Fragile X Syndrome

The genetic defect in fragile X syndrome is dynamic and lies at the distal end of the long arm of the X chromosome. Careful examination of the karyotype of affected individuals' lymphocytes, cultured in a folate-depleted and thymidine-depleted medium, reveals a constriction followed by a thin strand of genetic material that extends beyond the long arm at the highly conserved band Xq27.3. This constriction and thin strand produce the appearance of a fragile portion of the X chromosome, leading to the term fragile X.

The function of the band Xq27.3, which is also termed the FMR1 gene, is to synthesize FMRP, a regulatory protein that binds messenger RNA (mRNA) in neurons and dendrites. ^[3]  In patients with a full mutation in the FMR1 gene, FMRP is not manufactured because of hypermethylation of FMR1, and brain development is impaired primarily because of abnormal synapse connections. Additionally, mutations in the FMR1 gene lead to excessive activity of the metabotropic glutamate receptor 5 (mGluR5), which results in many fragile X syndrome symptoms. FMRP is present in other tissues; however, its role is less understood.

Once identified and sequenced, the gene was discovered to contain a repeating base pair triplet (CGG) expansion, which is responsible for fragile X syndrome.

Unaffected individuals have 5–54 CGG repeats in the first exon at the 5' end of band Xq27.3. Individuals with 45–54 repeats are unaffected, but they risk passing a premutation on to future generations. A span of 55-199 repeats is known as a premutation, whereas 200 or more repeats is a full mutation. Full mutation results in hypermethylation of the cysteine bases and restricts protein binding, leading to gene inactivation and absent FMRP. Mosaic patterns are common. The number of repeats is unstable from generation to generation, making the pattern of inheritance difficult to predict. In addition, the degree of methylation is directly proportional to the signs and symptoms of fragile X syndrome.

Males with a full mutation have fragile X syndrome. Mothers of nearly all males with fragile X syndrome have premutation or fragile X syndrome. Males with fragile X syndrome pass a premutation to their daughters because sperm cells are mosaics. Sons are unaffected because they receive the Y chromosome from their fathers.

Half of females with the full mutation on a single X chromosome are unaffected because of inactivation of the other X chromosome. The other half of females have fragile X syndrome, although with less severe intellectual disability than males with the disorder. These affected females can pass the gene to their children.

Males with a premutation are usually unaffected to mildly affected and transmit the premutation to their daughters. The mutation is stable; thus, the CGG triplets are not increased. Sons of affected males are unaffected because they receive the Y chromosome from their fathers.

Females with a premutation are usually unaffected to mildly affected with fragile X syndrome. However, they have a 20% chance of having fragile X – associated primary ovarian insufficiency. Unlike their male counterparts, the CGG triplets are unstable and increase in size during oogenesis. If the number of repeats exceeds 200 and the oocyte is fertilized, a male child will have fragile X syndrome, and a female child will have a 50% chance of having fragile X syndrome. The number of repeats is directly proportional to the risk of the disorder in an offspring.

Although most patients with fragile X syndrome have a CGG triplet expansion, few patients have a point mutation in the FMR1 gene or a deletion of the gene. ^[4]

No spontaneous FMR1 full mutations have been reported. ^[5]

A study by Hall et al indicated that in fragile X syndrome, the microstructure of white matter is abnormal in areas of the inferior longitudinal and uncinate fasciculi. The study, included 20 patients with fragile X syndrome and 20 matched controls, found a significant increase in fractional anisotropy in the left and right inferior longitudinal fasciculi, the right uncinate fasciculus, and the left cingulum hippocampus, in the fragile X syndrome group, as well as a significant reduction in mean diffusivity in the right inferior longitudinal fasciculus. The investigators stated that the abnormalities probably result from inefficient synaptic pruning, caused by decreased or absent FMRP. ^[6]

Cognitive, behavioral, and neuropsychological difficulties characterize the syndrome. ^[7] These signs are especially important in alerting physicians, parents, and teachers to deficits exhibited by preschool-aged children and elementary school–aged children. This group represents the age at which the diagnosis of fragile X syndrome is often made or considered.

Problems include mild-to-moderate autisticlike behavior (most notably, hand flapping and avoidance of eye contact), shyness, sensory integration difficulties, attention deficits, hyperactivity, impulsivity, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), depressed affect, anxiety, intellectual disablity (intelligence quotient [IQ] is typically 35–70), mathematical learning disabilities, ^{[8, 9]} aggressive tendencies, deficiency in abstract thinking, developmental delays after reaching early milestones (especially speech and language delays), and decreasing IQ with increasing age.

The wide range of these abnormalities is partially related to each individual's environment, maternal psychopathology, and available educational and therapeutic opportunities, especially in affected males. Patients with high-functioning home environments and appropriate education services demonstrate higher IQs and improved behavioral outcomes.

A prospective study indicated that in patients with fragile X syndrome, a higher level of fragile X messenger ribonucleoprotein (FMRP) and a lower ratio of affected-to-total chromosomes are associated with better gains in fluid intelligence (but not in crystallized intelligence). The evidence also indicated that the affected-to-total chromosome ratio is related to anxiety and social withdrawal levels. ^[10]

In addition, physical signs are associated with fragile X syndrome; however, these signs are more obvious during adolescence or after puberty and rarely result in disabilities. In addition to the cognitive, behavioral, and neuropsychological findings, the organ systems most frequently involved include the craniofacial, genital, and musculoskeletal systems.

Fragile X-associated tremor ataxia syndrome (FXTAS) has been reported in 33–46% of men older than 50 years and, less frequently (4–8%), in older women with premutations in the FMR1 gene. Full mutations of this gene result in fragile X syndrome. Clinical features of FXTAS include incontinence, impotence, cerebellar ataxia, peripheral neuropathy, autonomic dysfunction/orthostatic hypotension, severe intention tremor, and other signs of neurodegeneration, such as brain atrophy, memory loss and dementia, anxiety, depression, and irritability. Premature ovarian failure is reported in 25% of women with premutations; this represents a 30-fold increase compared with the general population.

The risk of fragile X–associated primary ovarian insufficiency is directly related to the number of CGG repeats. Symptoms include irregular menses, decreased fertility, premature ovarian failure, and laboratory abnormalities, such as elevated follicle-stimulating hormone (FSH) levels. Studies attempting to develop a predictive model for the timing of premature ovarian failure are underway and include the number of CGG repeats, environmental effects, and genetic factors. ^[11] Associations between women with premutations and autoimmune diseases (hypothyroidism and fibromyalgia) have been reported. In women with a diagnosis of ovarian insufficiency, 2–15% have a premutation. ^[12]

Prevalence

Conservative estimates report that fragile X syndrome affects approximately 1 in 7000 males and 1 in 11,000 females. ^{[13, 2]} The prevalence of female carrier status has been estimated to be as high as 1 in 130-250 population; the prevalence of male carrier status is estimated to be 1 in 250-800 population. As many as 10% of cases of previously undiagnosed intellectual disability in males and 3% of cases of previously undiagnosed intellectual disability in females are attributed to fragile X syndrome.

Demographics

Fragile X syndrome has been described in all racial and ethnic groups. The overall frequency in other countries is slightly lower than in the United States. Whether this is related to racial or ethnic diversity or to diagnostic technology is unclear.

Females carry the gene abnormality 2–4 times more often than males; however, only about one third of females who carry the abnormal gene demonstrate decreased intelligence. Females with the disorder are more likely to have less impairment and less obvious physical characteristics. Males with the disorder are more likely to be sensitive to environmental factors.

The pattern of inheritance most closely resembles X-linked dominance with variable penetrance. Occasionally, females are severely affected because of the complex genetics of the disorder.

Fragile X syndrome is an inherited disorder and is present at birth.

If the intellectual disability is discovered during a prenatal or family history, diagnosis is typically made at a younger age. If the physician is intimately acquainted with the patient’s family, providers may be alerted to possible maternal carrier states in mothers who display cognitive impairment. Therefore, developmental delays in children are appreciated earlier.

As patients complete puberty, the characteristic craniofacial features, in addition to the cognitive, behavioral, and neuropsychological disabilities, alert physicians to the possibility of a genetic disorder.

Despite provider education and fragile X syndrome advocates, the average age of diagnosis is 35–37 months for boys and 42 months for girls. ^[2]

Mortality/Morbidity

Aside from the morbidity associated with intellectual disability and cognitive, behavioral, and neuropsychological problems, the morbidity and mortality associated with fragile X syndrome are unremarkable. Life span is generally unaffected by the disorder.

Family members should attempt behavior modification techniques and be involved with a counselor to assist with appropriate modes of discipline.

Adult patients should reside in the least restrictive environment that is safely acceptable to foster independent living.

Patients should receive special education classes that are appropriate for cognitive ability. Work programs should be sought for patients who are trainable.

Early childhood intervention for children with significant developmental delays is essential, especially in patients with speech and cognitive delays.