What is Fragile X Syndrome?

What is Fragile X Syndrome?
Fragile X syndrome is the most common inherited cause of mental impairment. The syndrome occurs in approximately 1 in 3600 males and 1 in 4000 to 6000 females. The majority of males with Fragile X syndrome will have a significant intellectual disability. The spectrum ranges from learning disabilities to severe cognitive impairment (formerly referred to as mental retardation) and autism. In addition, males have a variety of physical and behavioral characteristics and problems. However, no male has all of these features. Enlarged ears, long face with prominent chin, and large testicles (in post-pubertal males) are common. Connective tissue problems may include ear infections, mitral valve prolapse, flat feet, hyperflexible fingers and joints and a variety of skeletal problems. Behavioral characteristics in males include attention deficit disorders, speech and language disturbances, hand biting, hand flapping, autistic behaviors, poor eye contact, and unusual responses to various tactile, auditory or visual stimuli. Some children with Fragile X syndrome also develop seizures.

The characteristics seen in males can also be seen in females, though females often have milder intellectual disability and a milder presentation of the behavioral or physical features. About a third of the females have a significant intellectual disability. Others may have more moderate or mild learning difficulties. Similarly, the physical and behavioral characteristics are often expressed to a lesser degree.

What causes Fragile X Syndrome? 

A change or mutation in a gene on the X chromosome causes Fragile X syndrome. Chromosomes are packages of genes that are passed from generation to generation. Most individuals have 46 chromosomes, two of which are sex chromosomes. In females, there are two X chromosomes; males have one X and one Y. Genes are given names to identify them and the gene responsible for Fragile X syndrome is called the FMR1 (Fragile X mental retardation 1) gene. The mutation is in the DNA (the chemical that makes up genes) on the X chromosome. The gene appears in several forms that are defined by the number of repeats of a pattern of DNA called CGG repeats. Individuals with fewer than 45 CGG repeats have a normal gene. Individuals with 55-200 CGG repeats have a “premutation”, which is an unstable version of the FMR1 gene that can expand in future generations. Individuals with over 200 repeats have a “full mutation” which causes Fragile X syndrome. The full mutation causes the FMR1 gene to shut down or fail to be expressed normally. Normally, the FMR1 gene produces an important protein called FMRP. When the FMR1 gene is turned off by the full mutation, the individual does not make FMRP. The lack of this specific protein causes Fragile X syndrome.

Are there treatments for Fragile X Syndrome?

At this time, there is no cure for Fragile X syndrome. However, special education, speech and language therapy, occupational therapy and behavioral therapies are helpful in addressing many of the behavioral, and cognitive issues in Fragile X syndrome. In addition, certain medications may be helpful for aggression, anxiety, hyperactivity and poor attention span. In Fragile X patients with seizures, medications are usually very effective in treating the seizures. Because the impact of Fragile X is so different between people, it is important to do a careful evaluation of abilities and difficulties to tailor a treatment plan to address specific needs.

Testing

During the 1970's and 1980's the test available for diagnosing Fragile X syndrome was the chromosomal or cytogenetic test. While it was helpful, it was not always accurate. In the 1990's, two molecular DNA tests became available. These are: 1) Southern Blot analysis -this determines if the gene has a full mutation and its approximate size, if the gene has been methylated and if there is mosaicism (a mixture of different cell types). 2) The polymerase chain reaction (PCR) analysis can determine the actual number of repeats in individuals with a normal size gene or with a premutation. Recently, a highly efficient PCR-based assay (Filipovic-Sadic et al., Clinical Chemistry 56: 399-408(2010)) capable of amplifying normal, premutation and full mutation CGG repeats with equal efficiency was developed, which many laboratories are now using and is performed at The University of Michigan in the Michigan Medical Genetics Laboratories.

Premutation

Fragile X syndrome is one of a group of conditions called nucleotide repeat disorders. A common feature of these conditions is that the gene can change sizes over generations, becoming more unstable, and thus the conditions may occur more frequently or with greater severity in subsequent generations. These conditions are often caused by a gene change that begins with a premutation and then expands to a full mutation in subsequent generations.

Approximately 1 in 250 females and 1 in 800 males carry the Fragile X premutation. Fragile X premutations are defined as having 55 to less than 200 CGG repeats and can be present in both males and females. In males with a premutation, the premutation usually does not expand to a full mutation when passed on to daughters (a male never passes on the Fragile X gene to his sons, since males pass their Y chromosomes to their sons). A female carrier of a premutation is at increased risk of passing on a larger, full expansion, version of the mutation to her children.  As the size of the premutation increases, there is an increased possibility that a child will receive the full mutation.

Typically, the Fragile X premutation has no observable impact. However, some females with a premutation will experience early menopause and/or fertility difficulties (primary ovarian insufficiency). Additionally, some older adults with a premutation may develop a neurological condition called FXTAS (Fragile X Tremor and Ataxia Syndrome), which is often misdiagnosed as a "Parkinson's-like" condition. Patients with FXTAS have difficulties walking, tremors, and some cognitive difficulties.

Full mutation

A full mutation is defined as having over 200 CGG repeats. In addition, most full mutation FMR1 genes are methylated (a process associated with "shutting down" the expression of the FMR1 gene). Males with a full mutation usually have Fragile X syndrome, though there is a very small percentage of males with a full mutation who do not have cognitive impairment. About 30% of females with a full mutation have no cognitive deficits. The remaining 65-70% of females with a full mutation will have some difficulties with cognitive, behavioral, or social functioning and may have some of the physical features found in males.
 
Inheritance

Fragile X is an "X-linked" condition, which means that the FMR1 gene is physically located on the X chromosome. Since a woman has two X chromosomes, woman with either a premutation or a full mutation have a 50% chance of passing on the X with the CGG expansion in each pregnancy. If she carries a premutation, and it is passed on (to either males or females), it can remain a premutation or it can expand to a full mutation. If she has a full mutation and it is passed on (to either males or females), it will remain a full mutation. In many X-linked conditions only males who inherit the abnormal gene are affected; however, in Fragile X syndrome females can also be affected as mentioned above. Additionally, in other X-linked conditions, all males who carry the gene are affected; however, in Fragile X syndrome, unaffected males can have a premutation and have no symptoms of Fragile X syndrome. Males with the premutation will pass it on to all of their daughters and none of their sons (they pass their Y chromosome on to their sons).

History of Fragile X syndrome

In 1943, Martin and Bell showed that a particular form of mental retardation (later known as Fragile X syndrome) was X-linked. In 1969, Herbert Lubs developed the chromosomal test for Fragile X. The test was not used extensively until the late 1970's. In 1991, the FMR1 gene and the mutational basis of Fragile X syndrome were discovered.  In 2001, the initial cases of FXTAS and FXPOI were recognized.




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