Fragile X Syndrome
Fragile X Syndrome (FXS) is an inherited X-linked dominant genetic disorder characterized by intellectual disability, behavioral and emotional challenges, and distinct physical features. The syndrome results from a mutation in the FMR1 gene located on the X chromosome, specifically an expansion of the CGG trinucleotide repeat in the 5' untranslated region. In normal individuals, the CGG sequence is repeated less than 45 times, but in FXS, the repeat number exceeds 200, leading to hypermethylation and subsequent silencing of the FMR1 gene. The absence or deficiency of the fragile X mental retardation protein (FMRP) disrupts synaptic function and neurodevelopment, resulting in a spectrum of cognitive, behavioral, and physical manifestations. Health impacts range from mild learning disabilities to severe intellectual impairment, as well as autism spectrum disorder features, anxiety, attention deficits, hyperactivity, and, in some cases, seizures. Physical characteristics may include a long face, prominent ears, macroorchidism in males, and connective tissue abnormalities. FXS is the most common inherited cause of intellectual disability and a leading single-gene cause of autism.
This type occurs when the FMR1 gene contains over 200 CGG repeats, leading to methylation and transcriptional silencing of the gene. Individuals with the full mutation typically exhibit the classical features of Fragile X Syndrome, including significant intellectual disability, behavioral disturbances, and physical features such as elongated face and macroorchidism. The severity of manifestations is generally greater in males due to the presence of a single X chromosome, while females may have a milder phenotype due to X-inactivation.
Individuals with 55–200 CGG repeats in the FMR1 gene are classified as premutation carriers. Although they usually do not display the classic symptoms of Fragile X Syndrome, they are at risk for specific clinical conditions. Male premutation carriers are susceptible to Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), a late-onset neurodegenerative disorder, while female carriers are at increased risk for Fragile X-associated Primary Ovarian Insufficiency (FXPOI), which can lead to early menopause and infertility.
Some individuals with Fragile X Syndrome exhibit mosaicism, in which both full mutation and premutation or unmethylated alleles are present. Mosaic cases may have variable levels of FMRP expression, resulting in a spectrum of clinical severity. Depending on the proportion of cells with full mutation versus premutation alleles, individuals may experience milder intellectual disability and fewer behavioral or physical features compared to those with the full mutation alone.
Fragile X Syndrome affects approximately 1 in 4,000 males and 1 in 8,000 females worldwide, making it the most common inherited form of intellectual disability. The prevalence of FMR1 premutation carriers is estimated at 1 in 250–800 males and 1 in 130–250 females. The condition occurs across all ethnic and racial groups. Due to X-linked inheritance, males are more severely affected, while females often have milder symptoms due to random X-chromosome inactivation. Fragile X-associated disorders, including FXTAS and FXPOI, further broaden the clinical and epidemiological spectrum of FMR1-related conditions.
The diagnosis of Fragile X Syndrome is primarily established through molecular genetic testing of the FMR1 gene. The gold standard diagnostic method is polymerase chain reaction (PCR) combined with Southern blot analysis, which accurately determines the number of CGG repeats and assesses methylation status. Diagnostic criteria include the presence of more than 200 CGG repeats with associated methylation of the FMR1 gene, confirming a full mutation. Premutation carriers are identified by 55–200 repeats, while intermediate or 'gray zone' alleles contain 45–54 repeats. Prenatal diagnosis is possible via chorionic villus sampling or amniocentesis for at-risk pregnancies. Clinical suspicion may arise based on characteristic physical, cognitive, and behavioral features, particularly in boys with intellectual disability or autism spectrum disorder. Additional assessments may include neuropsychological testing, physical examination for dysmorphic features, and family history analysis to identify potential carriers.
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