Fragile X syndrome (FXS) is the leading cause of inherited mental retardation. It is caused by a change (mutation) in the fragile X mental retardation 1 (FMR1) gene located near the end of the X chromosome. This change is associated with a broad range of symptoms from speech delay and hyperactivity early in development to mild emotional problems, learning disabilities, and severe mental retardation with or without autism. The physical, behavioral, and intellectual difficulties tend to be greater in boys than in girls.
Although everyone has the FMR1 gene, those with the mutation have an increase in the number of CGG (cytosine and guanine) repeats at the 5’ end of the gene. The increase in CGG repeats is transmitted from generation to generation and is prone to expansion when passed through a female to a child. People who are carriers of fragile X have between 55 and 200 CGG repeats; this is referred to as the premutation. When the expansion becomes more than 200 CGG repeats, known as the full mutation, the individual will have FXS. The full mutation is associated with methylation of the repeat region, which results in silencing of the FMR1 gene and absence of the FMR1 protein (FMRP), causing FXS.
Current estimates are that 1 in 4000 males and 1 in 8000 females in the general population have the full mutation and are affected with FXS. Additionally, 1 in 250 females and 1 in 800 males are “carriers” of the FXS premutation and are typically unaffected intellectually, although they may present with clinical symptoms and carry the risk for having children or grandchildren with FXS.
Studies have documented a subgroup of children who are carriers of the gene mutation that present with mild physical features of FXS; emotional problems including anxiety, obsessional thinking, or depression; and sometimes more severe clinical involvement including mental retardation and autism spectrum disorders. A group of older premutation carriers have been identified as having fragile X–associated tremorataxia syndrome (FXTAS), which is characterized by progressive intention tremor, gait ataxia, parkinsonism, and autonomic dysfunction.
The classic physical features of FXS include long face; prominent ears, chin, and forehead; large head circumference; high arched palate; and large testicles (macroorchidism). In addition, loose joints, heart murmurs, low muscle tone, flat feet, and a variety of skeletal problems are often observed. Many of the physical features are associated with connective tissue problems, leading to ear infections, sinusitis, or gastric reflux.
The social and behavioral phenotype of FXS includes impulsivity, attention deficit disorders, hyperactivity, rapid speech, and hypersensitivity to a variety of sensory stimuli. As many as 25% to 30% of individuals with FXS meet the diagnostic criteria for autism and display autistic spectrum behaviors such as hand flapping, poor eye contact, and social anxiety.
At this time, there is no cure for FXS, but there are effective methods for treating many of the symptoms. A combination of special education, speech and language therapy, occupational therapy, and behavioral therapy may be helpful in addressing many of the physical, behavioral, and cognitive impacts of FXS. In addition, medical intervention can improve aggression, anxiety, and hyperactivity.
Because the impact of FXS is so varied, early diagnosis of FXS is important to ensure that both genetic counseling and appropriate treatment are attained as early as possible. Since 1991, highly accurate procedures for testing have been developed and are widely available. A blood test followed by polymerase chain reaction (PCR) and Southern blot analysis identifies the size of the repeat. This test can identify carriers and those affected and is used for prenatal diagnosis.
- Hagerman, R. J., & Hagerman, P. J. (2002). Fragile X syndrome: Diagnosis, treatment, and research (3rd ). Baltimore: Johns Hopkins University Press.
- National Fragile X Foundation, http://www.fragileorg/
- National Institute of Child Health and Human Development. (n.d.). Families and Fragile X syndrome. Retrieved from http://www.nichd.nih.gov/publications/pubs/fragileX/index.htm