What is Fragile X (FX) syndrome and its typical presentation, diagnosis, and treatment options?

Fragile X Syndrome Overview

Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability and a major genetic cause of autism spectrum disorder, caused by expansion of CGG repeats (>200) in the FMR1 gene leading to loss of fragile X mental retardation protein (FMRP), affecting approximately 1 in 4,000 males and 1 in 5,000-8,000 females. 1, 2

Molecular Basis and Pathophysiology

The fundamental defect is loss of FMRP, an RNA-binding protein that normally suppresses translation of specific mRNAs at neuronal synapses. 1

• FMRP functions as a translation suppressor regulating protein synthesis locally in dendrites in response to synaptic stimulation signals 1
• In FXS, translation of certain messages becomes exaggerated because normal FMRP inhibition is absent 1
• The FXS brain exhibits unusually long and thin dendritic spines in cortical regions where excitatory synaptic transmission occurs 1
• Over 99% of cases result from CGG repeat expansion (>200 repeats) in the 5′ untranslated region of FMR1, causing hypermethylation and transcriptional silencing 1

Clinical Presentation

Males with Full Mutation

All males with full mutations have virtually 100% penetrance for intellectual disability, making diagnosis definitive rather than predictive. 1, 2

• Intellectual disability ranging from mild to severe, representing the most common inherited cause 3
• Autism spectrum disorder features in approximately 20% when evaluated by objective diagnostic criteria 3
• Characteristic physical features: macroorchidism, long face, prominent ears, joint hypermobility 4
• Behavioral manifestations: hyperactivity, impulsivity, anxiety, attention problems, aggressive behavior 5, 6
• Speech and language delays are prominent 5

Females with Full Mutation

Less than 50% of females with full mutations develop intellectual disability due to variable X-inactivation patterns, though many experience behavioral and psychiatric manifestations. 1, 2

• Variable expression includes avoidance personality, mood disorders, stereotypic disorders 1, 2
• Phenotypic prediction cannot be reliably made from X-inactivation patterns in blood 1

Associated Medical Complications

Multiple organ systems are affected, requiring systematic screening and monitoring. 4, 3, 7

• Cardiac: Mitral valve prolapse and aortic root dilation occur in 50-80% of males, requiring baseline echocardiography 4
• Seizures: Develop in 10-20% of individuals, warranting EEG if clinically suspected 4, 3
• Otologic: Recurrent otitis media and hearing difficulties necessitate audiologic assessment 4, 3
• Ophthalmologic: Strabismus and refractive errors require evaluation 4, 3
• Endocrine: Hypothyroidism occurs with increased frequency 4

Premutation Carriers (55-200 CGG Repeats)

Premutation carriers face distinct clinical risks that differ from full mutation FXS. 1, 3

Fragile X-Associated Primary Ovarian Insufficiency (FXPOI)

• Affects approximately 20% of female premutation carriers, particularly those with >80 CGG repeats 4, 3
• Requires counseling about reproductive implications 4

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)

• Late-onset progressive intention tremor and ataxia typically manifesting in males over age 50 4, 3
• Penetrance increases with age and premutation repeat length 3
• Associated symptoms include cognitive decline and neuropathy 4
• RNA-mediated toxicity mechanism differs from FXS protein loss 1

Premutation Carrier Features

• Most individuals with premutations do not show FXS-related features 3
• Those with high repeat sizes (>100 repeats) may present with learning difficulties, emotional problems, or intellectual disability 3
• Reduction in FMRP occurs even in premutation carriers, associated with increased FMR1 mRNA levels 1

Epidemiology and Prevalence

FXS affects all major ethnic groups and races worldwide with some population variation. 1, 2

• General prevalence: 1 in 4,000 males and 1 in 5,000-8,000 females 1, 2
• US newborn screening: 1 in 5,161 males 1, 2
• Canadian newborn screening: 1 in 6,209 males 1, 2
• African-American males: 1 in 2,545 1, 2
• Caucasian males: 1 in 3,717 to 1 in 8,198 1, 2
• Taiwanese population: 1 in 10,046 males 1, 2

Diagnostic Testing

CGG repeat expansion testing is >99% sensitive and 100% specific for FXS diagnosis. 1

Testing Indications

• Identification of full mutation in males is diagnostic with virtually 100% penetrance 1
• Identification of full mutation in females may be diagnostic but phenotype is variable 1
• Testing detects CGG repeat expansion and methylation status of FMR1 gene 1

Prenatal Testing Considerations

Prenatal testing can be performed on amniocentesis and chorionic villus sampling (CVS) specimens with specific technical considerations. 1

• Methylation associated with lyonization is usually not present in CVS tissue 1
• Methylation analysis may be omitted entirely when testing CVS specimens 1
• Degree of somatic variation in full mutation has wider range in CVS than blood specimens 1
• Follow-up amniocentesis may be required if CVS result is ambiguous between large premutation and small full mutation 1

Family Cascade Testing

All first-degree female relatives should be offered FMR1 testing as they may be premutation or full mutation carriers. 4

• Maternal lineage screening should extend to aunts, female cousins, and other maternal relatives due to X-linked inheritance with anticipation 4
• Male relatives through maternal lineage should be tested for premutation carrier status and FXTAS risk 4
• Premutation carrier females require counseling about 20% FXPOI risk and increased FXTAS risk with aging 4
• Older male premutation carriers (typically >50 years) should be monitored for FXTAS symptoms 4

Initial Clinical Evaluation

Complete physical examination should assess for characteristic FXS features and associated medical complications. 4

• Physical features: macroorchidism, long face, prominent ears, joint hypermobility, cardiac abnormalities 4
• Baseline echocardiography to screen for mitral valve prolapse and aortic root dilation 4
• Ophthalmologic examination for strabismus and refractive errors 4
• Audiologic assessment for hearing difficulties 4
• Developmental and cognitive assessment using standardized tools to establish baseline functioning 4
• Behavioral and psychiatric evaluation screening for ADHD, anxiety disorders, autism spectrum features 4

Additional Testing When Indicated

• Thyroid function tests as hypothyroidism occurs with increased frequency 4
• EEG if seizures are suspected (10-20% develop epilepsy) 4
• Brain MRI only if focal neurologic findings, significant microcephaly/macrocephaly, or atypical features present 4
• Chromosomal microarray if clinical presentation includes atypical features, as approximately 10% may have additional pathogenic copy number variants 4
• Metabolic screening only if specific clinical features suggest additional metabolic disorder 4

Treatment Approaches

A combination of early non-pharmacological interventions and targeted pharmacotherapy represents the most effective current treatment strategy for FXS. 5, 6

Current Targeted Treatments

• Metformin, sertraline, and cannabidiol can be used by clinicians to treat FXS symptoms 5
• No FDA-approved medications specifically for FXS exist; treatment focuses on symptom management 5
• Pharmacotherapy addresses behavioral problems, sleep disturbances, anxiety, inattention, and seizures 5, 6

Non-Pharmacological Interventions

• Early interventions have improved many behavioral symptoms associated with FXS 5, 6
• Educational interventions guided by baseline developmental assessment 4
• Behavioral therapies targeting specific symptoms 6

Future Therapeutic Directions

• Gene therapy is rapidly developing and holds potential as prospective treatment option 5
• Multiple targets for therapeutic intervention identified based on proteins regulated by FMRP 8
• Targeted treatments aim to reverse dysregulated brain pathways 6

Critical Clinical Pitfalls

Early diagnosis and comprehensive initial evaluation are fundamental to achieving optimal clinical outcomes and quality of life. 6, 7

• Do not assume females with full mutations are unaffected; less than 50% have intellectual disability but many have behavioral manifestations 1, 2
• Do not use methylation status or X-inactivation patterns from blood to predict phenotype in females 1
• Do not overlook cascade testing of maternal lineage relatives for premutation carrier status and associated conditions 4
• Do not miss cardiac screening, as 50-80% of males have mitral valve prolapse or aortic root dilation 4
• Do not confuse FXS with the unrelated syndrome associated with the FRAXE locus 1