Fragile X syndrome is a genetic condition that impacts an individual’s development and learning abilities. It is a common inherited cause of intellectual disability and is also linked to features of autism spectrum disorder. The condition affects approximately 1 in 3,600 boys and between 1 in 4,000 to 6,000 girls, although symptom severity can vary widely.
Understanding the Gene Behind Fragile X
Fragile X syndrome results from a change in the FMR1 gene, located on the X chromosome. This gene is responsible for producing a protein called FMRP, which plays a role in the normal functioning of the brain and the development of specialized connections between nerve cells called synapses. When the FMR1 gene is altered, it cannot produce enough FMRP, leading to the signs and symptoms of Fragile X syndrome.
The alteration in the FMR1 gene involves a repeating DNA segment called the CGG triplet repeat. A normal FMR1 gene has 5 to 44 CGG repeats. Individuals with 45 to 54 repeats have an “intermediate” or “gray zone” allele, which does not cause Fragile X syndrome or related disorders.
A “premutation” occurs when there are 55 to 200 CGG repeats. People with a premutation do not have Fragile X syndrome, though they may experience subtle symptoms. When the CGG segment expands to more than 200 repeats, it is considered a “full mutation,” leading to Fragile X syndrome because the gene is turned off.
How Fragile X is Passed Through Generations
Fragile X syndrome follows an X-linked dominant inheritance pattern. The FMR1 gene is located on the X chromosome. Females have two X chromosomes, while males have one X and one Y chromosome. This difference explains why males are often more severely affected than females, as they only have one copy of the FMR1 gene.
When a woman carries a premutation in one of her FMR1 genes, she has a 50% chance of passing on either the premutation or a full mutation to each child. The number of CGG repeats in her egg cells can increase from the premutation range to the full mutation range. The larger her premutation, the higher the likelihood her child will inherit a full mutation and thus Fragile X syndrome.
A man with a premutation will pass his premutation to all of his daughters, as they inherit his only X chromosome. However, the premutation in men does not expand to a full mutation when passed to the next generation. Sons of a male premutation carrier will not inherit the premutation because they receive their father’s Y chromosome.
A phenomenon called “anticipation” is observed in Fragile X inheritance, where symptoms can become more severe and appear at an earlier age in successive generations. This occurs because the unstable CGG repeat can expand further as it is passed down, particularly from mother to child. A mother with a premutation might have a child with a full mutation, even if she herself does not have Fragile X syndrome.
Beyond Fragile X Syndrome: Related Conditions
The FMR1 premutation can lead to conditions distinct from Fragile X Syndrome, primarily affecting carriers. Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a late-onset neurodegenerative disorder predominantly observed in male premutation carriers after age 50. Features of FXTAS include problems with movement, such as cerebellar gait ataxia (uncoordinated walking) and intention tremor (shaking during voluntary movements). Other symptoms can include parkinsonism, cognitive decline, and issues with the autonomic nervous system.
Another condition linked to the FMR1 premutation is Fragile X-associated Primary Ovarian Insufficiency (FXPOI), which affects women. FXPOI involves reduced ovarian function, leading to irregular menstrual cycles, early menopause, and infertility. Approximately 20% to 30% of women with the Fragile X premutation develop FXPOI, compared to about 1% in the general population.
Symptoms of FXPOI can include hot flashes, night sweats, trouble sleeping, mood swings, and vaginal dryness, similar to those experienced during menopause. Women with FXPOI undergo menopause about five years earlier than women without the premutation. While both FXTAS and FXPOI are caused by the FMR1 premutation, the underlying biological mechanisms differ from those causing Fragile X Syndrome.
Genetic Counseling and Testing for Families
Genetic testing for the FMR1 gene is available and can diagnose Fragile X syndrome and identify carriers. This testing can be performed at any age, including prenatally. It is often considered for individuals with developmental delay, intellectual disability, or a family history of Fragile X syndrome or unexplained intellectual disabilities.
Genetic counselors play a significant role in assisting families affected by Fragile X. They interpret test results, explain complex inheritance patterns, and discuss the risks of transmission. Counselors also provide information about reproductive options and offer support, helping families navigate the implications of a Fragile X diagnosis.