The most common problems that bring a male patient with fragile X syndrome to medical attention are mental retardation and behavioral disturbances, with 4% to 8% of mental retardation or developmental delay caused by fragile X mutation (Sutherland et al 2002). The clinical severity is directly related to the number of repeats in the FMR1 gene. Attention has been directed to the increasingly recognized clinical features of the premutation expansion (55 to 200 CGG repeats). Females are less severely affected than males due to X-inactivation.
Physical features. General clinical features include hyperkinetic or autistic behavior, macroorchidism in mature males (testicular volume greater than 30 mL in the adult) and abnormal adult craniofacial features, including macrocephaly; long, narrow face with a long, prominent jaw; high, broad forehead; prominent supraorbital ridges with puffy upper eyelids and lower epicanthal folds; and large alae nasi with mild fullness at the nasobuccal border. The ears have normal configuration but are long (greater than 60 mm in length in the adult). The philtrum is long, with a thin upper lip and a wide mouth. The palate may be high-arched and may contain a cleft. Dental malocclusion is common.
Esotropia or exotropia and errors of refraction are common, as are high myopia and hyperopia (Hatton et al 1998). Ptosis is seen in a few patients.
Fragile X patients have an underlying defect in connective tissue elastin. This results in excessive joint laxity (particularly hyperextensibility of the metacarpal-phalangeal joint of the hand), pes planus, hernias, pectus excavatum, and remarkably smooth skin. Individuals with the fragile X syndrome also appear at high risk for mitral valve prolapse and, occasionally, mild dilatation of the aortic root, but cardiac manifestations are rarely symptomatic.
Endocrine abnormalities are subtle. In childhood, patients are often bigger than their peers, but as adults they are shorter than might be expected. Severe obesity has been reported but is rare. Fertility is impaired both in affected males and in carrier females, who may have premature menopause and raised serum follicle-stimulating hormone with premature ovarian failure (Murray et al 2000).
Neurobehavioral impairment. Mental retardation is the most serious manifestation of the fragile X syndrome. Affected persons may have IQs ranging from 20 to 60 (Bardoni and Mandel 2002; Jin and Warren 2003). It affects males with the full mutation and full methylation most severely. Males with partial methylation of a full mutation and patients with a mosaic genotype of premutation and mutation express variable amounts of FMRP and have IQ scores in the 60 to 80 range. Females with the full mutation are also affected to various degrees, depending on the ratio of X inactivation with 50% to 70% of heterozygote women having an IQ of 84 or less.
Mental impairment was further investigated by Annangudi and colleagues (Annangudi et al 2010). Neuropeptide release was impaired in FMR1 knockout mice, specifically a reduced level Rab3A, an mRNA cargo of FMRP involved in the recruitment of vesicles. Docking and fusion abnormality of peptidergic dense-core-vesicles causes defective maturation and maintenance of synaptic connections, leading to mental retardation (Annangudi et al 2010).
Voxel-wise gray and white matter volumes were examined over a 2-year period in a 1- to 3-year-old boy (n=41). Region-specific alterations in brain development were seen, with enlarged gray matter volume in the caudate, thalamus, and fusiform gyri and reduced gray matter volume in the cerebellar vermis in fragile X syndrome--suggesting prenatal, genetically mediated alterations in neurodevelopment of patients with fragile X syndrome. White matter volume of striatal-prefrontal regions was greater in patients with fragile X syndrome than in controls (Hoeft et al 2010; 2011). The same group investigated the whole-brain morphometric pattern of boys with fragile X syndrome and idiopathic autism using genotyping, cognitive measures, neuropsychiatric assessments, MRI, preprocessing procedures, and cross-site validation of imaging parameters. They found that both groups exhibit distinct neuroanatomical profiles relative to one another. Those with idiopathic autism are more likely to exhibit patterns similar to controls than those with fragile X syndrome (Hoeft et al 2010; 2011). Improvement in detection of fragile X syndrome is made possible by early and accurate human brain phenotype in humans affected with this disease.
Fragile X syndrome is also the most common cause of autism spectrum disorder, and reports have found that even carriers in the premutation range can have this disorder. Behavioral features in fragile X syndrome include hand flapping or biting, poor eye contact, perseverative speech and behavior, tactile defensiveness and social anxiety. These features are common in 60% to 90% of boys and 25% to 85% of girls with this disorder (Hagerman and Hagerman 2002).
Hatton and colleagues (Hatton et al 2006) looked at the CARS score of patients with fragile X syndrome to determine the prevalence of autistic behaviors and found that only 21% of the 129 patients had a score at or above the cutoff for autism. Additionally, they also reported that low levels of FMRP were associated with higher mean levels of autistic behavior as measured by CARS. Hall and colleagues also found that compulsive behavior, commonly seen in individuals with fragile X syndrome, correlates with lowered levels of FMRP and cortisol (Hall et al 2008).
Visual perceptual difficulties, dyspraxia, impaired visual-spatial abilities, and visual-motor coordination may cause the affected patient to be clumsy. Performance IQ is less than verbal IQ in most patients. Decreased attention span, hyperactivity, impaired processing of sequential information, and poor short-term memory further compromise the patient’s ability to learn. Unusual responses to sensory stimuli and stereotypic behaviors are observed in affected males.
Temporal order impairment is also seen in patients with fragile X syndrome. The CGG knock-in mouse model allowed evaluation of the nature of neurocognitive deficits in carriers of the fragile X permutation. Female knock-in mice with CGG repeat expansions between 150 and 200 at 48 weeks of age showed poor temporal order test results as compared to the wild-type mice, whereas female CGG knock-in mice with repeat expansions between 80 and 100 had similar performance with wild-type mice. Therefore, female CGG knock-in mice showed deficits in temporal ordering when the upper end of permutation range is reached (Hunsaker et al 2010).
Mental retardation is common in fragile X syndrome; it is the most common form of inherited mental impairment in patients with extensive spine dysgenesis. There is an increased density and abnormal morphology of dendritic spine, the postsynaptic sites of the majority of excitatory synapses. Dendritic spines are found to be unstable and insensitive to modulation by sensory experience in a mouse model of fragile X syndrome. Loss of the FMR1 gene in these patients leads to overproduction of transient spines in the primary somatosensory cortex (Pan et al 2010). Development of neurons in fragile X patients was studied on a mouse model, wherein significant difference in terms of increased dendritic and cell-body branching of hippocampal neurons grown on fragile X astrocytes was found from the neurons grown with normal astrocytes after 7 days in vitro, but no difference was seen between the 2 groups after 21 days in culture. The study establishes the role astrocytes contribute to symptoms of delayed growth characteristics and abnormal morphological features in fragile X syndrome (Jacobs et al 2010).
The increase in density of dendritic spines is found on the cortical pyramidal neurons in affected individuals and FMR1 knockout mice. A rapid decrease in dendritic spine dynamics on the layer 2/3 neurons of wild-type mice during the first 2 postnatal weeks is then replaced by mushroom spines. Knockout mice on the other hand, show a developmental delay in the downregulation of spine turnover and in the transition from immature to mature spine subtypes. Blocking mGluR signal does not correct the instability of spines, but pharmacologic approach aimed in several other signaling pathways in the mutant mice at early postnatal ages can reverse the maturational defect in dendritic protrusions (Cruz-Martin et al 2010).
Dopamine release and uptake impairment was analyzed in FMR1 knockout mice, which model fragile X syndrome mental retardation syndrome, and then was compared to wild-type control mice. Increased dopamine release was observed, uncorrected for uptake, and normalized against the predrug release peaks in FMR1 knockout mice, but not in wild-type mice. Thus, decrease in extracellular dopamine levels in the striatum result in diminished expression of focused stereotypy in FMR1 knockout mice (Fulks et al 2010).
Seizures. Although seizures are relatively common in males with fragile X syndrome (approximately 15% to 20%), the precise prevalence is unknown. Partial-complex and generalized, tonic-clonic are the most frequently described seizure types in males with fragile X syndrome. Seizures, tics, and behavioral problem exacerbation in fragile X syndrome was associated with the autoimmune disease carrier status of mothers with FMR1 premutation (Chonchaiya et al 2010).
Berry Kravis and colleagues enrolled 1,394 individuals with an FMR1 full mutation. Families completed the national fragile X survey either online or over the telephone with a trained interviewer; the survey included an additional set of questions concerned with the child’s experiences with seizures. Respondents reported that 173 (12%) had seizures--154 (14%) males and 19 (6%) females; age of onset was in young and mid-childhood, between 4 and 10 years of age (53% of males and 32% of females). Seizures were considered mild to moderate in severity; partial seizures were most common. Many of the respondents reported that medication was effective in controlling seizures (Berry-Kravis et al 2010b).
A typical EEG pattern has been reported to occur in males with fragile X syndrome, including some without clinically apparent seizures (Musumeci et al 1988). This pattern is described as consisting of uni- or bitemporal spikes of medium to high voltage that occur during sleep and resemble benign rolandic spikes. One study showed interictal centrotemporal spikes in children with fragile X syndrome with seizures compared to 23% in children with fragile X syndrome without seizures (Berry-Kravis 2002). The seizures were classified as benign focal epilepsy of childhood; the seizures were easy to treat and remission was achieved. Epilepsy in individuals with fragile X syndrome is known to follow a benign course with seizures disappearing before the age of 20 years. However, in a proportion of individuals with a history of epilepsy, the seizures continued after the age of 20 years (Sabaratnam et al 2001). Among these, the most common abnormal EEG findings have been reported as rhythmic theta activity and a slowing of background activity.