Fragile X syndrome, also termed Martin-Bell syndrome or marker X syndrome, is the most common cause of inherited mental retardation, intellectual disability, and autism and is the second most common cause of genetically associated mental deficiencies, after trisomy 21. Conservative estimates are that fragile X syndrome affects approximately 1 in 2500-4000 males and 1 in 7000-8000 females. 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.
Patients with fragile X syndrome present with problems in the following areas[1] :
Developmental features
Cognitive features
Neuropsychological features
Musculoskeletal features
Feeding difficulties
Sleep disturbance
Recurrent sinusitis
The phenotype of fragile X syndrome is difficult to diagnose in prepubertal children. Most physical examination findings are notable only after onset of puberty. Physical findings are as follows:
See Clinical Presentation for more detail.
DNA testing for fragile X syndrome is recommended. Karyotyping may reveal other chromosomal anomalies, and both a standard karyotype and DNA testing are suggested when a possible diagnosis of fragile X syndrome is considered. The criterion standard diagnostic test involves molecular genetic techniques that detect the FMR1 gene. The exact number of CGG triplet repeats can be determined. Southern blot and polymerase chain reaction (PCR) are the 2 methods of genetic analysis that are currently available.
Features of Southern blot analysis are as follows:
Features of PCR are as follows:
See Workup for more detail.
Routine care involves treating the medical problems that these patients commonly experience, including gastroesophageal reflux, sinusitis, and otitis media. During infant and early childhood healthcare maintenance visits, focus examination on possible hip dislocations, hernias, and hypotonia.
Consultations may include the following:
See Treatment and Medication for more detail.
Fragile X syndrome, also termed Martin-Bell syndrome or marker X syndrome, is the most common cause of inherited mental retardation, intellectual disability, and autism and is the second most common cause of genetically associated mental deficiencies after trisomy 21. In 1943, Martin and Bell investigated a family with multiple male members who had mental retardation.[4] They were able to link the cognitive disorders to an unidentified mode of X-linked inheritance. In 1969, Lubs discovered excessive genetic material that extended beyond the long arm of the X chromosome in affected males and in their unaffected female relatives.[5] These results were impossible to reproduce until the importance of the folate-deficient thymidine-deficient medium, which was used in the initial studies to culture lymphocytes, was realized.
Since the 1960s and early 1970s, progress toward mapping the gene has been steady and rewarding, and the precise genetic defect that causes fragile X syndrome has been characterized. Advances in molecular genetics have provided reliable diagnostic testing. Clinically, patients with fragile X syndrome have an array of physical, cognitive, and neurobehavioral features.
Because fragile X syndrome is underdiagnosed, has a high prevalence, and is inheritable, preconceptual and antenatal molecular genetic screening is encouraged for women.
Obstetricians and primary care providers should recommend screening in high-risk cases. Additionally, a geneticist, genetic counselor, or both should be available to provide accurate information to families if screening findings are positive for fragile X mutations.
Southern blot analysis, polymerase chain reaction (PCR), and immunocytochemical testing are used for diagnosing maternal, preimplantation, and fetal premutations; full mutations; and associated proteins.
Fetal testing involving chorion villus sampling or amniocentesis may be performed and incurs the risks inherent to these procedures.
It is advisable to recommend prepregnancy or prenatal fragile X syndrome screening to women with a family history of fragile X syndrome or mental retardation and to women with learning difficulties, mental retardation, or both. All women who are known carriers of the premutation or full mutation should be offered prenatal testing.
In females with premutations, use of PCR testing to assess the number of AGG repeats that exist within the CGG repeats can assist in prepregnancy counseling.[3] Two or more AGG repeats within the CGG repeats appear to stabilize the premutation and decrease the likelihood that a mother will pass a full mutation to her offspring.[3]
Genetic counseling is important for women who have premutations and full mutations or who are carrying an affected child.
Fragile X syndrome testing should be considered for women with premature ovarian failure, for older adults with ataxia or tremor that could be associated with fragile X-associated tremor/ataxia syndrome (FXTAS), and in children with autism, autism-spectrum disorder, or mental retardation.
Some states are considering adding fragile X syndrome to their newborn screening programs.
Public awareness about fragile X syndrome is increasing thanks to media attention, including an article in Time Magazine on June 26, 2008.
Cognitive, behavioral, and neuropsychological difficulties characterize the syndrome.[1] 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, mental retardation (intelligence quotient [IQ] is typically 35-70), mathematical learning disabilities,[6, 7] 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 by Del Hoyo Soriano et al indicated that in patients with fragile X syndrome, a higher level of FMR1 protein 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.[8]
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 fragile X mental retardation (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.[9] 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.[10]
Conservative estimates report that fragile X syndrome affects approximately 1 in 2500-4000 males and 1 in 7000-8000 females. 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 mental retardation in males and 3% of cases of previously undiagnosed mental retardation in females are attributed to fragile X syndrome.
Exact frequency is unknown. However, data collected from England and Australia are comparable to data from the United States.
Aside from the morbidity associated with mental retardation 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.
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 mental retardation 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 for males (35-37 mo) and fully-mutated females (41 mo) remained unchanged between 2001 and 2007.[11]
Significant family, developmental, cognitive, and neuropsychological histories are keys to diagnosis. Unusual musculoskeletal anomalies, feeding difficulties, sleep disturbances (eg, difficulty falling asleep, frequent awakening, loud snoring with/without obstructive sleep apnea), and recurrent nonspecific medical problems are infrequently reported.
Screening and diagnosis in utero or during infancy is usually the result of a family history that features multiple male relatives with mental retardation.
Other clues to the diagnosis include a mother with learning disabilities, mental retardation, or both or family members with ataxia and tremors.
Female infertility secondary to premature ovarian failure and increased rates of dizygotic twinning have been discovered to be more common in fragile X carriers and may provide another clue to the diagnosis.
During infancy, developmental milestones may be delayed, especially gross motor development secondary to hypotonia.
After the first year of life, delays in speech and language are notable, and fine motor skills are impaired.
As the patient matures, perseveration and echolalia may dominate speech patterns. Expressive language ability, short-term memory, and attempts at problem solving are significantly impaired.
Intelligence quotient (IQ) frequently indicates mild-to-severe mental retardation (20-70). Females and less-affected males may have IQs that approach 80.
IQ may be higher in childhood than in adulthood because of slowing mental development and difficulties with IQ test taking rather than loss of intellect.
IQ in patients with premutations can be normal or slightly decreased.
Patients have many neuropsychological features, including depression, general and separation anxiety, and oppositional defiant disorder.
Autisticlike behavior (especially poor eye contact, social avoidance, and hand biting/hand flapping) is present in 16-30% of patients with fragile X syndrome. However, some patients with autisticlike behavior may have social conversation abilities. Autism is diagnosed in 20% of females and 30% of males with fragile X syndrome; furthermore, an additional 30% of patients with fragile X syndrome are diagnosed with autism spectrum disorder. Molecular investigation for fragile X syndrome is the single laboratory test proven to aid in definitively diagnosing infantile autism.
Near-universal behavioral features of males with fragile X syndrome are similar to those observed in patients with attention deficit hyperactivity disorder (ADHD), including aggressive tendencies and attention deficits.
Approximately 20% of male patients and 5% of female patients have a seizure disorder, with nearly one half of those having persistent seizures that require anticonvulsant therapy. The onset of seizures is typically at age 6-24 months. The seizure type most often diagnosed is complex partial seizure. Additionally, simple febrile partial seizures and generalized tonic-clonic seizures may be present.
Many children have difficulty when routines are altered.
Some people with fragile X syndrome display features of obsessive-compulsive disorder, sensory integration disorder, or both. Others display self-injurious behavior and significant tantrums. Anxiety disorder is common.
Features include pes planus, pectus excavatum, joint laxity, scoliosis, and joint dislocation.
Affected individuals may manifest symptoms of reflux, vomiting, or both and, rarely, failure to gain weight during infancy and childhood. A minority of patients with fragile X syndrome demonstrate a Prader-Willi phenotype, which includes obesity due to severe hyperphagia.
Patients typically have delayed toilet training and frequent enuresis after toilet training.
Patients may have recurrent sinusitis, otitis media, and decreased visual acuity.
During the history taking, ask about apnea.[12]
The phenotype of fragile X syndrome is difficult to diagnose in prepubertal children. Most physical examination findings are notable only after onset of puberty.
Childhood growth is marked by an early growth spurt. However, adult height is often average or slightly below average. Additionally, obesity during adolescence and early adulthood is common.
A study by Lachiewicz et al reported 3 statistically significant phenotypic characteristics of young males with fragile X syndrome compared with young males with other developmental delays.[2] These characteristics included the presence of a hallucal crease (a single crease between the first and second toes), sensitivity to touch, and the inability to touch the tongue to the lips.
A small subset of male patients were reported with obesity, poor linear growth, small hands and feet, and diffuse hyperpimentation.
Adolescent and adult patients have a long, thin face with prominent ears, prominent foreheads, facial asymmetry, a head circumference higher than the 50th percentile, and a prominent jaw.
The mouth has dental overcrowding and a high-arched palate.
Ears are typically large and may protrude.
Strabismus is frequently noted. Occasionally, nystagmus, astigmatism, and ptosis are present.
Hands and feet manifest nonspecific findings, including hyperextensible finger joints, hand calluses, double-jointed thumbs, a single palmar crease, and pes planus. Clubfeet may be present at birth.
Pectus excavatum and scoliosis are frequent findings.
Macroorchidism is nearly universal in postpubertal males. In unaffected males, average testicular volume is 17 mL; in patients with fragile X syndrome, testicular volume is more than 25 mL and can be as high as 120 mL. During childhood, an increased incidence of inguinal hernias is reported.
A heart murmur or click consistent with mitral valve prolapse is often auscultated and requires consultation with a cardiologist.
The genetic defect 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 fragile X mental retardation-1 (FMR1) gene, is to synthesize fragile X mental retardation protein (FMRP), a regulatory protein that binds messenger RNA (mRNA) in neurons and dendrites.[13] 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 mental retardation 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.[14]
No spontaneous FMR1 full mutations have been reported.[15]
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.[16]
Radiography of the spine is recommended in patients with fragile X syndrome to evaluate for scoliosis.
Echocardiography is recommended to exclude mitral valve prolapse.
Cytogenetic testing for fragile X syndrome is not as sensitive as molecular testing, with a false-negative result rate of approximately 20%. Thus, DNA testing for fragile X syndrome is recommended. Karyotyping may reveal other chromosomal anomalies, and both a standard karyotype and DNA testing are suggested when a possible diagnosis of fragile X syndrome is considered.
The criterion standard diagnostic test involves molecular genetic techniques that detect the FMR1 gene. The exact number of CGG triplet repeats can be determined. Southern blot and polymerase chain reaction (PCR) are the 2 methods of genetic analysis that are currently available. Southern blot analysis provides a more accurate estimation of the number of CGG triplet repeats if a full mutation is present (with a large CGG expansion). It can also be used to evaluate the degree of methylation at the CGG repeat site.
PCR is faster, requires a minimal sample, and is less expensive than Southern blot analysis. Additionally, PCR more accurately estimates the number of CGG triplet repeats if a premutation is present (with small-to-moderate increases in CGG repeats). More recent success with fluorescent methylation-specific PCR and GeneScan analysis may further expand diagnostic options.
A comprehensive developmental evaluation by a speech and language therapist, physical therapist, and occupational therapist is recommended to assess weaknesses and to identify areas in which improvement is needed most. As the patient matures, repeat evaluation may be necessary.
Ophthalmology examinations are required.
Routine auditory examinations are advised; otolaryngology referral for chronic otitis media and evaluation for pressure equalization (PE) tube placement are recommended.
Workup and diagnosis of fragile X syndrome can be done on an outpatient basis. Routine care involves treating the medical problems that these patients commonly experience, including gastroesophageal reflux, sinusitis, and otitis media. During infant and early childhood healthcare maintenance visits, focus examination on possible hip dislocations, hernias, and hypotonia.
Consultations may include the following:
A special diet is indicated in infants with significant gastroesophageal reflux. In these patients, thickened feeds may decrease the incidence of reflux; otherwise, no special diet is indicated.
The results of folic acid supplementation to curb the inattention and aggressiveness in prepubertal males are controversial; thus, folic acid supplementation is currently not the standard of care in fragile X syndrome. No effect has been observed in adults treated with folic acid.
Trials of medications, such as fenobam, that act as mGluR5 antagonists are underway. Excess mGluR5 signaling occurs when FMRP is decreased or absent. Therefore, downregulation of mGluR5 may improve outcomes in patients with fragile X syndrome. Lithium also inhibits mGluR5 signaling (as well as other pathways) and may benefit patients with fragile X syndrome.
Other trials with γ -aminobutyric acid agonists are underway.
Routine outpatient care and immunization schedule are indicated in patients with fragile X syndrome.
Family counseling assists with behavior modification strategies.
Stimulants (eg, methylphenidate, dextroamphetamine) have been used in fragile X syndrome patients for attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD) in the doses prescribed for patients with typical ADHD. Responses vary, but 70% of patients experience some improvement in their behavior. For patients younger than 5 years, alpha-adrenergic receptor agonists (clonidine and guanfacine) may be used to improve behavioral difficulties. Clonidine may be preferred in patients with sleep disorders.
Patients with anxiety may benefit from selective serotonin reuptake inhibitors (SSRIs). Fluoxetine is advised for patients with social anxiety, selective mutism, and autism but should be avoided in patients with impulsivity and other activating symptoms.
Atypical antipsychotics may improve extreme behaviors, including severe agression, mood lability, and self-injury.
Most patients with fragile X syndrome and seizure disorders are treated with a single antiepileptic medication. Phenobarbital, phenytoin, and gabapentin should be avoided. First-line agents include carbamazepine and valproic acid. Other options for patients who do not respond to or cannot tolerate carbamazepine or valproic acid include lamotrigine, oxcarbazepine, zonisamide, and levetiracetam; however, levetiracetam occasionally worsens irritability and aggression.
Antireflux, sleep (eg, trazodone, melatonin), and mood-stabilizing medications (risperidone and aripiprazole) are useful in patients with these symptoms.
Complications may include scoliosis or mitral valve prolapse (most frequently encountered cardiac defect).
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.
For more information by mail, send a request to the following address:
For further information, visit the Fraxa Research Foundation Web site or the National Fragile X Foundation Web site.
The American Academy of Pediatrics, Committee of Genetics publshed a clinical report, "Health Supervision for Children With Fragile X Syndrome" in May 2011 to assist primary care providers in assuring patients receive comprehensive care and anticiparory guidance.[17]