Fragile X syndrome, or Martin-Bell syndrome, is a genetic syndrome which results in a spectrum of characteristic physical, intellectual, emotional and behavioural features which range from severe to mild in manifestation. Fragile X syndrome (also called FXS) is the most common cause of inherited mental retardation. It is also the most common known cause of autism. It affects about 1 in 4000 males and 1 in 8000 females.
There are four generally accepted forms of Fragile X syndrome which relate to the length of the repeated CGG sequence:
Normal (29-31 CGG repeats), Premutation (55-200 CGG repeats), Full Mutation (more than 200 CGG repeats), and Intermediate or Gray Zone Alleles (40 – 60 repeats).
Symptoms – Fragile X syndrome
Not everyone with fragile X syndrome has the same signs and symptoms. Even affected people in the same family don’t show the same symptoms. The signs and symptoms fall into six categories: Intelligence and learning Physical Social and emotional Speech and language Sensory Disorders commonly associated or sharing features with Fragile X.
Individuals affected with Fragile X syndrome usually have
- delayed development of speech and language by age 2 (cluttered or nervous speech)
- most males with fragile X syndrome have mild to moderate intellectual disability
- about one-third of affected females are intellectually disabled
Children with fragile X syndrome may also have
- anxiety and hyperactive behavior such as fidgeting or impulsive actions
- attention deficit disorder (ADD)
- about one-third of individuals with FXS have features of autism spectrum disorders that affect communication and social interaction
- Seizures occur in about 15 percent of males and about 5 percent of females with fragile X syndrome
- Social and emotional problems, such as aggression in boys or shyness in girls
- Very sensitive to stimuli
- Great sense of humor
- Excellent memory
- Frequent tantrums
Most males and about half of females have characteristic physical features that become more apparent with age. These features include:
- long and narrow face
- low muscle tone
- large ears
- prominent jaw and forehead
- unusually flexible fingers
- flat feet
- in males: enlarged testicles (macroorchidism) after puberty
People with a small change in the FMR1 gene might not show any sign of the syndrome. Bigger changes in the gene cause more severe symptoms.
Causes – Fragile X syndrome
Fragile X syndrome is an inherited genetic disorder. It is caused by mutation of a gene (FMR1) on the X-chromosome. Normally, the gene makes a protein needed for brain development. But the mutation causes a person to make less or none of the protein, which causes FXS.
Normally, the FMR1 gene contains between 6 and 55 repeats of the CGG codon (trinucleotide repeats). In people with the fragile X syndrome, the FMR1 allele has over 230 repeats of this codon. Expansion of the CGG repeating codon to such a degree results in a methylation of that portion of the DNA, effectively silencing the expression of the FMR1 protein. This methylation of the FMR1 locus in chromosome band Xq27.3 is believed to result in constriction of the X chromosome which appears “fragile” under the microscope at that point, a phenomenon that gave the syndrome its name. Mutation of the FMR1 gene leads to the transcriptional silencing of the fragile X-mental retardation protein, FMRP. In normal individuals, FMRP is believed to regulate a substantial population of mRNA: FMRP plays important roles in learning and memory, and also appears to be involved in development of axons, formation of synapses, and the wiring and development of neural circuits
Mothers may be a carrier of the mutation and pass it on to their children.
Or, a mother may have a pre-mutation that expands to a full mutation when passed on to the next generation.
Boys are affected more severely than girls, because girls have another X chromosome, which usually does not have the mutation and can partially compensate for the nonfunctioning one. Boys have only one X chromosome (and one Y chromosome).
The damaged gene can be passed along silently (without symptoms) for generations before a child is affected by FXS.
Prevention – Fragile X syndrome
Diagnosis – Fragile X syndrome
Fragile X syndrome was originally diagnosed by culturing cells in a folate deficient medium and then assessing the cultures for X-chromosome breakage by cytogenetic analysis of the long arm of the X chromosome. This technique proved unreliable for both diagnosis and carrier testing. The fragile X abnormality is now directly determined by analysis of the number of CGG repeats and their methylation status using restriction endonuclease digestion and Southern blot analysis.
Genetic testing is available to diagnose FXS and to test for female carriers. The DNA testprovides definite diagnosis and very accurate carrier detection. Testing is recommended for:
- Any person with developmental delay, signs of autism, a learning disability or intellectual disability (borderline to severe) of unknown cause
- Any person who has:
- any of the physical features or behaviors that are typical in FXS
- a relative who has FXS
- any relatives with intellectual disability of unknown cause
- Any person with autism, or who has autism-like behaviors
- Anyone who previously had the chromosome test (an older, costly, and often inaccurate test) for FXS
- Women with primary ovarian insuffiency (or POI, which used to be called primary ovarian failure, or POF), or “early menopause”, or with a family history of POI
- Couples who have one or more relatives with mental retardation of unknown cause may want to be tested before deciding to have a child.