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Home , Autism, Autism spectrum, Fragile X syndrome, Tardive dyskinesia

European Journal of (2008) 16, 666–672 & 2008 Nature Publishing Group All rights reserved 1018-4813/08 $30.00 www.nature.com/ejhg

PRACTICAL GENETICS In association with

Fragile X syndrome, an X-linked dominant disorder with reduced , is associated with intellectual and emotional ranging from learning problems to mental retardation, and mood instability to . It is most often caused by the transcriptional silencing of the FMR1 , due to an expansion of a CGG repeat found in the 50-untranslated region. The FMR1 gene product, FMRP, is a selective RNA-binding that negatively regulates local protein synthesis in neuronal . In its absence, the transcripts normally regulated by FMRP are over translated. The resulting over abundance of certain results in reduced synaptic strength due to AMPA receptor trafficking abnormalities that , at least in part, to the fragile X .

In brief  for this repeat expansion is diagnostic for this syndrome, and testing is appropriate in all  Fragile X syndrome is a common inherited form of children with developmental delay, mental retardation mental retardation that can be associated with features or autism. of autism.  Fragile X syndrome is inherited from individuals,  The physical features of fragile X syndrome are subtle usually , who typically carry an unstable and may not be obvious. premutation of the CGG-repeat tract in  The vast majority of cases of fragile X syndrome are FMR1. caused by the expansion to over 200 copies of a CGG  Premutation carriers are themselves at risk of prema- repeat in the 50-untranslated region of FMR1 that shuts ture ovarian failure and the fragile X-associated / off transcription of the gene. syndrome.

Introduction transcriptionally silenced. The unstable that give Fragile X syndrome (FXS) is the most common inherited rise to full are called premutations and are cause of mental retardation with approximately 1 in 4000 associated with distinct from FXS. The muta- males affected.1 In the vast majority of cases, this X-linked tional mechanism, combined with the location of this gene disorder is caused by expansions of a CGG repeat in the 50- on the X , to remarkable inheritance untranslated (UTR) region of the FMR1 gene that arises due patterns in which the relevant alleles are passed from to the meiotic instability of certain alleles of this repeat intellectually normal men through their unaffected daugh- tract. FXS causing alleles, or full mutations, contain 200 or ters and then to affected sons.2 more copies of the repeat that are hypermethylated and FXS may be suspected in both sexes, and includes a variable clinical phenotype. Individuals with FXS may Kathryn B Garber1, Jeannie Visootsak1 and Stephen T Warren1 present with anything from learning problems and a normal IQ to severe mental retardation and autistic 1Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA behaviors. Physical features have been described but are often nonspecific. Thus, diagnosis is made based upon the European Journal of Human Genetics (2008) 16, 666–672; doi:10.1038/ detection of alterations to FMR1 (Figure 1). ejhg.2008.61; published online 9 April 2008

Keywords: Fragile X syndrome; FMR1; permutation; full ; autism Correspondence: Dr ST Warren, Department of Human Genetics, Emory Clinical overview University School of Medicine, 615 Michael Street, Room 301 Whitehead The physical characteristics of FXS are fairly subtle, and the Building, Atlanta, GA 30322, USA. Tel: þ 1 404 727 5979; Fax: þ 1 404 727 3949; first clinical indication is often delayed developmental E-mail: [email protected] milestones, such as mild motor delays and/or language 3 Received 6 December 2007; revised 8 February 2008; accepted 20 delays. Autistic-like behaviors such as hand flapping, poor February 2008; published online 9 April 2008 , and hand biting may be noted. Fragile X syndrome KB Garber et al 667

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 , balance problems, frequent falls, neuropathy, autonomic dysfunction, cognitive decline, and , which may progressively worsen over time.14

Behavioral aspects Figure 1 Four allelic classes of the FMR1 gene in humans. For each The behavioral phenotype may be helpful in suggesting the allele, the size of the CGG repeat in the 50-UTR of FMR1 is indicated in diagnosis of FXS. Autistic-like features are common in blue at the left of the gene schematic. The level of transcription is individuals with FXS and include hand flapping, hand indicated by the width of the arrow beneath each allele class. Increased transcription is associated with premutation alleles, whereas biting, gaze avoidance, tactile defensiveness, and hyperar- 15,16 full mutations are hypermethylated, as indicated by the red hash- ousal to sensory stimuli. These features – along with marks, and transcriptionally silent. Despite the ACMG definition, the impaired , such as socio-emotional reciprocity – smallest premutation allele known to expand to the full mutation in a are expressed with varying degrees in children with FXS single generation had 59 repeats. and may be indicative of a concurrent diagnosis of disorder or autistic-like behavior.17 Anxiety and The average IQ in adult men with the completely mood disorders, hyperactivity, impulsivity, and aggressive 18 methylated full mutation is approximately 40.4 Less- behavior can also be present. affected males typically have incomplete , The emotional and behavioral characteristics in females resulting in an incomplete activation of FMR1, and they with FXS are usually variable. Females with the full may even have an IQ in the borderline or low normal mutation are prone to , , social range. In general, for FXS, cognitive deficits include avoidance, withdrawal, language deficits, mood lability, 6 problems with working and short-term memory, executive and . Furthermore, females with the premuta- 19 function, and mathematic and visuospatial abilities.5 tion have also been described to have social anxiety. Because the disorder is X-linked, females are generally much more mildly affected than males, particularly in Physical features terms of cognitive functioning, but they tend to have Physical features include macroorchidism that is apparent higher risk for emotional problems compared to the 20 just prior to puberty and those related to a connective general population.6 Females with the full mutation tissue dysplasia, which include a long, narrow face, usually have normal or borderline IQ, and most will 21 prominent ears, joint , and . The have associated learning disabilities and/or emotional facial characteristics (Figure 2) can be subtle and may problems.7 become more apparent with increasing age. Individuals with FXS usually do not have significant medical issues. Recurrent and recurrent are common during childhood.8 Joint laxity with hyperextensibility finger joints and pes planus (flat feet) At autopsy, no gross abnormalities are observed in the may be present and usually improve with age.9 Gastro- brains of individuals with FXS.22 In males with FXTAS, MRI esophageal reflux occurs in a third of young infants findings include global brain atrophy and white matter with FXS, and may present with irritability or recurrent abnormalities, including involvement of the middle cere- emesis.9 and EEG findings consistent with bellar peduncles.23 are another common feature of FXS during childhood, A key neurological feature of individuals with FXS is that, with an incidence between 13 and 18% in boys and 5% in in certain areas of the brain, their have immature girls.10 and dense dendritic spines.24 The spines are the site at The majority of individuals with the premutation have which the majority of excitatory occur, and, normal intelligence, but males are prone to have atten- although it is not known whether they are a cause or an tional problems, , social deficits, and effect, similar abnormalities have been associated with obsessive-.11 Approximately 20% of other forms of mental retardation.25 It is believed that women who carry an FMR1 premutation have premature these differences represent a defect in ovarian failure (POF), which is the premature cessation of development and maturation.24

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to the full mutation occurs only in females because the full mutation cannot be maintained during .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 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 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 Figure 2 Facial features of fragile X syndrome. As illustrated by the and the importance of these spines in synaptic transmis- photographs of four children with FXS, the facies associated with this sion, synaptic plasticity, learning, and memory suggest syndrome are subtle. They can include a long, thin face, and prominent ears that often project away from the head, and a that understanding the function of FMRP at the prominent forehead. 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 Molecular and genetic basis of the disease 1 metabotropic (mGluR) activation.34 In 1991, the gene responsible for FXS, FMR1, was FXS, then, is at least partially a result of exaggerated identified.26 Fragile X was the first known example of a responses to mGluR . In particular, one of the trinucleotide repeat disorder (Figure 1). primary defects associated with the absence of FMRP There are four allelic classes for the CGG-repeat tract in appears to be excessive AMPA receptor internalization in the 50-UTR of FMR1. The repeat sizes for each group are not response to mGluR signaling.35 These alterations to AMPA well defined, and this complicates . In receptor trafficking effect persistent changes in synaptic the general population, the repeat tract contains up to 40 activity. This disease model is supported by the fact that repeats, with 30 being the most common (normal or treatment with the mGluR antagonist 2-methyl-6-pheny- common alleles).27 Next are the intermediate alleles, which lethynyl-pyridine rescues the defect in AMPA receptor range from 41to 54 repeats and which usually are not trafficking in cultured FMRP-deficient neurons,35 as well as associated with instability of the repeat tract. some of the defects associated with the lack of FMRP in Full mutations, which cause FXS, have over 200 copies of Drosophila and mouse models lacking FMRP function.36,37 the repeat.27,28 Hypermethylation of this expanded repeat In addition, Fmr1-deficient mice that express 50% of the tract and the upstream CpG island silences FMR1 expression.29 normal level of mGluR5 are rescued for several phenotypes, Full mutations arise from the allele class known as including changes to the density of dendritic spines, premutations, which range in size from approximately susceptibility to audiogenic seizures, and altered plasticity 55–200 repeats and are meiotically unstable.27,28 Premuta- in the visual cortex.38 tions are unmethylated, transcriptionally active, and produce FMRP, although possibly in lower quantities than normal.30 These alleles can expand in small amounts to Diagnostic approaches yield a slightly larger premutation allele, or they can A checklist of phenotypic criteria has been established expand massively into the full mutation range. Expansion in order to identify individuals with undiagnosed

European Journal of Human Genetics Fragile X syndrome KB Garber et al 669 Table 1 Phenotypic checklist (after Maes et al3) Table 2 Suggested targeted family questionnaire for Fragile X Syndrome (after McConkie-Rosell et al42) The following checklist was proposed by Maes et al3 to be used in men of any age who have developmental delays of unknown This questionnaire is appropriate for use in cases of suspected cause. Each of the items in the checklist is to be answered by a FXS, families with a confirmed diagnosis, and at-risk or known ‘yes’ or ‘no’. Referral is recommended by a score of at least 17, carriers. The history and age of onset should be noted for each and a score of 26 or higher indicates that referral is necessary. It relevant family member. is important to recognize that FXS is not uniform or distinctive in 1. Cognitive effects its presentation. The items in the checklist may not be Mental retardation, developmental delay, learning recognizable in early childhood and may emerge over time. disabilities, specific problems with mathematics Indeed, other factors (eg family history) must be considered in 2. Speech delay or unusual speech pattern suspecting the diagnosis. 3. Autistic spectrum disorders or autistic-like behaviors 1. Narrow and elongated face Gaze avoidance, repetitive behaviors, hand flapping, hand 2. High forehead biting, touch avoidance) 3. Prominent lower jaw 4. -deficit disorder or attention-deficit hyperactivity 4. Large, protruding ears disorder 5. Macroorchidism 5. Dysmorphic features 6. Hyperextensible finger joints , large ears, long face, broad forehead, 7. Hyperextensible joints (other) prominent jaw, 8. Hyperactivity 6. Features of loose connective tissue 9. Sensory oversensitivity Hyperextensible joints, flat feet, , mitral valve 10. Impulsivity prolapse, large testicles, hernias, recurrent ear 11. Being chaotic 7. Neurologic symptoms 12. Shyness Seizures, late-onset progressive tremor, ataxia, difficulty 13. Being too helpful walking, balance problems, short-term memory loss, loss of 14. Approach–avoidance conflict sensation in limbs 15. Fearfulness 8. Mental illness/personality disorders 16. Gaiety, cheerfulness Depression, , , obsessive- 17. Hypersensitivity for changes compulsive disorder, , schizoid 18. Hand biting personality 19. Stereotypic hand movements 9. Behavioral problems 20. Flapping hands and arms Impulsiveness, anger outbursts, violent behavior, solitary 21. Avoiding eye contact behavior, counseling or for behavioral difficulties 22. Turning away the face 10. Shyness, social anxiety, excessive worrying, counseling, or 23. Tactile defensiveness medication for emotional difficulties 24. Rapid speed of language 11. Premature , problems 25. Being talkative 26. Abbreviation: FXS, fragile X syndrome. 27. 28. Imitation of own language detection of fragile X-associated mutations has a sensitivity Abbreviation: FXS, fragile X syndrome. of 99%. The remaining 1% of mutations include missense mutations and full or partial deletions of FMR1.39 There is a developmental delay who would be appropriate candidates deficit of reported missense mutations of FMR1 due to the for FXS molecular testing3 (Table 1). These checklists, of over reliance on CGG-repeat testing. Thus, in any indivi- which several had been devised prior to that of Maes, may dual presenting with a clinical suspicion of FXS but with increase the diagnostic yield slightly, but because children normal CGG-repeat lengths, sequencing of FMR1, which may not have apparent physical features, it is accepted also uncovers deletions in males, should be considered. practice to order fragile X testing in all children with Fragile X testing of an individual with isolated cognitive developmental delay, mental retardation, or autism,39 impairment should be done in conjunction with cytoge- although this may have a diagnostic yield of only netic evaluation because constitutional chromosomal approximately 1–2%.40 The presence in the proband’s abnormalities are as common, if not more common, than family of movement disorders, learning disabilities, mental FXS in this population.39 retardation, or primary ovarian insufficiency should in- The same testing approach can also be used to identify crease suspicion of the presence of FMR1 mutations in the premutation carriers. Prenatal diagnosis for full mutations family.41 A suggested targeted family history questionnaire can be performed on either chorionic villus or amniocen- can be found in Table 2. tesis samples and has proven to be highly reliable.43 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 50-UTR, Management and a Southern blot of genomic DNA is used to determine Genetic counseling the methylation status and to gauge the size of full If a positive FXS test is discovered, the proband and family mutations, which are often resistant to PCR amplifica- should be referred for genetic counseling and cascade tion.18 The combination of Southern blot and PCR for the testing of family members at risk of carrying a full

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mutation or premutation.41 Premutation carriers should be , and aggression.44 Individuals treated with SSRIs counseled regarding their risks of a full mutation should be monitored for restlessness, mood changes, hyper- onto their children, and they should also be counseled of activity, and disinhibited behavior including aggression.44 their own risks of POF and/or FXTAS. When planning Atypical have been used to treat self-injury, cascade testing in an affected family, particular attention aggressive behaviors, and autism. Parental reports of im- should be considered for family members with mental provement in mood stabilization, attention, and academic retardation, learning disabilities, autism, or social and performance have been noted with the atypical antipsycho- behavioral disorders; relatives with infertility or , which should be used at low doses to avoid premature menopause; and those with tremor, ataxia, or the agitation that can be induced by higher doses.45 Adverse other neurological and psychiatric problems. events associated with antipsychotics include weight gain Genetic counseling becomes difficult when FMR1 alleles (although not with aripiprazole), sedation, nausea, constipa- in the B45–54 repeat range are identified. This is a ‘gray tion, diabetes, and tardive . In individuals with zone’ because unstable alleles of this size have been rapid weight gain, monitoring for diabetes and metabolic reported in families but the expansion is unlikely. Pre- syndrome must be considered. mutations are most often clinically reported when the As mentioned previously, the phenotype in FXS is caused repeat tract is 55 repeats or greater, although the smallest by excessive mGluR5 signaling, thus drugs targeting repeat known to expand to a full mutation in a single mGluR5 may be an effective treatment for FXS.34 Several generation was 59 repeats. The American College of mGluR5 anatagonists are presently in pharmaceutical provides guidelines for fragile X testing development for an array of targeted clinical symptoms, at http://www.acmg.net/Pages/ACMG_Activities/stds-2002/ such as , Parkinson’s Disease, and sub- fx.htm. stance .46 In addition, a recent -controlled clinical trial of the AMPA receptor positive modulator Treatment and care (Ampakine) CX 516 indicates no significant improvements Current approaches to therapy for FXS are all symptom in memory, language, attention/executive function, beha- based, and few controlled trials have been performed to vior, and cognitive functioning in subjects with FXS, but determine their effectiveness.44 Psychopharmacologic in- suggest improvement in subjects cotreated with antipsy- tervention should be combined with other supportive chotics compared with those on placebo.47 Similar to other strategies, including speech therapy, sensory integration studies, it is possible that CX516 is a low potency agent and , individualized educational plans, the dosing may have been inadequate for therapeutic and tailored behavioral interventions to maximize effect. Future clinical trials involving mGluR5 antagonists functioning. and AMPA receptor signaling may potentially provide a In boys with FXS, the most frequently used targeted treatment of FXS in alleviating the core psychia- are .44 These medications are targeted to symp- tric and neurologic symptoms. toms of hyperactivity, impulsivity, and distractability and Environmental variables may influence an individual’s can be quite helpful in these areas.44 Despite being the development of adaptive behaviors, cognitive abilities, and most common medication in FXS, the of these behavioral symptoms.48 For instance, children with FXS drugs and their side effects vary for each individual. The residing in a higher quality home environment displayed response rate to stimulants may be relatively lowered in fewer autistic behaviors, better , and adult men with FXS because of their increased anxiety and higher IQ level. Some of the characteristics of the home decreased activity level.44 environment that may be a factor in these effects are Some researchers believe that many of the behavioral parenting ability, parental expectations of child behavior, problems observed in individuals with FXS are secondary organization of the home, emotional climate, and enrich- to problems with hyperarousal to sensory stimuli.18 ments in the home.48 Further studies in this area may lead Although it can be difficult to implement, structuring the to the development of nonpharmaceutical therapies that environment of the affected individual such that they are can help improve the outcomes of individuals with FXS. At comfortable with their surroundings is one approach to present, there are virtually no studies on the effectiveness alleviating this issue.18 Another approach is the use of of specific behavioral interventions in FXS despite our a2-adrenergic agonists, which are thought to dampen the knowledge regarding their distinct behavioral phenotypes. response to sensory input to the brain and show good efficacy in treating some of these behaviors in boys with FXS.44 Selective reuptake inhibitors (SSRIs) are quite Conclusions commonly used to treat , anxiety, and Although current therapies for FXS are aimed at symptom obsessive-compulsive behaviors associated with FXS. They management, it is hoped that future molecular therapies, are effective, particularly in alleviating social anxiety, whether they are aimed at mGluR5, the AMPA receptor, or

European Journal of Human Genetics Fragile X syndrome KB Garber et al 671 other molecular targets, will be directed at preventing the 16 Brown WT, Jenkins EC, Cohen IL et al: Fragile X and autism: a development of some of the symptoms of FXS. This may be multicenter survey. Am J Med Genet 1986; 23: 341 –352. 17 Kaufmann WE, Cortell R, Kau AS et al: Autism a challenge because neurological evidence of FXS on a in fragile X syndrome: , social interaction, and 49 cellular level can be seen very early postnatally. Early specific behaviors. Am J Med Genet 2004; 129: 225 –234. diagnosis will be key to making these therapies more 18 Tsiouris JA, Brown WT: Neuropsychiatric symptoms of fragile X effective, and there are efforts to implement newborn or syndrome: and pharmacotherapy. CNS Drugs 2004; 18: 687 – 703. infant screening for FXS. 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38 Dolen G, Osterweil E, Rao BS et al: Correction of fragile X 45 Hagerman RJ: Lessons from fragile X regarding neurobio- syndrome in mice. Neuron 2007; 56: 955 – 962. logy, autism, and neurodegeneration. J Dev Behav Pediatr 2006; 39 Sherman S, Pletcher BA, Driscoll DA: Fragile X syndrome: 27: 63 – 74. diagnostic and carrier testing. Genet Med 2005; 7: 584 – 587. 46 Slassi A, Isaac M, Edwards L et al: Recent advances in 40 Rauch A, Hoyer J, Guth S et al: Diagnostic yield of various non-competitive mGlu5 receptor antagonists and their genetic approaches in patients with unexplained developmental potential therapeutic applications. Curr Top Med Chem 2005; 5: delay or mental retardation. Am J Med Genet 2006; 140: 2063–2074. 897 –911. 41 McConkie-Rosell A, Abrams L, Finucane B et al: Recommenda- 47 Berry-Kravis E, Krause SE, Block SS et al: Effect of CX516, an tions from multi-disciplinary focus groups on cascade testing and AMPA-modulating compound, on cognition and behavior in genetic counseling for fragile X-associated disorders. J Genet fragile X syndrome: a controlled trial. J Child Adolesc Psychophar- Couns 2007; 16: 593 – 606. macol 2006; 16: 525 –540. 42 McConkie-Rosell A, Finucane B, Cronister A, Abrams L, Bennett 48 Glaser B, Hessl D, Dyer-Friedman J et al: Biological and RL, Pettersen BJ: Genetic counseling for fragile x syndrome: environmental contributions to adaptive behavior in fragile X updated recommendations of the national society of genetic syndrome. Am J Med Genet 2003; 117:21–29. counselors. J Genet Couns 2005; 14: 249 – 270. 49 Nimchinsky EA, Oberlander AM, Svoboda K: Abnormal develop- 43 Brown WT, Houck Jr GE, Jeziorowska A et al: Rapid fragile X ment of dendritic spines in FMR1 knock-out mice. J Neurosci carrier screening and prenatal diagnosis using a nonradioactive 2001; 21: 5139 – 5146. PCR test. JAMA 1993; 270: 1569 –1575. 50 Bailey DB, Skinner D, Sparkman K, Moore CA, Olney RS, 44 Berry-Kravis E, Potanos K: Psychopharmacology in fragile X Crawford DC: Delayed diagnosis of fragile X syndrome – United syndrome – present and future. Ment Retard Dev Disabil Res Rev States, 1990 –1999. MMWR Morb Mortal Wkly Rep 2002; 51: 2004; 10: 42 – 48. 740 –742.

European Journal of Human Genetics