Fragile X syndrome, also termed Martin-Bell syndrome or marker X syndrome, is the most common cause of inherited mental retardation 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.1 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.2 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.
Cognitive, behavioral, and neuropsychological difficulties characterize the syndrome. 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,3,4 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.
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 33-40% 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 cerebellar ataxia, neuropathy, autonomic dysfunction, severe intention tremor, and other signs of neurodegeneration, such as brain atrophy, memory loss and dementia, anxiety, and irritability. Premature ovarian failure is reported in 25% of women with premutations; this represents a 30-fold increase compared with the general population. Recent associations between women with premutations and autoimmune diseases (hypothyroidism and fibromyalgia) have been reported.
Conservative estimates report that fragile X syndrome affects approximately 1 in 4000 males and 1 in 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.
Significant family, developmental, cognitive, and neuropsychological histories are keys to diagnosis. Unusual musculoskeletal anomalies, feeding difficulties, and recurrent nonspecific medical problems are infrequently reported.
- Family history
- 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 recently been discovered to be more common in fragile X carriers and may provide another clue to the diagnosis.
- Developmental history
- During infancy, developmental milestones are achieved as expected or are slightly delayed.
- However, 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.
- Cognitive history
- 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.
- Neuropsychological history
- Patients have many neuropsychological features, including depression and anxiety.
- Autisticlike behavior (especially poor eye contact and hand biting or hand flapping) is present in 16-30% of patients with fragile X syndrome. However, even patients with autisticlike behavior may have social conversation abilities. Molecular investigation for fragile X syndrome is the single laboratory test proven to aid in definitively diagnosing infantile autism.
- 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.
- Musculoskeletal features: Features include pes planus, pectus excavatum, joint laxity, scoliosis, and joint dislocation.
- Feeding difficulties: 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.
- Recurrent nonspecific medical problems
- Patients may have recurrent sinusitis, otitis media, and decreased visual acuity.
- During the history taking, ask about apnea.5
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.
- A study by Lachiewicz et al (2000) reported 3 statistically significant phenotypic characteristics of young males with fragile X syndrome compared with young males with other developmental delays.6 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.
- Craniofacial: Adolescent and adult patients have a long, thin face with prominent ears, facial asymmetry, a head circumference higher than the 50th percentile, and a prominent forehead and jaw.
- Mouth: The mouth has dental overcrowding and a high-arched palate.
- Ears: Ears are typically large and may protrude.
- Eyes: Strabismus is frequently noted.
- Extremities: Hands and feet manifest nonspecific findings, including hyperextensible finger joints, hand calluses, double-jointed thumbs, a single palmar crease, and pes planus.
- Back and chest: Pectus excavatum and scoliosis are frequent findings.
- Genitals: Macroorchidism is universal in adult 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.
- Cardiac: 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.7 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. 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. A span of 55-200 repeats is known as a premutation, whereas more than 200 repeats is a full mutation. Full mutation results in hypermethylation of the cysteine bases and restricts protein binding, leading to gene inactivation. 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 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. 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.8