Chapter 27 Fragile X Syndrome
PATHOPHYSIOLOGY
Mutations in the fragile X mental retardation (FMR1) gene are associated with fragile X syndrome, fragile X–associated tremor/ataxia syndrome (FXTAS), and FMR1-related premature ovarian failure. Individuals with fragile X syndrome have an intellectual disability; individuals with FXTAS and FMR1-related premature ovarian failure usually do not have an intellectual disability, but they are at high risk for having children or grandchildren with fragile X syndrome.
The FMR1 gene is located on the X chromosome; thus women inherit two copies (alleles) of the FMR1 gene and men inherit one allele. A particular region on the FMR1 gene (often referred to as the fragile site) has three DNA bases (cytocine [C], guanine [G], guanine) that are repeated (trinucleotide repeat) many times. There are essentially four allelic categories that define repeat length.
A normal allele is characterized by 5 to 40 CGG repeats. An intermediate (gray zone) allele has 41 to 58 repeats. A premutation allele has 59 to 200 CGG repeats. A premutation allele is not associated with intellectual disability, but does convey an increased risk for FXTAS and FMR1-related premature ovarian failure. Women who have 59 to 200 CGG repeats are considered to be at risk for having children affected with fragile X syndrome. Individuals who have more than 200 hypermethylated CGG repeats (usually several hundred to several thousand) have full mutations; they have fragile X syndrome. The number of repeats is unstable from generation to generation, making the pattern of inheritance difficult to predict.
The FMR1 gene codes for a protein called the FMR protein, made in many tissues and having a high concentration in the brain and testes. The FMR protein plays a role in the development of synapses between nerve cells in the brain where cell to cell communication occurs. The connection between nerve cells can change and adapt over time in response to experience (synaptic plasticity). The FMR protein is thought to help regulate synaptic plasticity, which is important for learning and memory. Consequently, an individual born with a full mutation in his or her FMR1 gene suffers from cognitive and neuropsychologic problems.
The more profound intellectual disability (formerly known as mental retardation) seen in males can be explained by X inactivation that occurs during embryogenesis. A female embryo inherits two X chromosomes; two active X chromosomes are not compatible with life, and thus one X chromosome in every cell has to be inactivated. The inactivation process is random; in a female embryo, it does not automatically inactivate the X chromosome that has a defective FMR1 gene.
For example, if a female inherits a defective FMR1 gene from her father, it could work out that 80% of his X chromosomes will be inactivated. That, in turn, means that 80% of her cells will be making adequate FMR1 protein; she will probably not have a severe intellectual disability, and perhaps not any. On the other hand, if 80% of her mother’s X chromosomes were inactivated, the child would most likely have an intellectual disability.
INCIDENCE
1. Fragile X syndrome is the number one cause of inherited intellectual disability.
2. Fragile X affects 1 in 4000 males and 1 in 8000 females.
3. The prevalence is similar in most ethnic and racial groups.
4. High repeat numbers (41 to 199 CGG repeats) occur in 4% of all males and 8% of all females; they are considered carriers.
5. Approximately 15% of women with premature ovarian failure have 35 to 54 CGG repeats.
6. Approximately 3% of men over age 50 years with unexplained ataxia have 83 to 109 CGG repeats.
CLINICAL MANIFESTATIONS
2. Developmental characteristics
LABORATORY AND DIAGNOSTIC TESTS
Refer to Appendix D, Laboratory Values, for normal values and ranges of laboratory and diagnostic tests.
2. Prenatal genetic testing is conducted when a mother is a known carrier.
3. Preimplantation genetic testing (see Box 27-1 for CLIA-approved clinics in the United States)
