Can females have Fragile X (FXS) syndrome?

From the Guidelines

Females can have Fragile X syndrome (FXS), though they typically experience milder symptoms than males due to having two X chromosomes. In females, one X chromosome may have the FMR1 gene mutation while the other X chromosome is usually normal, providing some protection through a process called X-inactivation 1. Approximately 1 in 4,000-6,000 females are affected by FXS. Female patients may show intellectual disability ranging from mild to moderate, learning difficulties, anxiety, attention problems, and social challenges. Physical features can include a long face, large ears, and connective tissue problems, though these are often less pronounced than in males.

Some key points to consider:

• The identification of a full mutation in a female may be diagnostic, but less than 50% of females with full mutations have intellectual disability 1.
• Nonrandom X inactivation may explain the milder phenotype in females, although the extent of symptoms cannot be determined by X-inactivation patterns from diagnostic tests that determine the expansion and methylation in blood 1.
• Women with premutations have a theoretical 50% chance of passing on the fragile X mutation with each pregnancy, with the chance of expansion to a full mutation depending on the size of the maternal allele 1.
• Diagnosis involves genetic testing to detect the CGG repeat expansion in the FMR1 gene, and treatment focuses on managing symptoms through educational interventions, behavioral therapy, speech therapy, and sometimes medications for specific symptoms like anxiety or attention issues.
• Genetic counseling is important for affected females, as they have a chance of passing the mutation to their children, with probabilities ranging from 3% for maternal alleles with CGG repeats from 55 to 59 to ~100% for maternal alleles with 90 CGGs and above 1.

From the Research

Fragile X Syndrome in Females

• Females can have Fragile X syndrome (FXS), although the prevalence is lower than in males, with a population prevalence of 1 in 8000 in females compared to 1 in 4000 in males 2.
• The disorder is caused by a mutation in a gene on the X chromosome, which includes a trinucleotide repeat sequence, and females with the full mutation (FM) are less likely to be affected than males, with only half of females with the FM being affected 2.
• Females with FXS are more likely to have borderline IQs, with a range of 70-85, and may exhibit physical characteristics such as facial atypia and joint laxity, although these are less pronounced than in males 2.
• Behavioral problems in females with FXS can be similar to those seen in autism and attention-deficit disorders, and may include anxiety, inattention, and learning difficulties 3.
• Females who are carriers of the fragile X premutation (PM) are at risk of passing the expanded CGG repeat to their offspring, and may experience partial phenotypic expression, including mental development that is borderline to subnormal and psychiatric disturbances 4.
• The risk of expansion to the full mutation may be correlated with maternal age and the parental origin of the premutation, although more data are needed to confirm these trends 5.
• Gene therapy is being developed as a potential treatment for FXS, and may offer a promising approach for managing the symptoms of the disorder in the future 3.