ABSTRACT Fragile X syndrome, an X-linked dominant disorder with reduced penetrance, is associated with intellectual and emotional disabilities ranging from learning problems to mental

retardation, and mood instability to autism. It is most often caused by the transcriptional silencing of the _FMR1_ gene, due to an expansion of a CGG repeat found in the 5′-untranslated

region. The _FMR1_ gene product, FMRP, is a selective RNA-binding protein that negatively regulates local protein synthesis in neuronal dendrites. In its absence, the transcripts normally

regulated by FMRP are over translated. The resulting over abundance of certain proteins results in reduced synaptic strength due to AMPA receptor trafficking abnormalities that lead, at

07 April 2021 IN BRIEF * Fragile X syndrome is a common inherited form of mental retardation that can be associated with features of autism. * The physical features of fragile X syndrome are

subtle and may not be obvious. * The vast majority of cases of fragile X syndrome are caused by the expansion to over 200 copies of a CGG repeat in the 5′-untranslated region of _FMR1_ that

shuts off transcription of the gene. * Genetic testing for this repeat expansion is diagnostic for this syndrome, and testing is appropriate in all children with developmental delay, mental

retardation or autism. * Fragile X syndrome is inherited from individuals, usually females, who typically carry an unstable premutation allele of the CGG-repeat tract in _FMR1_. *

Premutation carriers are themselves at risk of premature ovarian failure and the fragile X-associated tremor/ataxia syndrome. INTRODUCTION Fragile X syndrome (FXS) is the most common

inherited cause of mental retardation with approximately 1 in 4000 males affected.1 In the vast majority of cases, this X-linked disorder is caused by expansions of a CGG repeat in the

5′-untranslated (UTR) region of the _FMR1_ gene that arises due to the meiotic instability of certain alleles of this repeat tract. FXS causing alleles, or full mutations, contain 200 or

more copies of the repeat that are hypermethylated and transcriptionally silenced. The unstable alleles that give rise to full mutations are called premutations and are associated with

phenotypes distinct from FXS. The mutational mechanism, combined with the location of this gene on the X chromosome, leads to remarkable inheritance patterns in which the relevant alleles

are passed from intellectually normal men through their unaffected daughters and then to affected sons.2 FXS may be suspected in both sexes, and includes a variable clinical phenotype.

Individuals with FXS may present with anything from learning problems and a normal IQ to severe mental retardation and autistic behaviors. Physical features have been described but are often

nonspecific. Thus, diagnosis is made based upon the detection of alterations to _FMR1_ (Figure 1). CLINICAL OVERVIEW The physical characteristics of FXS are fairly subtle, and the first

clinical indication is often delayed developmental milestones, such as mild motor delays and/or language delays.3 Autistic-like behaviors such as hand flapping, poor eye contact, and hand

biting may be noted. The average IQ in adult men with the completely methylated full mutation is approximately 40.4 Less-affected males typically have incomplete methylation, resulting in an

incomplete activation of _FMR1_, and they may even have an IQ in the borderline or low normal range. In general, for FXS, cognitive deficits include problems with working and short-term

memory, executive function, and mathematic and visuospatial abilities.5 Because the disorder is X-linked, females are generally much more mildly affected than males, particularly in terms of

cognitive functioning, but they tend to have higher risk for emotional problems compared to the general population.6 Females with the full mutation usually have normal or borderline IQ, and

most will have associated learning disabilities and/or emotional problems.7 Individuals with FXS usually do not have significant medical issues. Recurrent otitis media and recurrent

sinusitis are common during childhood.8 Joint laxity with hyperextensibility finger joints and pes planus (flat feet) may be present and usually improve with age.9 Gastroesophageal reflux

disease occurs in a third of young infants with FXS, and may present with irritability or recurrent emesis.9 Seizures and EEG findings consistent with epilepsy are another common feature of

FXS during childhood, with an incidence between 13 and 18% in boys and 5% in girls.10 The majority of individuals with the premutation have normal intelligence, but males are prone to have

attentional problems, executive dysfunction, social deficits, and obsessive-compulsive behavior.11 Approximately 20% of women who carry an _FMR1_ premutation have premature ovarian failure

(POF), which is the premature cessation of menses before the age of 40.12 A subgroup of men with a premutation develop neurologic deficits beyond age 50.13 Although many of these individuals

would have been given a diagnosis of parkinsonism in the past, a distinct tremor/ataxia syndrome due to premutations in _FMR1_ has been recently recognized. The fragile X-associated

tremor/ataxia syndrome (FXTAS) causes intentional tremors, balance problems, frequent falls, neuropathy, autonomic dysfunction, cognitive decline, and dementia, which may progressively

worsen over time.14 BEHAVIORAL ASPECTS The behavioral phenotype may be helpful in suggesting the diagnosis of FXS. Autistic-like features are common in individuals with FXS and include hand

flapping, hand biting, gaze avoidance, tactile defensiveness, and hyperarousal to sensory stimuli.15, 16 These features – along with impaired social skills, such as socio-emotional

reciprocity – are expressed with varying degrees in children with FXS and may be indicative of a concurrent diagnosis of autism spectrum disorder or autistic-like behavior.17 Anxiety and

mood disorders, hyperactivity, impulsivity, and aggressive behavior can also be present.18 The emotional and behavioral characteristics in females with FXS are usually variable. Females with

the full mutation are prone to social anxiety, shyness, social avoidance, withdrawal, language deficits, mood lability, and depression.6 Furthermore, females with the premutation have also

been described to have social anxiety.19 PHYSICAL FEATURES Physical features include macroorchidism that is apparent just prior to puberty20 and those related to a connective tissue

dysplasia, which include a long, narrow face, prominent ears, joint hypermobility, and flat feet.21 The facial characteristics (Figure 2) can be subtle and may become more apparent with

increasing age. NEUROANATOMY At autopsy, no gross abnormalities are observed in the brains of individuals with FXS.22 In males with FXTAS, MRI findings include global brain atrophy and white

matter abnormalities, including involvement of the middle cerebellar peduncles.23 A key neurological feature of individuals with FXS is that, in certain areas of the brain, their neurons

have immature and dense dendritic spines.24 The spines are the site at which the majority of excitatory synapses occur, and, although it is not known whether they are a cause or an effect,

similar abnormalities have been associated with other forms of mental retardation.25 It is believed that these differences represent a defect in dendritic spine development and maturation.24

MOLECULAR AND GENETIC BASIS OF THE DISEASE In 1991, the gene responsible for FXS, _FMR1_, was identified.26 Fragile X was the first known example of a trinucleotide repeat disorder (Figure

1). There are four allelic classes for the CGG-repeat tract in the 5′-UTR of _FMR1_. The repeat sizes for each group are not well defined, and this complicates genetic counseling. In the

general population, the repeat tract contains up to 40 repeats, with 30 being the most common (normal or common alleles).27 Next are the intermediate alleles, which range from 41to 54

repeats and which usually are not associated with instability of the repeat tract. Full mutations, which cause FXS, have over 200 copies of the repeat.27, 28 Hypermethylation of this

expanded repeat tract and the upstream CpG island silences _FMR1_ expression.29 Full mutations arise from the allele class known as premutations, which range in size from approximately

55–200 repeats and are meiotically unstable.27, 28 Premutations are unmethylated, transcriptionally active, and produce FMRP, although possibly in lower quantities than normal.30 These

alleles can expand in small amounts to yield a slightly larger premutation allele, or they can expand massively into the full mutation range. Expansion to the full mutation occurs only in

females because the full mutation cannot be maintained during spermatogenesis.31 The expanded repeat may be unstable and exhibits somatic heterogeneity in affected individuals, called

mosaics. Mosaicism may be both in terms of repeat length as well as methylation status (methylation mosaics). Affected males with methylation mosaicism have, on average, higher IQ scores

than those with fully methylated alleles, presumably because they express some FMRP.32 Although _FMR1_ premutation carriers are not affected by FXS, they are at risk for the additional

phenotypes of POF and FXTAS, as mentioned previously. In contrast to the lack of _FMR1_ transcription associated with FXS, the premutation-associated diseases are caused by a toxic RNA

effect caused by an excess of _FMR1_ transcription and/or repeat-containing mRNA.33 With FXTAS, this toxic effect is associated with the presence of intranuclear inclusions in the neurons

and astrocytes of affected brains.33 FRAGILE X MENTAL RETARDATION PROTEIN FMRP binds to specific mRNAs and has an important role in the regulation of protein synthesis at a local level in

the dendrites of neurons. The finding of abnormally long and immature dendritic spines in the brains of people with FXS and the importance of these spines in synaptic transmission, synaptic

plasticity, learning, and memory suggest that understanding the function of FMRP at the synapse could be the key to understanding the development of FXS syndrome. A proposed role for FMRP at

the synapse is that it is a negative regulator of protein synthesis stimulated by group 1 metabotropic glutamate receptor (mGluR) activation.34 FXS, then, is at least partially a result of

exaggerated responses to mGluR stimulation. In particular, one of the primary defects associated with the absence of FMRP appears to be excessive AMPA receptor internalization in response to

mGluR signaling.35 These alterations to AMPA receptor trafficking effect persistent changes in synaptic activity. This disease model is supported by the fact that treatment with the mGluR

antagonist 2-methyl-6-phenylethynyl-pyridine rescues the defect in AMPA receptor trafficking in cultured FMRP-deficient neurons,35 as well as some of the defects associated with the lack of

FMRP in _Drosophila_ and mouse models lacking FMRP function.36, 37 In addition, _Fmr1_-deficient mice that express 50% of the normal level of mGluR5 are rescued for several phenotypes,

including changes to the density of dendritic spines, susceptibility to audiogenic seizures, and altered plasticity in the visual cortex.38 DIAGNOSTIC APPROACHES A checklist of phenotypic

criteria has been established in order to identify individuals with undiagnosed developmental delay who would be appropriate candidates for FXS molecular testing3 (Table 1). These

checklists, of which several had been devised prior to that of Maes, may increase the diagnostic yield slightly, but because children may not have apparent physical features, it is accepted

practice to order fragile X testing in all children with developmental delay, mental retardation, or autism,39 although this may have a diagnostic yield of only approximately 1–2%.40 The

presence in the proband's family of movement disorders, learning disabilities, mental retardation, or primary ovarian insufficiency should increase suspicion of the presence of _FMR1_

mutations in the family.41 A suggested targeted family history questionnaire can be found in Table 2. The testing procedure encompasses two complementary analyses. PCR with primers flanking

the repeat is used to determine the number of CGG repeats in the _FMR1_ 5′-UTR, and a Southern blot of genomic DNA is used to determine the methylation status and to gauge the size of full

mutations, which are often resistant to PCR amplification.18 The combination of Southern blot and PCR for the detection of fragile X-associated mutations has a sensitivity of 99%. The

remaining 1% of mutations include missense mutations and full or partial deletions of _FMR1_.39 There is a deficit of reported missense mutations of _FMR1_ due to the over reliance on

CGG-repeat testing. Thus, in any individual presenting with a clinical suspicion of FXS but with normal CGG-repeat lengths, sequencing of _FMR1_, which also uncovers deletions in males,

should be considered. Fragile X testing of an individual with isolated cognitive impairment should be done in conjunction with cytogenetic evaluation because constitutional chromosomal

abnormalities are as common, if not more common, than FXS in this population.39 The same testing approach can also be used to identify premutation carriers. Prenatal diagnosis for full

mutations can be performed on either chorionic villus or amniocentesis samples and has proven to be highly reliable.43 MANAGEMENT GENETIC COUNSELING If a positive FXS test is discovered, the

proband and family should be referred for genetic counseling and cascade testing of family members at risk of carrying a full mutation or premutation.41 Premutation carriers should be

counseled regarding their risks of passing a full mutation onto their children, and they should also be counseled of their own risks of POF and/or FXTAS. When planning cascade testing in an

affected family, particular attention should be considered for family members with mental retardation, learning disabilities, autism, or social and behavioral disorders; female relatives

with infertility or premature menopause; and those with tremor, ataxia, or other neurological and psychiatric problems. Genetic counseling becomes difficult when _FMR1_ alleles in the ∼45–54

repeat range are identified. This is a ‘gray zone’ because unstable alleles of this size have been reported in families but the expansion is unlikely. Premutations are most often clinically

reported when the repeat tract is 55 repeats or greater, although the smallest repeat known to expand to a full mutation in a single generation was 59 repeats. The American College of

Medical Genetics provides guidelines for fragile X testing at http://www.acmg.net/Pages/ACMG_Activities/stds-2002/fx.htm. TREATMENT AND CARE Current approaches to therapy for FXS are all

symptom based, and few controlled trials have been performed to determine their effectiveness.44 Psychopharmacologic intervention should be combined with other supportive strategies,

including speech therapy, sensory integration occupational therapy, individualized educational plans, and tailored behavioral interventions to maximize functioning. In boys with FXS, the

most frequently used medications are stimulants.44 These medications are targeted to symptoms of hyperactivity, impulsivity, and distractability and can be quite helpful in these areas.44

Despite being the most common medication in FXS, the efficacy of these drugs and their side effects vary for each individual. The response rate to stimulants may be relatively lowered in

adult men with FXS because of their increased anxiety and decreased activity level.44 Some researchers believe that many of the behavioral problems observed in individuals with FXS are

secondary to problems with hyperarousal to sensory stimuli.18 Although it can be difficult to implement, structuring the environment of the affected individual such that they are comfortable

with their surroundings is one approach to alleviating this issue.18 Another approach is the use of _α_2-adrenergic agonists, which are thought to dampen the response to sensory input to

the brain and show good efficacy in treating some of these behaviors in boys with FXS.44 Selective serotonin reuptake inhibitors (SSRIs) are quite commonly used to treat mood disorder,

anxiety, and obsessive-compulsive behaviors associated with FXS. They are effective, particularly in alleviating social anxiety, tantrums, and aggression.44 Individuals treated with SSRIs

should be monitored for restlessness, mood changes, hyperactivity, and disinhibited behavior including aggression.44 Atypical antipsychotics have been used to treat self-injury, aggressive

behaviors, and autism. Parental reports of improvement in mood stabilization, attention, and academic performance have been noted with the atypical antipsychotic aripiprazole, which should

be used at low doses to avoid the agitation that can be induced by higher doses.45 Adverse events associated with antipsychotics include weight gain (although not with aripiprazole),

sedation, nausea, constipation, diabetes, and tardive dyskinesia. In individuals with rapid weight gain, monitoring for diabetes and metabolic syndrome must be considered. As mentioned

previously, the phenotype in FXS is caused by excessive mGluR5 signaling, thus drugs targeting mGluR5 may be an effective treatment for FXS.34 Several mGluR5 anatagonists are presently in

pharmaceutical development for an array of targeted clinical symptoms, such as anxiety disorder, Parkinson's Disease, and substance abuse.46 In addition, a recent placebo-controlled

clinical trial of the AMPA receptor positive modulator (Ampakine) CX 516 indicates no significant improvements in memory, language, attention/executive function, behavior, and cognitive

functioning in subjects with FXS, but suggest improvement in subjects cotreated with antipsychotics compared with those on placebo.47 Similar to other studies, it is possible that CX516 is a

low potency agent and the dosing may have been inadequate for therapeutic effect. Future clinical trials involving mGluR5 antagonists and AMPA receptor signaling may potentially provide a

targeted treatment of FXS in alleviating the core psychiatric and neurologic symptoms. Environmental variables may influence an individual's development of adaptive behaviors, cognitive

abilities, and behavioral symptoms.48 For instance, children with FXS residing in a higher quality home environment displayed fewer autistic behaviors, better adaptive behavior, and higher

IQ level. Some of the characteristics of the home environment that may be a factor in these effects are parenting ability, parental expectations of child behavior, organization of the home,

emotional climate, and enrichments in the home.48 Further studies in this area may lead to the development of nonpharmaceutical therapies that can help improve the outcomes of individuals

with FXS. At present, there are virtually no studies on the effectiveness of specific behavioral interventions in FXS despite our knowledge regarding their distinct behavioral phenotypes.

CONCLUSIONS Although current therapies for FXS are aimed at symptom management, it is hoped that future molecular therapies, whether they are aimed at mGluR5, the AMPA receptor, or other

molecular targets, will be directed at preventing the development of some of the symptoms of FXS. This may be a challenge because neurological evidence of FXS on a cellular level can be seen

very early postnatally.49 Early diagnosis will be key to making these therapies more effective, and there are efforts to implement newborn or infant screening for FXS. In a survey of

parents of children with FXS during the 1990s, a significant delay was found between the time they first became concerned about the child's development (median age: 12 months) and the

time they received a diagnosis of FXS (median age: 26 months).50 Thus, clinicians should address parental concern and consider the diagnosis of FXS in any infant or toddler with

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syndrome – United States, 1990–1999. _MMWR Morb Mortal Wkly Rep_ 2002; 51: 740–742. Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Human

Genetics, Emory University School of Medicine, Atlanta, GA, USA Kathryn B Garber, Jeannie Visootsak & Stephen T Warren Authors * Kathryn B Garber View author publications You can also

search for this author inPubMed Google Scholar * Jeannie Visootsak View author publications You can also search for this author inPubMed Google Scholar * Stephen T Warren View author

publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Stephen T Warren. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS

ARTICLE CITE THIS ARTICLE Garber, K., Visootsak, J. & Warren, S. Fragile X syndrome. _Eur J Hum Genet_ 16, 666–672 (2008). https://doi.org/10.1038/ejhg.2008.61 Download citation *

Received: 06 December 2007 * Revised: 08 February 2008 * Accepted: 20 February 2008 * Published: 09 April 2008 * Issue Date: June 2008 * DOI: https://doi.org/10.1038/ejhg.2008.61 SHARE THIS

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Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * Fragile X syndrome * FMR1 * permutation * full mutation * autism