Fragile X Syndrome
Overview
Plain-Language Overview
Fragile X Syndrome is a genetic condition that causes a range of developmental problems including learning disabilities and cognitive impairment. It is the most common inherited cause of intellectual disability and autism spectrum disorders. People with this syndrome often have distinctive physical features such as a long face, large ears, and flexible joints. Behavioral challenges like anxiety, hyperactivity, and social difficulties are also common. The condition results from a mutation in the FMR1 gene, which affects brain development and function.
Clinical Definition
Fragile X Syndrome is an X-linked dominant genetic disorder caused by a CGG trinucleotide repeat expansion in the 5' untranslated region of the FMR1 gene on the X chromosome. This expansion leads to hypermethylation and transcriptional silencing of the gene, resulting in deficiency or absence of the fragile X mental retardation protein (FMRP), which is critical for normal synaptic development and plasticity. Clinically, affected males typically present with moderate to severe intellectual disability, while females often have milder cognitive impairment due to X-inactivation. Characteristic physical features include a long, narrow face, prominent ears, macroorchidism after puberty, and joint hypermobility. Behavioral manifestations often include attention deficit, anxiety, autistic-like behaviors, and speech delays. Diagnosis is confirmed by molecular genetic testing identifying the CGG repeat expansion exceeding 200 repeats, known as a full mutation. Premutation carriers (55-200 repeats) may be asymptomatic or develop fragile X-associated tremor/ataxia syndrome or premature ovarian insufficiency. The syndrome is the most common inherited cause of intellectual disability and a significant cause of autism spectrum disorder. Management is supportive and multidisciplinary, focusing on developmental, educational, and behavioral interventions.
Inciting Event
- Fragile X Syndrome results from a genetic mutation rather than an external inciting event.
Latency Period
- none
Diagnostic Delay
- Mild or variable clinical features can delay suspicion and diagnosis.
- Lack of awareness about Fragile X Syndrome among clinicians may contribute to delayed testing.
- Overlap with other neurodevelopmental disorders can obscure diagnosis.
Clinical Presentation
Signs & Symptoms
- Intellectual disability ranging from mild to severe.
- Behavioral features including autism spectrum disorder, anxiety, and hyperactivity.
- Speech delay and language impairment.
- Sensory hypersensitivity.
- Seizures in some cases.
History of Present Illness
- Developmental delay in speech and motor milestones is common.
- Behavioral features include hyperactivity, anxiety, and autistic-like behaviors.
- Physical features may include a long face, large ears, and macroorchidism in post-pubertal males.
Past Medical History
- History of developmental delays or learning disabilities.
- Previous diagnosis of autism spectrum disorder or attention deficit hyperactivity disorder (ADHD) may be present.
Family History
- Family members with intellectual disability or learning difficulties.
- Maternal relatives may carry the FMR1 premutation with mild or no symptoms.
- History of fragile X-associated tremor/ataxia syndrome (FXTAS) or premature ovarian insufficiency in female carriers.
Physical Exam Findings
- Prominent forehead and chin with a long face.
- Large, protruding ears.
- Macroorchidism (enlarged testes) in post-pubertal males.
- Hyperextensible joints.
- Mitral valve prolapse may be auscultated.
Diagnostic Workup
Diagnostic Criteria
Diagnosis of Fragile X Syndrome requires identification of a full mutation with over 200 CGG repeats in the FMR1 gene via molecular genetic testing. Clinical features supporting diagnosis include intellectual disability, characteristic facial features such as a long face and large ears, macroorchidism in postpubertal males, and behavioral symptoms like anxiety and autistic traits. Family history of intellectual disability or fragile X-associated disorders may also be present. Premutation carriers have 55-200 repeats but typically lack the full clinical syndrome.
Pathophysiology
Key Mechanisms
- Fragile X Syndrome is caused by a CGG trinucleotide repeat expansion in the FMR1 gene leading to hypermethylation and silencing of the gene.
- Loss of the FMRP protein results in abnormal synaptic plasticity and neuronal development.
- The absence of FMRP disrupts regulation of mRNA translation at synapses, impairing cognitive function.
| Involvement | Details |
|---|---|
| Organs | Brain is the primary organ affected, leading to intellectual disability and behavioral symptoms. |
| Testes may be enlarged (macroorchidism) in post-pubertal males with fragile X syndrome. | |
| Tissues | Brain tissue shows abnormal dendritic spine morphology characteristic of fragile X syndrome. |
| Cells | Neurons are affected by the loss of fragile X mental retardation protein leading to synaptic dysfunction. |
| Glial cells contribute to the brain's microenvironment and may be involved in neurodevelopmental abnormalities. | |
| Chemical Mediators | Glutamate is involved in excitatory neurotransmission and is dysregulated in fragile X syndrome. |
| Gamma-aminobutyric acid (GABA) mediates inhibitory signaling and is often deficient in this condition. |
Treatment
Pharmacological Treatments
Stimulants
- Mechanism: Enhance dopamine and norepinephrine signaling to improve attention and reduce hyperactivity
- Side effects: Insomnia, appetite loss, increased heart rate
Selective serotonin reuptake inhibitors (SSRIs)
- Mechanism: Increase serotonin levels to reduce anxiety and mood symptoms
- Side effects: Gastrointestinal upset, sexual dysfunction, headache
Atypical antipsychotics
- Mechanism: Block dopamine and serotonin receptors to manage irritability and aggression
- Side effects: Weight gain, sedation, extrapyramidal symptoms
Non-pharmacological Treatments
- Early intervention programs improve cognitive and social development in affected children.
- Speech therapy enhances communication skills and language development.
- Occupational therapy assists with sensory integration and fine motor skills.
- Behavioral therapy helps manage anxiety, hyperactivity, and social challenges.
Prevention
Pharmacological Prevention
- none
Non-pharmacological Prevention
- Genetic counseling for families with known FMR1 gene premutation carriers.
- Prenatal testing to identify affected fetuses.
- Early intervention programs including speech, occupational, and behavioral therapies.
Outcome & Complications
Complications
- Progressive intellectual disability.
- Social and communication difficulties leading to impaired functioning.
- Seizure-related morbidity.
- Mitral valve prolapse complications such as regurgitation.
| Short-term Sequelae | Long-term Sequelae |
|---|---|
|
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Differential Diagnoses
Fragile X Syndrome versus Autism Spectrum Disorder (ASD)
| Fragile X Syndrome | Autism Spectrum Disorder (ASD) |
|---|---|
| Presence of intellectual disability with characteristic physical features | Social communication deficits and repetitive behaviors without associated physical dysmorphisms |
| Macroorchidism and elongated face are common | Normal head circumference and absence of macroorchidism |
| Confirmed by FMR1 gene CGG repeat expansion testing | No known genetic mutation such as FMR1 expansion |
Fragile X Syndrome versus Down Syndrome
| Fragile X Syndrome | Down Syndrome |
|---|---|
| Characteristic elongated face with large ears and prominent jaw | Presence of simian crease and characteristic facial features such as flat nasal bridge and epicanthal folds |
| Presence of macroorchidism in post-pubertal males | Hypotonia present at birth with congenital heart defects like atrioventricular septal defect |
| Fragile X mental retardation 1 (FMR1) gene CGG trinucleotide repeat expansion on X chromosome | Intellectual disability with trisomy 21 confirmed by karyotype |
Fragile X Syndrome versus Williams Syndrome
| Fragile X Syndrome | Williams Syndrome |
|---|---|
| Elongated face with large ears and intellectual disability | Distinctive elfin facial features including broad forehead and full cheeks |
| Macroorchidism and behavioral features such as hand-flapping | Supravalvular aortic stenosis and hypercalcemia in infancy |
| FMR1 gene CGG repeat expansion confirms Fragile X syndrome | Strong verbal abilities with relative sparing of language |