It might be helpful for parents of children with FXS to talk with one another. One parent might have learned how to address some of the same concerns another parent has. Often, parents of children with special needs can give advice about good resources for these children.
CDC is working to learn more about the natural history of fragile X so that better approaches to intervention can be developed.
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What is Fragile X Syndrome? Minus Related Pages. Signs and Symptoms Signs that a child might have FXS include: Developmental delays not sitting, walking, or talking at the same time as other children the same age ; Learning disabilities trouble learning new skills ; and Social and behavior problems such as not making eye contact, anxiety, trouble paying attention, hand flapping, acting and speaking without thinking, and being very active.
Links with this icon indicate that you are leaving the CDC website. Among these, the most common abnormal EEG findings have been reported as rhythmic theta activity and a slowing of background activity. Life expectancy for patients with fragile X syndrome is normal.
These patients have been found to have decreased cancer risk due to the diminished expression of WNT7A gene, which widely relates to oncogenic processes, found on quantitative real-time PCR Adult females with the full mutation show a much wider range of effects, with approximately half testing in the mentally retarded range of intellectual function, usually mild.
Even when cognitive impairment is absent, females with the full mutation can show learning and psychiatric problems. A 5-year-old boy came for evaluation by his pediatrician for developmental delay. The patient's mother reported a history of speech delay, behavior problems, and hyperactivity.
The patient also displayed aversion to touch and had some hand-biting behaviors. The patient's mother reported that her sister's 8-year-old son had speech delays, problems with attention and learning, and was in a special education class These are inherited from the mother and arise from an unstable "premutation" of approximately 55 to repeats.
The risk of premutation expansion to full mutation increases with increase in number of repeats The cause of cognitive impairment is the loss of FMR1 protein expression. The full-blown expansion is associated with hypermethylation of the repeat, which in turn reduces expression of FMR1.
Rarely, the syndrome can occur with deletions or inactivation point mutations of FMR1 , which points to the loss of FRMP function as the cause of fragile X syndrome. Of note, the premutation alleles have been associated with premature ovarian failure in women 52 and with the fragile X associated tremor ataxia syndrome in males The CGG repeat expansion is found in the promoter region of the FMR1 gene and leads to the silencing and loss of gene products Males with fragile X are hemizygous and females heterozygous for the condition.
Amplification of the premutation to the full mutation occurs only in the ovum. A male who has the premutation on his only X chromosome passes the premutation to each of his daughters without significant change in the size of the repeat. A female with the premutation would pass on the affected gene to half her children, either unchanged or as a full mutation. A female with a full mutation would transmit the affected gene after further amplification to half her children.
This amplification in the ovum of both premutations and full mutations is related to the phenomenon of anticipation whereby the genetic defect manifests earlier in successive generations in a family and where longer expanded repeats typically cause earlier symptom onset and more severe disease in successive generations. It is postulated that repeat expansion diseases are caused by unusual secondary structures adopted by DNA repeats that make them unstable, which may in turn cause many errors at multiple levels of DNA metabolism ie, strand slippage during DNA replication The general principle of the type 2 trinucleotide expansion disorders is a dynamic repeat expansion that occurs outside of the coding region of a mutated gene vs.
The repeat expansions lead to reduced expression of the affected genes, resulting in loss of gene function.
Spinocerebellar ataxia-1, Huntington disease, myotonic dystrophy, and spinobulbar muscular atrophy Kennedy disease are 4 of at least 10 now recognized inherited neurologic diseases with type 2 repeat disease classification. Despite their unusual similar features related to anticipation and their typical inheritance pattern, they are clinically diverse The FMRI protein plays an important role in mediating appropriate synaptic protein synthesis in response to neuronal activity levels, although the biochemical mechanisms involved in the pathological phenotype are mostly unknown.
Fragile X-associated translational dysregulation causes wide-ranging neurologic deficits, including severe impairments of biological rhythms, learning processes, and memory consolidation. Dysfunction in cytoskeletal regulation and synaptic scaffolding disrupts neuronal architecture and functional synaptic connectivity The pattern of expression in the cortex of the adult mouse brain was consistent with concentration within specific neuronal populations involved in synaptogenesis.
It also has been postulated that the lack of FMR1 protein function leads to a moderate increase of the oxidative stress status in the brain that may contribute to the pathophysiology of fragile X syndrome. Higher levels of reactive oxygen species were found in the knockout fragile X mouse when compared with brains from wild-type mice Structural and functional neuroimaging studies suggest abnormal activity in the striatum of patients with fragile X syndrome, the most common form of inherited cognitive impairment in males.
The absence of FMRP is associated with apparently normal striatal glutamate-mediated transmission but abnormal gamma-aminobutyric acid GABA transmission. This effect is likely secondary to increased transmitter release from GABAergic nerve terminals. Earlier studies identified a role for aberrant synaptic plasticity mediated by the metabotropic glutamate receptors mGluRs Metabotropic glutamate receptors mGluRs , implicated in a diverse variety of neuronal functions, showed exaggerated signaling secondary to unchecked activation in the mice model of the disease Observed symptoms in fragile X syndrome, mental impairment, and autism are derived primarily from dysfunction in the hippocampus.
It has been found that surface expression of the AMPA receptor subunit, GluR1, is reduced also in the lateral amygdala of knockout mice. A lower presynaptic release is manifested by a decrease in the frequency of spontaneous miniature excitatory postsynaptic currents mEPSCs , increased paired pulse ratio, and slower use-dependent block of NMDA receptor currents. Synaptic defects in the amygdala of knockout mice can be reversed by pharmacologic intervention against mGluR5 Targeting the GABAergic system is a good approach to treat amygdala-based symptoms in patients with fragile X syndrome.
Neuronal hyperexcitability in neurons of amygdala of mouse models in fragile X syndrome can be treated by pharmacological augmentation of tonic inhibitory tone using the GABA agonist gabaxodal THIP Fragile X mouse models with deleted FMR1 gene also have NMDA receptor hypofunction in the dentate gyrus, causing NMDAR-dependent electrophysiological and behavioral impairments particularly impaired performance in context discrimination tasks In the human fetal brain, the highest levels of FMR1 mRNA were detected in fetal cholinergic neurons of the nucleus basalis and in pyramidal neurons of hippocampus Moreover, disruption of the cholinergic system secondary to fragile X mental retardation protein deficiency was found to contribute to the cognitive-behavioral impairments associated with fragile X syndrome.
Kesler and colleagues measured choline in the dorsolateral prefrontal cortex of 9 males with fragile X and 9 age-matched, typically developing controls using 1 H magnetic resonance spectroscopy. The deficits in visual motor skills mentioned above have been attributed to impairment in the magnocellular portion of the thalamus as well as to higher cortical centers in the parietal lobe 54 and, thus, contribute to the disability and deficits in cognition in fragile X syndrome.
An MRI study showed decreased gray matter, increased white matter, increased ventricular CSF, and increased caudate volume that decreased with age.
The loss of gray matter did not correlate with IQ, suggesting a defect in the structural organization in patients with the fragile X mutation. A sex difference for relative amounts of gray and white matter was noted Premutation carriers.
Of note, carriers of premutation-sized fragile X repeats can develop a late-life tremor and ataxia syndrome, otherwise known as FXTAS 38 ; 36 , possibly affecting 1 in men older than 50 years in the general population. FXTAS was also seen in women who can also develop tremor, gait, ataxia, neuropsychiatric symptoms, and multisystem neurodegenerative disorder with central and peripheral nervous system involvement. Typically, these patients have 70 or more CGG repeats The progressive tremor of FXTAS resembles essential tremor with the compounding feature of ataxia, and affected persons may also have cognitive disturbances, parkinsonism, and findings of autonomic insufficiency, such as hypertension and impotence Hagerman and Hagerman Cognitive disturbances often first include memory and executive functional impairment, which may progress to dementia that is typically subcortical or frontal.
Apathy, disinhibition, and depression are additional behavioral and mental sequelae Physicians evaluating patients with dementia should consider FXTAS as an etiology, especially if there is a comorbid movement disorder. In general, the progression and severity seen in FXTAS is variable, but at least 1 case report demonstrates rapid progression of dementia 1 year as a possible clinical course Imaging of the brain with MRI shows classic T2-weighted signal abnormalities in the middle cerebral peduncles MCP sign and cerebellar white matter, the latter has been included as a major radiologic criterion in diagnosis of "definite" FXTAS The loss of whole-brain, cerebral, and cerebellar volume are also correlated with the number of CGG repeats Adams and colleagues found significant radiologic differences, demonstrating less cerebellar volume loss in females and a lower incidence of the MCP sign in females Furthermore, the association of brain volume with the degree of clinical disease is much more significant in affected males, likely due to the decreased radiographic findings in females.
Screening for the premutation may be considered in those males older than 50 years with ataxia and tremor or those males with parkinsonism, action tremor, or dementia with a family history of cognitive impairment, premature ovarian failure, or changes on MRI described above Premutation carriers have also been shown to have social, emotional, and cognitive problems, including autism spectrum disorder as well as schizoid and obsessive-compulsive symptoms.
Hessl and colleagues found this phenotype to be attributable to the impact of CGG repeats on limbic brain areas, including the amygdala and the hippocampus due to their role in emotion and social function These psychological disturbances associated with the premutation may herald the more severe neurologic sequelae of FXTAS in later life. Among asymptomatic premutation males, a relationship between increased CGG repeat size and impairment to central executive working memory has also been observed There has been 1 case report of a female carrier of the FMR1 premutation with a positive family history of fragile X syndrome who developed severe ataxic gait with administration of chemotherapy and returned to baseline on discontinuation of therapy.
This finding demonstrates the variability in those with the FXTAS gene but also indicates that environmental factors may play a role in clinical symptomology. Fragile X syndrome is the most common known inherited cause of cognitive impairment in males. Based on cytogenetic testing, it is thought to affect 1 in males and 1 in females. The condition is underdiagnosed, especially in females, because craniofacial abnormalities as well as neurobehavioral deficits are often subtle, and the variability in phenotype is tremendous.
The prevalence for the premutation is estimated at 1 in males and 1e in females. The findings of 1 study 20 suggest that fragile X carrier screening is an acceptable option for some women seeking prenatal genetic counseling, based on reported carrier frequency, cost effectiveness, and sensitivity of the available screening test.
To capture the behavioral phenotype of FMR1 mutations, increased FMR1 testing in individuals with intellectual disability is advised, and newborn screening methods for those with fragile X syndrome and other FMR1 mutations should be developed.
This is especially helpful due to the wide range of phenotypical expression of fragile X, specifically females who may not be diagnosed at all The differential for fragile X syndrome includes other possible causes of cognitive impairment or developmental delay, including genetic and nongenetic causes A fragile site may be identified by cytogenetic techniques using folate-deficient media for culture in other X-linked genetic disorders mentioned above, including Sotos syndrome, Prader-Willi syndrome, Angelman syndrome, and Rett syndrome, whose symptoms manifest in early childhood.
Other causes of developmental delay and behavioral disturbances should be considered, including fetal alcohol syndrome, cocaine exposure, lead poisoning, and hydrocephalus. The differential further includes autism, Asperger syndrome, and attention deficit disorder. Sutherland showed that cells cultured in folate-depleted media reliably demonstrated the characteristic fragile site on the distal end of the long arm of the X chromosome It is also less expensive than the formerly used chromosome analysis, which is no longer used as first line test.
It was found that RP PCR reduces the burden of Southern blot analysis to only those samples that require methylation information. Methylation-sensitive restriction enzymes can be used to assess FMR1 alleles, thus minimizing the need for Southern blot and contributing to the advancement toward a PCR-only workflow for FMR1 analysis The diagnosis of fragile X should be in the differential for all children with speech or developmental delay.
In addition, all patients with the full mutation should be evaluated for mitral valve prolapse. EEG should be obtained in individuals with seizures. Brainstem auditory evoked responses should be performed in patients with fragile X syndrome suspected of hearing loss.
Although fragile X syndrome patients have malformed ears, they do not have an increased incidence of hearing loss This important first step will allow the family to find information in lay language and support that will empower them to act as effective advocates for the patient.
The approach to management of fragile X syndrome patients is multidisciplinary, involving medical and nonmedical personnel. The team, ideally, should be led by a pediatrician, and the anticipatory guidelines outlined by the American Academy of Pediatrics should be followed Other key members of the team are educators, speech and language therapists, social workers, psychologists, counselors, and dentists.
Consulting physicians should include neurologists, psychiatrists, geneticists, ophthalmologists, cardiologists, and orthopedic surgeons. Active involvement of the parents in decisions governing the lives of affected children helps ensure communication and proper implementation of treatment plans. Referral to a genetics center with experience in the education and counseling of fragile X families is essential.
When possible, a clinical geneticist should be involved antenatally for extended discussion on the prognosis of the patient as well as the implications for recurrence in future pregnancies and the evaluation of risk to other family members.
There are no specific guidelines available for the transition of children or adults with fragile X syndrome This can be difficult, especially when parents report worsening of aggression and self-injurious behavior during episodes of high anxiety and arousal Symptomatic treatment can be provided for many problems suffered by the patient. Seizures are generally well managed with standard anticonvulsant medications.
Behavioral problems can be difficult to manage and require a combination of medical and nonmedical therapies. Behavior modification may be combined with stimulant drugs for attention deficit disorder.
Low doses of clonidine help control hyperactivity and aggressive behaviors. Valproic acid can be considered an alternative to alleviate ADHD symptoms in patients with fragile X syndrome, although further research is required to clarify the issue Depression may be treated with serotonin reuptake inhibitors. Intention tremor, parkinsonism, and neuropathic pain can also be managed pharmacologically with beta-blockers, levodopa, carbidopa, and gabapentin, respectively.
In one case report, levetiracetam was found to be effective and well tolerated in treating intention tremor associated with fragile X syndrome Folate 10 mg per day has been utilized in the past with variable results for treatment of behavioral problems. Difficulty falling asleep and maintaining sleep are the most common problems. Melatonin at 3 mg was effective in achieving sleep Antibiotic prophylaxis may be required for patients with mitral valve prolapse during dental procedures.
Malocclusion may require dental intervention. Strabismus and refractive errors are treated with prescription glasses, and in some cases surgery may be necessary. Flat feet may require orthotic intervention. The underlying toxic RNA mechanism may be slowed down by neuroprotective agents This family had a total of eleven males across two generations who exhibited symptoms of mental retardation.
After interviewing affected individuals and detailing the family's history, Martin and Bell suggested that the condition was sex linked, heritable, and caused specific sections of the brain to develop improperly. Because the patients had difficulty with speech, the two researchers hypothesized that the pre-frontal cortex was the affected area.
Later in her career Bell remained active in research, publishing research on Congenital Rubella Syndrome in Bell collected information on the conditions of infants whose mothers had contracted rubella during various periods during their pregnancy. She outlined a possible connection between a mother contracting rubella early in the pregnancy , before twelve weeks, and the fetus developing deafness, cataracts, or congenital heart disease.
Bell remained involved with the Galton Laboratory in some capacity until , when she retired at the age of Bell never married, and lived alone until she entered a supervised care facility at the age of When she was , Julia Bell died in St. Julia Bell By: Jesse King. About 1 in men carry Fragile X; their daughters will also be carriers.
Fragile X syndrome is the 1 inherited cause of intellectual disabilities and the most common known cause of autism worldwide. Most people with Fragile X are not yet diagnosed. Her children will either be carriers or they will have Fragile X syndrome.
Carrier men will pass the premutation to all their daughters but none of their sons. These daughters are carriers but they do not have Fragile X syndrome. The Fragile X premutation can be passed silently down through generations in a family before a child is born with the syndrome. Each cell in the body contains forty-six twenty-three pairs of chromosomes. These chromosomes consist of genetic material DNA necessary for the production of proteins which lead to growth, development and physical and intellectual characteristics.
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