Fragile X syndrome

Fragile X syndrome is a genetic disease that is characterized by developmental problems including learning difficulties and mental retardation. In fact, it is the most common inherited form of mental retardation in men and is also important in women.

Symptoms can range from mild to severe and are usually more severe in men than in women.

Symptoms of fragile X syndrome: Individuals with this disease usually present with anxiety and hyperactive behavior that manifests as restlessness, excessive physical movements, or impulsive actions. They may also have attention deficit disorder that involves impaired ability to maintain attention, and difficulty concentrating on certain tasks. About one-third of males with fragile X syndrome have autism or autistic behaviors that affect communication and social interaction, such as waving or biting hands. Additionally, approximately 15% of males and 5% of females also have seizures.

Physical characteristics of this syndrome may become more evident with age, especially in men. These include a long, narrow face, large ears, prominent jaw and forehead, arched and high palate, flat feet, and excessively flexible fingers. Men may also have larger-than-normal testicles after puberty. Children with this disorder are more likely to suffer from heart murmur, usually caused by mitral valve prolapse.

Most people with fragile X syndrome do not suffer serious health problems and in general their life expectancy is normal. Although this disease has no cure, timely treatment by a coordinated team of health and education professionals can greatly help children in their development. Sometimes, medicines such as antidepressants, stimulants, and anticonvulsants are used to treat certain symptoms.

In the early 90s, it was discovered that fragile X syndrome is caused by a mutation in a gene called FMR-1, which is located on the X chromosome. This gene encodes a protein called FMRP. The function of this protein is not yet well understood, although it seems that it may play an important role in the connections between nerve cells, which is important for the transmission of nerve impulses.
Females have two X chromosomes, while males have one X chromosome and one Y chromosome. Women who inherit an X chromosome with the FMR-1 gene altered have another X chromosome with a normal copy, so this syndrome occurs less often in women, and when it does, it is less severe. Having only one X chromosome, males with the gene affected have more severe symptoms.

Almost all cases of fragile X syndrome are caused by a mutation in a segment of DNA in the FMR-1 gene that is characterized by CGG triplet repeats. This segment of DNA is normally repeated 5 to 40 times in the gene, but in people with this syndrome, it is repeated more than 200 times. This causes the gene to be deactivated and not produce the corresponding protein correctly, leading to the appearance of symptoms. In a small percentage of cases, there is another type of mutations that cause this syndrome.

Individuals who have 55 to 200 CGG segment repeats are said to have a premutation of the FMR-1 gene. Most of these people are intellectually normal, although in some cases they have less FMRP protein than normal. They usually present some physical symptom of this syndrome, but attenuated, such as prominent ears. In some cases, they may even suffer from anxiety or depression. Some children have learning problems or are autistic. About 20% of women with the disorder have premature ovarian problems. In general, these individuals have an increased risk of developing a disorder called fragile X-associated ataxia syndrome, which is characterized by progressive movement problems, tremors, loss of sensation in the lower extremities, memory loss, and behavioral changes.

It is estimated that the frequency of people affected by fragile X syndrome is 1 in 4,000 men and 1 in 8,000 women. In addition, one in 600 women is a carrier. This disease occurs equally in individuals of all races and ethnic groups.

This syndrome follows an X-linked dominant inheritance pattern, meaning that one copy of the altered gene, located on the X chromosome, in each cell is sufficient to cause the disease.

Women carrying a premutation have a 50% chance of passing on the affected gene to their children. Some children who inherit the affected gene have a premutation but have no symptoms of the disease. In other cases, the number of repeats increases when the gene is passed from mother to child, so the child inherits the complete mutation (more than 200 repeats) and has symptoms of fragile X syndrome. Men carrying a premutation pass it on to all their daughters, who will be carriers of the premutation, but not to sons, since they do not receive an X chromosome from the father. In this case, the premutation does not usually increase when passed on by the father to his daughters.

Women carrying a complete mutation have a 50% chance of passing it on to their children. In men with a complete mutation, they pass on the premutation to all their daughters, since in sperm the complete mutation is reduced to a premutation, but it is unclear why this happens.

Síndrome X Frágil – Spanish Federation of Fragile X Syndrome Associations.

Libro descargable – Reference book for families and professionals. GIRMOGEN Association and Spanish Federation of Fragile X Syndrome. Edited by Real Patronato sobre Discapacidad.