Fragile X syndrome occurs in individuals who carry the gene, FMR1 on an X-chromosome. The condition which occurs twice as frequently in males (1:1,200) as compared to females (1:2,500) is the most common genetic cause of mental impairment and ranges from learning disabilities to more severe cognitive or intellectual disabilities.

Fragile X syndrome is also the most common known cause of autism or “autistic-like” behaviors. Symptoms include characteristic physical and behavioral features, and delay in speech and language development. Other manifestations include a variant known as Fragile X Associated Tremor/Ataxia Syndrome – a condition characterized by loss of balance, tremors and memory loss – which occurs in some older male carriers of the gene. Also, since some female carriers of the FMR1 gene may have associated diminished ovarian reserve, infertility and early menopause, it is important to test women who present in this way, for Fragile X.

Most males who have fragile X syndrome are mentally compromised and usually have many of the physical and behavioral characteristics cited above. When Fragile X syndrome occurs in females it is often less severe. However, some gene carriers do not exhibit any of these features.
The severity of the manifestations of Fragile X syndrome varies, but most males with full blown clinical fragile X syndrome are mentally retarded and exhibit physical and behavioral characteristics, while only about one third of females are mentally retarded. Another one third are partially mentally impaired, while the remaining third are unaffected.

The Fragile X gene, FMR1, can be passed on in a family by individuals who have no apparent signs of this genetic condition. In some families, a number of members appear to be affected, whereas in other families a newly diagnosed individual may be the first family member to exhibit symptoms.

Fragile X syndrome is diagnosed through DNA testing of cells using one of two methods:

1. Polymerase Chain Reaction (PCR) or
2. Southern blot analysis

Both methods exhibit a high degree of interpersonal variability and thus when it comes to interpreting results, there are significant limitations. This is especially the case when diagnosing a “carrier state.” Interpretation is further complicated by the presence of other fragile sites in the same region of the X chromosome.

The fragile X gene (FMR1) contains a repeated sequence – called a “CGG Repeat” which is responsible for fragile X syndrome. In a normal population, the number of repeated FMR1 genes varies from six to about 50. Carriers are categorized into two types based on the number of repeats:

A. Individuals who have approximately 50 to 200 repeats have an unstable mutation which can expand in future generations.

B. Individuals with over 200 repeats have a full mutation which causes fragile X syndrome.

Individuals of Group A who carry a premutation are unaffected. Male carriers pass on the mutation to all their female offspring, so while they themselves remain unaffected, their offspring are at risk of being affected. There is no clear cut-off between the upper limit of normal and the lower limit of the premutation range. Accordingly, cases with 45-55 repeat copies fall into the so called “gray zone.” In some cases, premutations expand from generation to generation such that over time they ultimately express as full Fragile X syndrome. The larger the premutation in cases that fall in the “gray zone”, the greater is the risk of subsequent expansion to a full mutation in the offspring.

It is recommended that in the following circumstances, patients undergoing assisted reproduction be tested for Fragile-X:

• All mentally challenged individuals, those who are autistic, and in cases of developmental delay
• Women with unexplained premature reduction in ovarian reserve or premature ovarian failure (menopause)
• Individuals who have physical or behavioral characteristics of fragile X syndrome
• Those with a family history of fragile X syndrome
• Those with a family history of mentally challenged male or female relatives where no definitive cause has been ascertained.
• Offspring of known carrier mothers

Prenatal diagnosis can be made by 2nd trimester amniocentesis, which yields definitive results. In contrast, results obtained from 1st trimester chorionic villus sampling (CVS) should be interpreted with caution, because the status of the FMR1 gene often will not fully manifest in chorionic villi until the second trimester.