Fragile-X Syndrome
Genetics and Pathophysiology
Fragile-X syndrome is the most common inherited cause of intellectual disability. It is an X-linked condition caused by an abnormal expansion of a CGG trinucleotide repeat in the promoter region of the FMR1 gene on the X-chromosome (Xq27.3).
Normal: <45 CGG repeats.
Intermediate: 45-54 repeats.
Premutation: 55-200 repeats. This is a carrier state. While typically not associated with Fragile-X syndrome, premutation carriers are at risk of developing other related disorders and the repeat can expand to a full mutation in subsequent generations, particularly when passed down from a female.
Full Mutation: >200 CGG repeats. The excessive repeats lead to hypermethylation of the promoter region, which silences the gene. This results in the absence of the Fragile-X Mental Retardation Protein (FMRP), a protein crucial for normal synaptic development and function.
Clinical Features
Clinical presentation varies significantly, particularly with age and gender. A key point for diagnosis is that the characteristic physical features are often subtle or absent in young children, which can delay diagnosis.
Features in Young Children:
Developmental Delay: A primary presenting concern, often affecting speech, language, and motor skills.
Behavioural Issues: Hyperactivity, short attention span, impulsivity, and social anxiety. Autism spectrum disorder (ASD) is diagnosed in 50–70% of boys with Fragile-X.
Sensory Issues: Hypersensitivity to stimuli (e.g., sound, light, touch) is common.
Features in Older Children and Adolescents (Dysmorphic features become more apparent):
Craniofacial: A long, narrow face with a prominent jaw (prognathism) and large, prominent ears.
Connective Tissue: Mild joint laxity and flat feet.
Macroorchidism: Characteristically large testes, usually after puberty, is a key diagnostic clue in males.
Associated Conditions:
Learning disabilities: Ranging from mild to severe intellectual disability.
Autism Spectrum Disorder: As noted above, there is a high comorbidity.
ADHD and other behavioural issues.
Mood/Mental Health Disorders: Including anxiety and depression.
Seizures (affecting up to 20% of males).
Diagnosis and Recent Developments
The diagnosis is made through a DNA blood test to detect the CGG repeat expansion.
Recent Change in NHS England (2025): The targeted test for the FMR1 expansion has been withdrawn and replaced by Whole Genome Sequencing (WGS) for paediatric disorders. If Fragile-X is clinically suspected, testing will now be part of a broader genetic panel that also analyses genes associated with other syndromic intellectual disabilities.
Diagnostic Referral: Referral for testing is usually via a GP or paediatrician. It should be considered for any child with a learning disability, developmental delay, or autistic-like behaviours.
Supportive Management
Management is multi-disciplinary and should begin with early intervention.
Early Intervention: Early access to speech and language therapy, occupational therapy, and physiotherapy is critical for developmental support.
Educational Support: Tailored learning support in school is essential, often with a focus on visual learning and addressing sensory needs.
Behavioural Strategies: Behavioural therapy and structured routines can help manage hyperactivity, impulsivity, and anxiety.
Medications: Can be used to manage specific co-morbidities such as ADHD (e.g., methylphenidate), seizures, or mood disorders. Research on targeted pharmacological treatments continues, but there are no specific drugs to treat the underlying cause of Fragile-X syndrome.
Fragile-X Associated Conditions in Carriers
For UK paediatric doctors, it is important to be aware of conditions that affect parents or other relatives who are premutation carriers.
Fragile-X Associated Tremor/Ataxia Syndrome (FXTAS): A progressive neurological disorder that affects some older premutation carriers, more commonly males (>50 years). It is characterised by intention tremor, ataxia, and cognitive decline.
Fragile-X Associated Primary Ovarian Insufficiency (FXPOI): A condition affecting some female premutation carriers, leading to reduced ovarian function and early menopause.