Every July 22nd, the World Fragile X Syndrome Day is commemorated to support all individuals and families affected by this disease and, at the same time, to raise public awareness in our society about Fragile X syndrome.
What is Fragile X syndrome?
Fragile X syndrome (FXS) is a genetically caused disorder linked to the X chromosome and one of the most common causes of intellectual disability worldwide. Patients with FXS have variants in the FMR1 gene, which is in charge of the production of a protein essential for proper brain development. This disease is considered rare as it has an estimated prevalence in our population of approximately 1/2400 to 1/6000 affected individuals, depending on the geographic region.
This disorder follows an X-linked pattern of inheritance. The main cause of this syndrome (>99% of the cases) is due to a mutation in the activation region of the FMR1 gene. The mechanism by which the disease is caused by the affectations in this gene is that in order to produce the FMR1 protein, a previous activation is necessary to signal the cell to start producing this protein and in affected individuals, this activation is impaired.
The region in charge of this activation is adjacent to the FMR1 gene and consists mainly of sequential repeats of a specific “C-G-G” combination of 2 of the 4 basic DNA components (A, T, G, C), meaning that our DNA strand in this region is represented as follows: “CGG CGG CGG CGG CGG CGG CGG …”. However, these repeats are not the same for all people and, moreover, from generation to generation they can undergo changes and increase in number. Most people have a CGG repeat size of between 5 and 44 repeats, which is considered normal and generally remains stable between generations.
Similarly, 45 to 54 CGG repeats (gray zone or intermediate allele) is also considered normal, although the risk of expansion to the next repeat range in future generations begins to rise.
Between 55 and 200 CGG repeats (premutation range) the risk of expansion is much higher and future generations may be affected by fragile X syndrome. In addition, premutation carriers produce less protein and therefore may have symptoms associated with FMR1 (discussed in the next section).
When the number of CGG repeats exceeds 200 (full mutation range), this region does not function correctly and, therefore, does not produce functional protein, resulting in symptomatology associated with Fragile X syndrome in these individuals.
What are the symptoms and signs of this disease?
Fragile X syndrome presents with a variable clinical phenotype. The age of onset in affected males is usually in infancy and presents with delayed psychomotor development (difficulty crawling or walking). Intellectual disability can be variable (from mild to severe) and behavioral disorders also present this variability, and can be mild (anxiety or unstable mood) or severe (aggression, attention deficit hyperactivity disorder, autism). In women, intellectual and behavioral disorders are usually mild, consisting of shyness, social anxiety and problems with learning. Most women usually have normal intelligence, however, some cases with intellectual disability have been described.
In relation to the other FMR1-related disorders developed in carriers of pre-mutation range repeats, both females and males are at risk for Fragile X-associated tremor or ataxia syndrome (FXTAS) and, in the case of females carrying a copy in this pre-mutation range, they may also develop premature ovarian failure (POF).
Are screening/diagnostic tests available?
Fragile X syndrome or associated disorders can be diagnosed in a person presenting symptoms of the disease by analyzing DNA from a blood sample. In addition, FMR1 gene study can also be analyzed on a preventive basis, as in the case of carrier screening tests for recessive and X-linked diseases, which are performed without previous symptoms of the disease in order to detect whether there is a risk that the future offspring of couples with reproductive desire may be affected by the diseases analyzed. In case a risk of expansion to full mutation in future generations is detected, carriers of the disease can choose different options to reduce the risk of this occurrence.
What treatments are available?
There is currently no cure for FXS. Management is based on symptom treatment and requires a multidisciplinary approach based on the use of drugs to manage behavioral disorders combined with speech therapy, physiotherapy and sensory integration therapies. For most patients, life expectancy is normal. However, the prognosis of Fragile X disease is variable and depends on the severity of symptoms. Therefore, early diagnosis of this disease is essential to provide adequate treatment in the early stages of the disease and significantly improve the quality of life of affected individuals.