risperdal)
• Olanzapine (Zyprexa)

Side effects of antipsychotic medications

• Early stages: restlessness, spasm movement of the eyeball, neck and mouth, and abnormal body movements that are involuntary⁴
• Later stages: stiff, jerky movement of the face and body, lethargy(fatigue, tiredness, and lack of energy) and weight gain⁴

Non-psychotic medications

Non-psychotic medications treat aggressive behaviours. These include selective serotonin reuptake inhibitors (SSRIs), which address self-injurious behaviour and anxiety spells.⁴ These medications treat a wide range of symptoms that do not involve psychosis, such as pain.

• Sertraline (Zoloft)
• Citalopram (Celexa)
• Escitalopram (Lexapro)

Side effects of non-psychotic medications

• Sleeping difficulties (can be managed by altering the dose or discontinuing it)
• Agitation
• Nausea
• Diarrhoea

Beta blockers

Beta blockers manage symptoms like aggression, anxiety and hyperactivity.⁴ They are used to block the effects of adrenaline (i.e., a hormone and neurotransmitter produced by adrenal glands to increase heart rate and elevate blood pressure), and related hormones, thereby helping to calm down the nervous system.

• Propranolol (Inderal)

Side effects of beta blockers

• Headaches
• Dizziness

Benzodiazepines

Benzodiazepines, in the context of FXS, are commonly used to treat emotional outbursts that are accompanied with increased levels of anxiety.⁴ These medications should be avoided for long-term treatment as they may interfere with memory and lead to increased confusion. Additionally, they are addictive and may be hard to wean off.

• Clonazepam (Klonopin)
• Lorazepam (Ativan)

Side effects of benzodiazepines

• Clonazepam is a sedating medication that may cause increased drooling⁴

Other medications

• Metformin is a medication that may address weight gain in individuals who are on other drugs that increase weight.⁴ Side effects are possible.

Benztropine (Cogentin) may be administered to address excessive drooling that is associated by taking antipsychotics.⁴

• There are a variety of medications that address self-injurious behaviour in those with FXS. Some include aripiprazole, ziprasidone and risperidone⁴
• Melatonin may be used to address sleeping problems if managing sleeping difficulties through other avenues, such as adjusting bedtime schedules, do not work⁴

Behavioural and educational interventions

The management of FXS symptoms often requires a multidisciplinary approach to ensure an individual lives optimally and has the necessary support throughout their life. Doctors work with other healthcare professionals to help determine the therapy that will best suit an individual’s personal needs. This may look different between two individuals with FXS.

Speech-language therapy

This form of therapy aims to address challenges in communication amongst people with FXS. Therapists often provide assistance in the articulation and pronunciation of words, the development of language (e.g., enhancing vocabulary and comprehension), improving conversational skills and understanding social cues.⁵

Occupational therapy

Occupational therapy aims to enhance an individual’s daily living skills, as well as to promote independence. Therapists work with FXS patients to improve fine motor skills (e.g., coordination and dexterity for tasks like writing), adaptive skills such as dressing and self-care routines, social skills (e.g., interacting with peers and participating in group activities), as well as sensory integration to improve sensory processing challenges.⁵

Physical therapy

Motor skills are a crucial part of life. Physical therapy addresses the development of motor skills by helping individuals who have coordination issues associated with FXS to enhance mobility. Techniques include improving muscle strength and balance.⁵

FAQs

What triggers fragile X syndrome?

Fragile X syndrome is an inherited condition caused by a mutation to the FMR1 gene on the X chromosome.⁶ FMR1 is responsible for the production of a protein called FMRP which helps the brain to develop and function normally. When there is a mutation in the FMR1 gene, this often leads to a decrease or complete cessation of FMRP production, which induces FXS.

What are the available technologies for fragile X syndrome?

Children with FXS who are currently not speaking may benefit from assistive technology such as a language board or a computerised device. For children with decreased muscle tone, they may benefit from using a special chair that improves posture.

What is the life expectancy for a person with fragile X Syndrome?

People with FXS often have a normal life expectancy. Most FXS patients have active lifestyles coupled with support from various healthcare providers such as occupational therapists.⁷

Summary

Fragile X syndrome (FXS) is an inherited genetic disorder characterised by intellectual disability and learning challenges more frequently observed in males than females. FXS is caused by a mutation in the FMR1 gene found on the X chromosome, which leads to a deficiency of FMRP that is needed for normal brain development. Common symptoms associated with FXS include a range of physical, behavioural and cognitive features. People with FXS may have a long face, large ears, hyperextensive joints, aggressive-like tendencies and sensory processing difficulties. There is currently no cure for FXS, but a combination of medications and motor skill development techniques may improve the standard of living for those affected. Common medications are antipsychotics and selective serotonin reuptake inhibitors (SSRIs) which aim to address aggression and anxiety, respectively. Other therapeutic interventions include physiotherapy and speech-language therapy to improve motor skills and communication.