States have created parent centers. These centers help families learn how and where to have their children evaluated and how to find services. Having support and community resources can help increase confidence in managing FXS, enhance quality of life, and assist in meeting the needs of all family members. 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. The ORDR website provides information about National Institutes of Health-sponsored biomedical research, scientific conferences, and rare and genetic diseases.
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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.
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When the stretch of DNA expands beyond a certain length, the gene is switched off and does not produce the protein that it normally makes. This gene change is called a full mutation. A male who inherits a full mutation exhibits Fragile X syndrome because his only X chromosome contains the mutated gene.
A female may not be as severely affected because each cell of her body needs to use only one of its two X chromosomes and randomly inactivates the other. Carriers have a small mutation in FMR1 a premutation. Women who carry Fragile X may be at risk for Primary Ovarian Insufficiency which causes early menopause.
More About Genes and Inheritance Each cell in the body contains forty-six twenty-three pairs of chromosomes. The Centers for Disease Control CDC published a study in which pegs the prevalence of carriers at: 1 in females, or about 1 million women in the United States. Next Steps: Testing, Treatment. Meet our Kids — Fragile X Portraits. Copy link. Copy Copied. 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 Identification of these patients is most important, and referral to appropriate specialists is very helpful. Target for treatment.
Research has indicated that receptors found on the surface of neurons called group 1 metabotropic glutamate receptors mGluRs may be a target for future therapy for fragile X. These receptors, which are selectively enhanced in the hippocampus of test mice lacking FMRP Fmr1-KO or knockout mice , weaken synaptic connections in these animal models called long-term depression. This long-term depression neural plasticity is important during brain development early and later in life.
The mGluR long-term depression state is exaggerated in the absence of the FMRP protein, which negatively regulate translation. Overactive group 1 MGluRs have been found to affect protein synthesis in early postnatal development, the cortex, and in long-term depression, but also in the hippocampus of mature animals, important in memory storage, learning, and synaptic potentiation of seizure activity and in the cerebellum important for learning motor reflexes.
These observations have coalesced into the "mGluR theory," and the suggestion has been made that many symptoms in fragile X might respond to drugs that inhibit group 1 mGluRs Research has also shown that flies missing the gene that encodes FMRP demonstrate altered courtship behavior, impaired learning and memory, and altered brain anatomy.
Studies of metabotropic glutamate receptor 5 pathway antagonists in animal models of fragile X syndrome have demonstrated benefits in reducing seizures, improving behavior, and enhancing cognition 59 ; Trials of metabotropic glutamate receptor 5 antagonists are beginning for individuals with fragile X syndrome 35 ; lithium is an example of this class of drugs.
A small study by Berry-Kravis and colleagues showed that lithium had beneficial effects in treating the behavioral disorders associated with fragile X syndrome Lower level of serine phosphorylation of glycogen synthase kinase-3 GSK3 was found in testis and liver of FMR1 knockout mice; thus, lithium administration was found to reduce macroorchidism and reactive astrocytes in the mouse model of fragile X syndrome The fragile X mental retardation protein FMRP has been associated with negative regulation of matrix metalloproteinase-9 with corresponding elevation.
Minocycline is a tetracycline analogue that has been used in clinical trials for stroke, multiple sclerosis, and several neurodegenerative conditions.
Studies in the Fmr1-KO, or knockout mice, show less anxiety and more strategic exploratory behavior as compared to untreated Fmr1 knockout mice. These effects of minocycline appear to relate to its inhibitory action on MMP-9 expression and activity, which is higher in the hippocampus of Fmr1 knockout mice.
Its application in human clinical trials has been under investigation Its side effect was studied using the adverse events checklist, complete blood count CBC , hepatic and renal function tests, and antinuclear antibody screen ANA at baseline and 8 weeks.
Minocycline showed promise in treatment of behavioral abnormalities in patients with fragile X syndrome Another study revealed that elevated MMP-9 is associated with immature dendritic spine morphology. Studies conducted in FMR1 knockout mice found that minocycline led to improvements in measures of anxiety, cognition, and maturation of dendritic spines However, a survey conducted in 50 patients with fragile X syndrome who received minocycline for at least 2 weeks have reported gastrointestinal difficulty, including loss of appetite as the most common side effect of the drug.
Additional minocycline randomized clinical trials focusing on the areas of language, attention, social communication, and anxiety are suggested by the group to furthermore establish efficacy of the drug Subsequent studies in the Drosophila model of fragile X confirmed the therapeutic potential of minocycline Some positive effects were noted in a placebo-controlled trial Dansie and colleagues showed that minocycline treatment shows effects long after drug treatment has ended This randomized control trial was complicated by an unusually wide age range in its subjects as young as 3.
However, minocycline did result in a modest but statistically significant improvement in the Clinical Global Impression Improvement Scale, and fragile X syndrome subjects showed normalization of excessive MMP-9 activation 23 and auditory evoked potentials 76 , suggesting potentially useful biomarkers for future clinical trials. Overall, minocycline has had a modest success in the treatment of fragile X and has gained some acceptance in off-label use for the treatment of fragile X patients Subjects with fragile X syndrome participating in a pilot open-label trial of donepezil, an acetylcholinesterase inhibitor, demonstrated significantly improved cognitive-behavioral function An activated, dimeric form of PDE4D provided potent memory enhancing effects in a mouse model of fragile X syndrome in novel object recognition with improved tolerability with reduced vascular toxicity over earlier PDE4 inhibitors.
The compound is being evaluated in human clinical trials at this time Pharmacologic agents targeting various neurotransmitters may also be helpful. There is some evidence that the incomplete silencing of toxic full mutation RNA may be associated with autistic features, but not intellectual functioning in fragile X males.
However, decreased levels of mRNA may be more predictive of intellectual functioning than autism features Targeted oligonucleotide therapy for the treatment of tandem repeat disorders is being explored and may have implications for fragile X syndrome. However, oligonucleotide therapies in fragile X syndrome would not be as straightforward as in some other conditions due to the variant phenotype with repeat expansion Treatment with noncoding RNA is in the development stages.
It has potential for changes in DNA methylation. Heterochromatinization is gene therapy, which has been successful in cell lines and animal models. Concerns about being able to cross the blood brain barrier are being addressed Cannabidiol is also being explored as it appears to have a positive impact on social avoidance and anxiety, as well as improvements in sleep, feeding, motor coordination, language skills, anxiety, and sensory processing More formal clinical trials are being done to explore these findings further.
Prenatal testing for the FMR1 mutation performed on either amniotic or chorionic villus sample is widely available At present, it is offered to patients with a positive family history of fragile X syndrome. Maria of Thomas Jefferson University has no relevant financial relationships to disclose. Every article is reviewed by our esteemed Editorial Board for accuracy and currency. General Child Neurology. Fragile X syndrome. Developmental disabilities. FMR1-Related Disorders.
Fragile X Research Foundation. Peripheral Neuropathies. Neuroacanthocytosis is a neurologic syndrome characterized by a broad spectrum of movement disorders that often share acanthocytes on the blood smear. A variety of other neurologic symptoms may accompany neuroacanthocytosis, including seizures, motor neuron disease, and dementia. Chorea-acanthocytosis is an autosomal recessive disorder due to mutations in the VPS13A gene chromosome 9q21 , and is among the disorders known to cause neuroacanthocytosis.
General Neurology. Neurologic conditions may be associated with occupational or environmental exposures to heavy metals, such as lead and manganese. Conditions resulting from metal exposure may mimic routine neurologic disease, such as encephalopathy, movement disorders, neuropathy, or seizures.
Neurotoxic illness is often a diagnosis of exclusion after considering other more common presentations for a condition. Leukodystrophies affect the brain, spinal cord, and peripheral nerves, and can cause problems with movement, vision, hearing, balance, ability to eat, memory, behavior, and thought. The various types of leukodystrophies are caused by gene abnormalities leading to destruction of the myelin sheath.
Sleep Disorders. Vasculitis rarely affects the CNS, as opposed to other organ systems and the peripheral nervous system, and the primary presentation of vasculitis as dementia is extremely rare. Dementia usually occurs late in the course of the disease and is preceded by a history of stroke attributable either to the vasculitis directly, to abnormal coagulation, or to cardiac embolism.
Primary angiitis of the CNS, an isolated granulomatous angiitis of the nervous system, is the archetypical vasculitic cause of dementia and the most difficult to diagnose because of its lack of associated extracranial abnormalities. Developmental Malformations. Vein of Galen malformations are congenital arteriovenous malformations involving the deep venous system of the brain that were first described in Sarcoidosis is a multisystem granulomatous disease of unknown etiology.
Optic and facial nerves are most commonly involved. Sign Up for a Free Account. Go to Pubmed. Updated Overview Fragile X syndrome is a classic neurologic disease with unique manifestations on the clinical and molecular level. Historical note and terminology Fragile X syndrome is the most common inherited cause of cognitive impairment in males.
Prognosis and complications Life expectancy for patients with fragile X syndrome is normal. Clinical vignette A 5-year-old boy came for evaluation by his pediatrician for developmental delay. The American College of Medical Genetics recommends consideration for testing in the following scenarios Shaffer and American College of Medical Genetics Professional Practice and Guidelines Committee : 1 Individuals of either sex with cognitive impairment, developmental delay or autism, especially with any physical characteristic of fragile X syndrome, a family history of the disorder, or male or female relatives with cognitive impairment of unknown etiology.
Pregnancy Prenatal testing for the FMR1 mutation performed on either amniotic or chorionic villus sample is widely available Anesthesia There are no known effects. Nucleus basalis magnocellularis and hippocampus are the major sites of FMR-1 expression in the human fetal brain. Nat Genet ; PMID Neurology ; Health Supervision for children with fragile X syndrome.
Pediatrics ;98 2 Pt 1 Neuropeptide release is impaired in a mouse model of fragile x mental retardation syndrome. ACS Chem Neurosci ; Incomplete silencing of full mutation alleles in males with fragile X syndrome is associated with autistic features.
Mol Autism ; Advances in understanding of fragile X pathogenesis and FMRP function, and in identification of X linked mental retardation genes. Curr Op Genet Dev ; Review of therapeutic implications of mGluR theory of fragile X mental retardation. Genes Brain Behav Epilepsy in fragile X syndrome. Dev Med Child Neurol ;44 11 New York: Springer, a Seizures in fragile X syndrome: characteristics and comorbid diagnoses.
American J Intellect Dev Disabil b; 6 Open-label treatment trial of lithium to target the underlying defect in fragile X syndrome. J Dev Behav Pediatr ; Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model. J Med Genet ;46 2 The behavioral phenotype of FMR1 mutations. Am J Med Genet ;C Biol Psychiatry ;63 10 An information-rich CGG repeat primed PCR that detects the full range of fragile X expanded alleles and minimizes the need for southern blot analysis.
J Mol Diagn ;12 5 Pharmacological reversal of synaptic plasticity deficits in the mouse model of fragile x syndrome by group II mGluR antagonist or lithium treatment. Brain Res ; Autoimmune disease in mothers with the FMR1 premutation is associated with seizures in their children with fragile X syndrome.
Hum Genet ; Lifespan changes in working memory in fragile X permutation males. Brain Cogn ;69 3 Fragile X syndrome carrier screening in the prenatal genetic counseling setting. Gen Med 4 Delayed stabilization of dendritic spines in fragile x mice.
J Neurosci ;30 23 Long-lasting effects of minocycline on behavior in young but not adult Fragile X mice. Neuroscience ; High MMP-9 activity levels in fragile X syndrome are lowered by minocycline. Role for metabotropic glutamate receptor 5 mGluR5 in the pathogenesis of fragile X Syndrome. J Physiol ; 6 Hippocampus ;22 2 Enhanced markers of oxidative stress, altered antioxidants and NADPH-oxidase activation in brains from fragile X mental retardation 1-deficient mice, a pathological model for fragile X syndrome.
Eur J Neurosci ;26 11 Brain anatomy, gender and IQ in children and adolescents with Fragile X syndrome.
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