Fragile X syndrome

Mutations (changes) in the FMR1 gene cause fragile X syndrome (FXS). This gene carries instructions to make a protein called the fragile X mental retardation 1 protein. The FMR1 gene contains a section of DNA called a CGG triplet repeat, which normally repeats from 5 to around 40 times. In most cases of FXS, this section of DNA is repeated more than 200 times, which "turns off" the FMR1 gene and disrupts the function of the nervous system. In a small portion of cases, other types of changes in the FMR1 gene cause FXS. These changes may involve a deletion of all or part of the gene, or a change in the building blocks (amino acids) used to make the gene's protein.

People with 55 to 200 repeats of the CGG segment are said to have an FMR1 premutation. Most people with a premutation are intellectually normal. In some cases, people with a premutation have lower levels of the gene's protein and may have some mild symptoms of FXS. About 20% of women with a premutation have premature ovarian failure, and some people with a premutation have an increased risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS).

Yes, genetic testing is available for fragile X syndrome. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the diagnosis of an FMR1 -related disorder (including fragile X syndrome) has been confirmed in a family member.

The Genetic Testing Registry (GTR) provides information about the labs that offer genetic testing for fragile X syndrome. The intended audience for the GTR is health care providers and researchers. People with questions about genetic testing should speak with a health care provider or genetics professional.

Fragile X syndrome (FXS) is inherited in an X-linked dominant manner. A condition is X-linked if the responsible gene is located on the X chromosome. The inheritance is dominant if having only one changed (mutated) copy of the responsible gene is enough to cause symptoms of the condition.

In women who carry an FMR1 gene premutation (approximately 55 to 200 CGG repeats), the repeats can expand to more than 200 repeats in their cells that develop into eggs. This means that women with a premutation (or a full mutation) have an increased risk to have a child with FXS. The size of the risk corresponds to the number of CGG repeats they have. By contrast, men with premutations are not at risk for the repeats expanding to over 200 when passing the gene to offspring. However, men with a premutation will pass the premutation on to all of their daughters and none of their sons. This is because boys receive only a Y chromosome from their fathers.

A comprehensive search of the resources available to us did not identify a heighted risk for fractures among individuals with Fragile X syndrome. However, other skeletal and connective tissue problems may be present, including flat feet (pes planus), soft velvet-like skin, joint hypermobility (especially in the fingers), congenital hip dislocation, scoliosis, and clubfoot.

While the life span of people with fragile X syndrome (FXS) is typically normal, there is very little information in the medical literature about adults with FXS. The effect of specific medical problems or associated complications on adults with FXS may vary because not all affected people have the same features.

While affected males usually have moderate to severe intellectual disability, one third to half of affected females have average intellectual function. Because of this, some adult women with FXS may have very normative adult lives, including living independently; having a spouse or romantic partner; pursuing higher education; holding full-time jobs; having friends; and participating in a range of leisure activities. Adult men with FXS are more likely to have much more limited independence. However, there are likely considerable differences between all people with FXS.

Specific factors that affect people in adulthood may include functional level (e.g., ability to dress, eat and communicate); the degree to which they are able to interact with others (contributing to employment and friendships); and the presence of mental health problems such as anxiety and depression. Adults with FXS who also have an autism spectrum disorder diagnosis may have more limited independence in adult life than those with FXS only.

Life expectancy for people with fragile X syndrome is generally normal. Many affected people participate in an active lifestyle and have good health. Some people are more prone to a number of medical problems, such as ear infections and/or seizures. Regular medical checkups and awareness of increased health risks may improve the outlook for affected people.

There is no specific treatment available for fragile X syndrome. Management of this condition is generally supportive and may include:

• recognizing the need for special education and avoiding excessive stimulation, which may help with behavioral problems
• early educational intervention and special education that is tailored to specific learning difficulties; small class size, individual attention and avoidance of sudden change is often needed
• medications for behavioral issues that affect social interaction
• routine medical management of strabismus, ear infections, reflux, seizures, mitral valve prolapse, and/or high blood pressure.

American Academy of Pediatrics Guidelines: Health Supervision for Children with Fragile X Pediatrics 2011; 127: 994-1006.

The American College of Medical Genetics (ACMG) Laboratory Quality Assurance (Lab QA) Committee has the mission of maintaining high technical standards for the performance and interpretation of genetic tests. In part, this is accomplished by the publication of the document "ACMG Standards and Guidelines for Clinical Genetics Laboratories." These standards and guidelines are designed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. To view the Technical Standards and Guidelines for Fragile X syndrome, visit the link above.