- Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and a leading single-gene cause of autism spectrum disorder. It arises from a genetic defect in the FMR1 gene on the X chromosome (Xq27.3), which normally produces the fragile X mental retardation protein (FMRP).
- FMRP is crucial for synaptic development, plasticity, and regulation of protein synthesis in neurons. In individuals with Fragile X syndrome, a trinucleotide CGG repeat within the 5′ untranslated region of FMR1 expands beyond a critical threshold. While the normal allele contains up to about 44 CGG repeats, a full mutation consists of more than 200 repeats. This excessive expansion leads to abnormal methylation and silencing of FMR1, preventing the production of FMRP. The absence of this protein disrupts normal neuronal signaling and connectivity, producing the neurological and cognitive features of the disorder.
- The clinical presentation of Fragile X syndrome is diverse and variable in severity. Males, who possess only one X chromosome, are generally more severely affected than females, who may retain partial FMR1 function due to X-inactivation. Core features include intellectual disability ranging from mild to severe, speech and language delays, deficits in executive function, and impaired social interactions. Many individuals with Fragile X exhibit behaviors overlapping with autism spectrum disorder, such as poor eye contact, social anxiety, repetitive behaviors, and hypersensitivity to sensory stimuli. Attention deficit hyperactivity disorder (ADHD)-like symptoms, mood instability, and aggression may also be present. Physical characteristics are not always pronounced but can include a long, narrow face, large protruding ears, hyperflexible joints, and in post-pubertal males, macroorchidism (enlarged testes).
- A unique feature of Fragile X syndrome is the presence of premutation carriers, individuals who have an intermediate number of repeats (55–200 CGG). These carriers do not usually develop Fragile X syndrome itself but may present with other clinical conditions. Female premutation carriers are at risk for Fragile X-associated primary ovarian insufficiency (FXPOI), characterized by early menopause and infertility. Both male and female premutation carriers can develop Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder characterized by intention tremor, gait ataxia, and cognitive decline. Unlike the full mutation, premutations lead to excess transcription of FMR1 mRNA, which is thought to exert toxicity in neurons.
- Diagnosis of Fragile X syndrome is made through molecular genetic testing to detect the number of CGG repeats in FMR1. Polymerase chain reaction (PCR) and Southern blot analysis remain standard techniques for identifying the full mutation, premutation, or normal allele. Clinical suspicion is raised in children presenting with developmental delays, intellectual disability, and behavioral features consistent with autism spectrum disorder, especially if there is a family history suggestive of X-linked inheritance.
- Currently, there is no cure for Fragile X syndrome, and treatment is focused on supportive care and symptom management. Educational interventions, behavioral therapy, speech and occupational therapy, and social support play critical roles in improving quality of life. Pharmacological management may include stimulants for ADHD-like symptoms, selective serotonin reuptake inhibitors (SSRIs) for anxiety, and antipsychotics for severe behavioral dysregulation. Research efforts are increasingly focused on targeted therapies, particularly those aiming to modulate pathways disrupted by the absence of FMRP, such as metabotropic glutamate receptor (mGluR) signaling. Although early trials of mGluR5 antagonists showed limited success, newer molecular and genetic approaches, including antisense oligonucleotides, CRISPR-based gene editing, and epigenetic reactivation of the FMR1 gene, hold promise for future treatments.
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