Fragile X Syndrome (FRAXA): Understanding the Genetic Basis and Clinical Manifestations

Fragile X Syndrome: A Comprehensive Overview

Introduction Fragile X syndrome (FRAXA) is the most common inherited form of intellectual disability worldwide. It affects 1 in 4,000 males and 1 in 8,000 females. FRAXA is caused by a mutation in the FMR1 gene, which prevents the production of the fragile X mental retardation protein (FMRP). FMRP is essential for normal intellectual development and function.

Genetics FRAXA is an X-linked genetic disorder, meaning that it is carried on the X chromosome. Males, who have only one X chromosome, are more severely affected than females, who have two X chromosomes. In females, the normal copy of the FMR1 gene on the other X chromosome often compensates for the mutation on one X chromosome.

Symptoms The symptoms of FRAXA can vary widely, depending on the individual’s genetic mutation and gender. In general, males with FRAXA exhibit more severe symptoms than females.

Cognitive and Behavioral Symptoms:

• Intellectual disability of varying degrees
• Speech and language delays
• Autism spectrum disorder (ASD)
• Hyperactivity and attention deficit
• Stereotypical behaviors (e.g., hand flapping, rocking)
• Social difficulties
• Anxiety and depression

Physical Symptoms:

• Prominent forehead
• Large ears
• Long and narrow face
• Hyperflexibility
• Flat feet
• Macroorchidism (enlarged testicles) in males
• Premature menopause in females

Other Symptoms:

• Increased risk of seizures
• Sleep problems
• Feeding difficulties
• Heart problems
• Gastrointestinal issues

Diagnosis FRAXA is diagnosed through genetic testing. The test can detect mutations in the FMR1 gene and determine the number of CGG repeats in the gene. The number of CGG repeats is inversely proportional to the production of FMRP.

• Normal: Less than 30 CGG repeats
• Premutation: 30-55 CGG repeats
• Full mutation: More than 200 CGG repeats

Treatment There is currently no cure for FRAXA. However, early intervention and therapies can help improve symptoms and function. These include:

• Special education and behavioral therapy
• Speech therapy
• Occupational therapy
• Physical therapy
• Medications for seizures, anxiety, and other symptoms

Complications Individuals with FRAXA may experience a number of medical and behavioral complications, including:

• ASD: Approximately 50% of males with FRAXA have ASD.
• Premature ovarian failure: Women with FRAXA may experience premature menopause, leading to infertility and other health issues.
• Fetal alcohol syndrome: Women with the FMR1 premutation who consume alcohol during pregnancy have an increased risk of having children with fetal alcohol syndrome.
• Fragile X-associated tremor/ataxia syndrome (FXTAS): This neurodegenerative disorder typically affects older men with the FMR1 premutation. Symptoms include tremors, difficulty walking, and cognitive decline.

Fragile X in Women Women with FRAXA typically have milder symptoms than males. However, they may still experience:

• Learning difficulties
• Social anxiety
• Infertility
• Premature menopause
• Health problems related to the FMR1 premutation (e.g., FXTAS)

Carrier Status People with the FMR1 premutation (30-55 CGG repeats) are carriers of the FRAXA gene. They do not typically have symptoms, but they can pass the mutation on to their children. Female carriers have a 50% chance of passing the premutation to their children, while male carriers have no risk of passing it on.

Prenatal Testing Prenatal testing is available for women who are carriers of the FRAXA gene. This can help determine the risk of having a child with the condition.

Genetic Counseling Genetic counseling is recommended for individuals with FRAXA, their families, and people with the FMR1 premutation. Counseling can provide information about the condition, inheritance patterns, and reproductive options.

Conclusion Fragile X syndrome is a complex genetic disorder that affects cognitive, behavioral, and physical development. While there is currently no cure, early diagnosis and intervention can significantly improve outcomes for individuals with FRAXA. Ongoing research is focused on understanding the underlying mechanisms of the condition and developing new therapies.