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Autism and Fragile X Syndrome Elizabeth Berry-Kravis, MD, PhD2

1 Division of Genetics and Genomics, Boston Children’s Hospital, and

Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 2 Departments of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, Chicago, Illinois Semin Neurol 2014;34:258–265.

Abstract

Keywords

► fragile X syndrome ► autism spectrum disorder ► fragile X mental retardation protein ► fragile X mental retardation 1 geneintellectual disability

Address for correspondence Timothy W. Yu, MD, PhD, Division of Genetics and Genomics, Boston Children’s Hospital, and Department of Pediatrics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115 (e-mail: [email protected]).Elizabeth Berry-Kravis MD, PhD, Departments of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, 1725 West Harrison Street, Suite 718, Chicago, IL 60612 (e-mail: [email protected]).

Autistic spectrum disorders (ASDs) are characterized by impairments in language, social skills, and repetitive behaviors, often accompanied by intellectual disability. Advances in the genetics of ASDs are providing new glimpses into the underlying neurobiological mechanisms disrupted in these conditions. These glimpses on one hand reinforce the idea that synapse development and plasticity are one of the major pathways disrupted in autism, but beyond that are providing fresh molecular support to the idea of mechanistic parallels between idiopathic ASD and specific syndromic neurodevelopmental disorders like fragile X syndrome (FXS). Fragile X syndrome is already recognized as the most common identifiable genetic cause of intellectual disability and ASDs, with many overlapping phenotypic features. Fragile X syndrome is associated with a variety of cognitive, behavioral, physical, and medical problems, which are managed through supportive treatment. Recent major advances in the understanding of the underlying neurobiology in FXS have led to the discovery of agents that rescue phenotypes in the FXS mouse model, and early clinical trials of targeted treatments in humans with FXS. Thus translational strategies in FXS may be poised to serve as models for ASD and other cognitive disorders.

Autism Autistic spectrum disorder (ASD) is a neurodevelopmental disorder characterized by early-onset deficits in language, impaired social skills, and patterns of repetitive behaviors or restricted interests. Once considered rare, recent studies have estimated ASD prevalence worldwide to be approximately 1% to 2%,1,2 with a striking 4:1 male bias.3 Autistic spectrum disorders are associated with serious medical and psychosocial comorbidity, including concomitant intellectual disability (16%–50%), epilepsy (7%–35%), sleep disorders (40%–80%), as well as additional conditions (gastrointestinal [GI] disorders, mitochondrial and metabolic disorders) whose prevalence is incompletely understood.1,4,5 Although some individuals with ASDs have relatively mild impairment compatible with independent living, many affected individuals require

Issue Theme Neurogenetics; Guest Editor, Ali Fatemi, MD

educational and lifelong social support, with significant economic impact on their families and society.6 Historically, the extreme heterogeneity of ASD has posed a major challenge to traditional clinicopathologic approaches to investigating disease mechanisms. With some exceptions (e.g., autism with regression,7 or autism with macrocephaly8), the diversity of symptoms and severities encompassed by ASD have made it difficult to formulate robust endophenotypes based on clinical symptoms alone.9,10 Similarly, neuroanatomical investigations of brain tissue from individuals with ASD have highlighted abnormalities in the cerebellum, amygdala, and frontal lobes, but a consistent and unifying neuropathology has not been forthcoming.11 Nonetheless, in recent years, genetic and molecular approaches have made significant progress in penetrating this heterogeneity, and are beginning to reveal autism’s neurobiological underpinnings.

Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0034-1386764. ISSN 0271-8235.

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Timothy W. Yu, MD, PhD1

Twin studies have long implicated a strong genetic component to autism, with formal heritability estimates of approximately 50% to 90%.12–19 Simultaneously, it has also been long recognized that many genetic disorders have higher rates of autism than the general population, including phenylketonuria, fragile X syndrome, Rett syndrome, tuberous sclerosis, Angelman syndrome, and Smith Lemli-Opitz syndrome,20 and over 100 different genetic disorders have been reported that may include autistic features as one of their presenting phenotypes,21 although many research studies have tried to include only cases considered to be clinically idiopathic—a somewhat awkward and shifting standard. Rare, recurrent chromosomal abnormalities were among the first genetic abnormalities reported in idiopathic autism, including contiguous gene syndromes (e. g.,15q11-q13 duplication, 22q13 deletion), but occasionally implicating single genes (e.g., FOXP1, FOXP2, NLGN3, NLGN4X, NRXN1, SHANK2, SHANK3).22–29 Most of these chromosomal abnormalities were hundreds of kilobases to megabases in size, and were discovered in close examination of a few sporadic or rare familial cases. More recently, microarray studies in large autism cohorts have revealed additional recurrent ASD-associated copy number variants (CNVs) and translocations (e.g., 16p11.2 deletion/ duplication, 7q11.23 duplication, and others) as well as an excess of many smaller rare CNVs in ASD.30–40 Many of these occur in a de novo fashion, whereas others are inherited with incomplete penetrance. These studies also allowed estimation of the contribution of CNVs to autism as a whole; in aggregate de novo or inherited CNVs likely account for approximately 5% to 7% of cases, and the number of ASD-associated CNV loci is likely in the several hundreds.35–39 Identification of these CNVs is a critical piece of the puzzle for understanding the genetic architecture of ASD, but notably, does not always point to single causative genes or mechanisms, even when largescale resequencing of candidate genes in the interval is undertaken,41 and arguments for plausible biological candidates can be made. 42 This and other evidence suggests that CNVs may exert their effects through the combinatorial action of more than one included or nearby gene, or in concert with additional genetic or nongenetic factors.43,44 The challenge of identifying specific, impactful ASD genes is now being met with advances in high-throughput sequencing. The declining costs and increasing efficiency of sequencing have enabled novel study designs, a particularly valuable example of which has been whole exome sequencing (WES) in ASD trios (affected children and their parents) or quartets (trios plus their unaffected siblings) to find de novo point mutations. Three pilot reports published in 2012 analyzed whole exome sequences from approximately 600 trios and quartets and demonstrated an excess of disruptive de novo mutations in ASD cases.45–47 This excess was particularly evident in brain-expressed genes, and its magnitude was consistent with the idea that de novo mutations may contribute to up to 5% to 15% of sporadic ASD cases. Because de novo

Yu, Berry-Kravis

mutations are rare (approximately 1 per exome per generation), finding multiple recurrent events in the same gene in different cases constitutes strong statistical evidence of disease association. Combined with an important follow-up study in which the top candidate genes were resequenced in an additional
2400 probands,48 this approach yielded six new specific ASD genes that act via de novo mutations (CHD8, DYRK1A, GRIN2B, TBR1, PTEN, and TBL1XR1), and which together contribute to approximately 1% of sporadic ASD. Large-scale efforts to extend this approach to larger and larger datasets are underway.49 In addition to offering insight into de novo mutations, WES has also begun to provide insights into the contribution of inherited point mutations to ASD, critical to understanding the heritability of this disorder. These insights range from recessive analyses of larger and larger cohorts of multiplex and/or consanguineous families, 50,51 to population analyses of large case-control datasets to provide baseline estimates for the proportion of sporadic ASD cases that might be affected by recessive mutations.52 These analyses have uncovered examples of ASD resulting from recessive mutations in previously unrecognized single gene disorders (e.g., UBE3B50,53), as well as examples in which ASD is due to an unusually mild clinical presentation of a more severe neurodevelopmental or neurometabolic single-gene disorder due to a hypomorphic mutation (e.g., functional missense mutations in AMT causing atypical glycine encephalopathy51). In parallel, sequencing advances are also fueling many smaller-scale (but equally biologically interesting) discoveries of genes associated with ASD and/or intellectual disability with autistic features (e.g., BCKDK,54 ANK2,55 and ADNP56). These advances are shaping and refining our understanding of ASD and its causes. Clinically, the heterogeneity of ASDs remains a critical issue and reinforces the importance of careful consideration of underlying neurometabolic or other syndromic single-gene disorders even in nominally idiopathic cases, especially when they may be potentially intervenable. Nonetheless, there is beginning to emerge evidence of core biological mechanisms. Autistic spectrum disorder genes implicated by copy number variation and/or point mutations, as well as parallel measurements of transcriptional modules altered in postmortem brain tissue of individuals with ASD,55,57,58 implicate several broad biological domains in ASD pathogenesis—synaptic function, neuronal signaling and development, and chromatin regulation32,36,45,55,59–63 —but more importantly, with the increasing resolution afforded by more established loci, evidence is strengthening for more specific molecular pathways, such as glutamatergic signaling61,63 and MAPK signal transduction.61 One of the most intriguing and increasingly replicated results is the finding of significant overlap of ASD loci with the fragile X mental retardation protein (FMRP) signaling pathway.47,60,64 These mechanistic connections raise the possibility of leveraging knowledge about well-studied conditions like fragile X syndrome to further hypotheses about ASD pathophysiology, and are being used to guide the development and evaluation of candidate therapies. Seminars in Neurology

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Autism and Fragile X Syndrome

Autism and Fragile X Syndrome

Yu, Berry-Kravis

Fragile X Syndrome Fragile X syndrome (FXS) is the most common identifiable single gene cause of intellectual disability (ID) and autism spectrum disorder (ASD), with an estimated frequency of approximately 1:4000 to 5000.65 The disorder affects all ethnic groups worldwide, although prevalence varies between different populations. Fragile X syndrome is one of the fragile X-associated disorders (FXDs), which arise from a trinucleotide repeat (CGG) expansion mutations in the promoter region of FMR1 (fragile X mental retardation 1 gene). This CGG sequence is transcribed into the FMR1 mRNA, but as the sequence is located in the 5′untranslated region of the mRNA, the number of repeat units does not affect the sequence of the protein product of the FMR1 gene (FMRP).66 Smaller mutations in the gene (55–200 CGG repeats) are termed a “premutation,” now known to have a prevalence of approximately 1:151 to 1:209 females and 1:430 to 1:468 males in populations in the United States.67,68 The premutation is associated with risk for two well-defined adult-onset diseases: fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). The mechanism for premutation-associated disease is thought to relate to elevated FMR1 mRNA levels and resultant CGG repeat-mediated RNA toxicity, although recent findings of elevated antisense FMR1 transcripts (ASFMR) containing the repeat in premutation carriers69 and polyglycine produced due to aberrant translation of the premutation repeat at the ribosome,70 have suggested multiple mechanisms of toxicity in FMR1 premutation diseases. Indeed, individuals with a large premutation (> 150 repeats) also have low FMRP levels due to repeat-mediated translational stalling and manifest symptoms milder than but overlapping with those seen with FXS.66 Large “full mutation” expansions in FMR1 (> 200 repeats) cause FXS, which results from the methylation and transcriptional silencing of the FMR1 promoter with consequent loss or significant reduction of FMRP.66 FMR1 expansions tend to increase in size as they are passed from generation to generation, so FXD affect families in multiple generations. Adults with FXTAS present with tremor and/or ataxia, and may have executive dysfunction, neuropathy, parkinsonism, vestibular dysfunction, psychiatric symptoms like anxiety, and in some cases autonomic dysfunction and dementia.71 Clinically, patients often have a mixture of neurologic symptoms that make them difficult to categorize diagnostically. Progression is variable, but is typically over many years. Brain atrophy, increased signal in the deep white matter, and middle cerebellar peduncle hyperintensity (MCP sign) are seen on magnetic resonance imaging (MRI) scans, whereas the hallmark pathological finding is that of intranuclear inclusions in neurons.71 Diagnosis is through FMR1 DNA testing by PCR to identify the premutation expansion. Consistent with the RNA toxicity mechanism, the CGG repeat length in the premutation correlates with onset and severity of disease, MRI findings, and number of inclusions.71 Treatment is supportive; β-blockers for tremor, L-DOPA for parkinsonism, antidepressants for anxiety, and donepezil or Seminars in Neurology

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memantine for executive and cognitive problems have sometimes been helpful anecdotally.71 Children with FXS typically present with developmental delay. Although motor delays are often seen, these tend to be mild, and affected males most commonly come to medical attention because of language delay. Hypotonia is often present early in life, but improves with development, and by school age evolves into coordination and praxis problems. Females and higher-functioning males with FXS may have fairly normal early language acquisition, and present with behavioral problems, anxiety, attention deficit hyperactivity disorder (ADHD) symptoms, or learning delays in school. Males with FXS typically display ID that can range from mild to severe, with characteristic strengths and weaknesses in specific areas of cognition and language. Their IQs tend to decline with age during childhood, and this is not the result of regression, but rather failure to keep pace with the normal rate of intellectual development. Average IQ in adult males with FXS is 40 to 50, with a mental age of about of 5 to 6 years.72 Physical features include macro-orchidism in most adult males, as well as prominent ears, macrocephaly, long face, prominent jaw and forehead, midfacial hypoplasia, high arched palate, and connective tissue laxity, leading to hyperextensible joints, flat feet, and soft skin. Physical features are sufficiently variable that they cannot be used as indicators of which patients to screen. Medical problems commonly include seizures (
11%–15%, usually in childhood), strabismus (10%–30%), and sleep disorders (32%).73 Frequent ear infections, gastroesophageal reflux, sleep apnea and other sleep problems, loose stools, and allergies have been reported to be more prevalent in FXS than the general population, although this awaits confirmation with more rigorous epidemiological studies that are currently underway through the Fragile X Clinical and Research Consortium (FXCRC), a group of 27 fragile X clinics organized to promote multi-institutional research and optimize clinical practices in FXS.73 Behavioral symptoms are very prominent in FXS and include hyperactivity, impulsivity, attention problems, anxiety, mood lability, aggression, self-injury, and autistic features such as poor eye contact, self-talk, hand flapping, hand biting, hyperarousal to sensory stimuli, and perseverative language and behavior.72,74 Females with a full mutation are more variably and typically more mildly affected than males, due to production of FMRP from the normal FMR1 allele in cells expressing the nonmutated X chromosome. Average IQ in females is approximately 80, with a range from severe impairment to normal or even superior ability. The pattern of cognitive strengths and weaknesses is similar to that seen in males. Even when females with FXS have a normal IQ, there is frequently learning disability, including particularly executive and social deficits, as well as anxiety, shyness, and attention problems. Severity of cognitive impairment in females with the full mutation is thought to be related to the activation ratio for the normal FMR1 allele and the amount of FMRP expression.75 Males with mosaicism for a full- and premutation or a partially unmethylated full mutation may also be mildly

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affected, with severity in this case also related to the amount of unmethylated DNA and FMRP levels.75 About a half to two-thirds of males and approximately 20% of females with FXS meet criteria for ASD.76 Behavioral and neurologic phenotypes common to FXS and ASD include social interactional and communication/language deficits, poor eye contact, repetitive motor movements such as stereotypies, unusual reactions to sensory input, including hypersensitivity (e.g., tactile defensiveness) and hyposensitivity (e.g., high tolerance for pain), cognitive strength in visual memory, increased prevalence of seizures relative to the general population (although peak incidence is in childhood in FXS and adolescence in ASD), macrocephaly, difficulties with regulation of attention, activity level, emotional behavior, and mood, often leading to additional diagnoses (e. g., ADHD, anxiety, mood disorder), other problematic behaviors (e.g., aggression, noncompliance, self-injury), and sleep problems. Some behavioral characteristics or symptoms are seen in both ASD and FXS, but for different underlying reasons. In FXS, for example, lack of social initiation and poor eye contact is thought to be mostly due to anxiety77 rather than lack of social awareness or interest commonly seen in ASD. Characteristics that tend to differ between the FXS and ASD phenotypes include a higher rate of ID in FXS than ASD, significantly more severe motor coordination deficits in FXS than ASD, worse expressive than receptive language in FXS with the reverse pattern more likely in ASD, generally higher interest in socialization in FXS (although limited by anxiety), and better imitation skills in FXS than ASD. Individuals with FXS þ ASD, relative to those with FXS alone, have less-developed language skills, lower IQ and adaptive skills, moresevere overall behavioral problems, and reduced social interaction.76 Current treatment of FXS is supportive,72,74 is similar to supportive treatment employed in ASD, and includes speech, occupational, and physical therapy, and educational strategies designed based on the pattern of cognitive and behavioral strengths and weaknesses in FXS. Treatment of medical problems is important, as these problems can impact development or behavior. Such treatment depends on symptoms manifested by the individual patient, and would include aggressive treatment of frequent otitis media to prevent an impact on already compromised language, management of obstructive sleep apnea with tonsillectomy/adenoidectomy to prevent cognitive and behavioral aggravation, orthotics when needed for foot pronation and flat feet to avoid leg pain and reduce gait problems, management of strabismus with eye patching, vision therapy, or surgery to avoid amblyopia and compounding of visual processing problems, use of antacids when needed for GE reflux to prevent pain and resulting behavioral decompensation, and seizure control with anticonvulsants that do not have a tendency to aggravate behavior. Behavior problems in FXS typically require intensive consistent behavioral modification strategies implemented at home, at school, and in other settings. Frequently psychopharmacology is employed for attention deficits, anxiety, or other problematic maladaptive behaviors to improve overall

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functioning.72,74 Psychopharmacologic treatment of ADHD symptoms, anxiety, hyperarousal, and irritable/aggressive behaviors with medications such as stimulants, SSRIs, αagonists, and antipsychotics, respectively, appears to be helpful in a clinical setting in approximately 50% to 70% of patients.74 Response is typically incomplete, and data from a National Survey on FXS showed that approximately 10% to 20% of respondents felt that medication was not helpful for the behavior problems being treated in their child with FXS, while only approximately 40% felt the medication was helping a lot.78 There is clearly an unmet need in FXS for better medications to treat behavior and for development of treatments that target cognitive deficits, and thus treatments that modify the underlying disorder would be a tremendously important advance. In the past decade, study of the neurobiology and synaptic mechanisms resulting from absence of FMRP in FXS has emerged as an important window to future targeted treatments for FXS and for ASD and related neurodevelopmental disorders (NDDs).76,79 The Fmr1 knockout mouse, which makes no functional FMRP, has been a critical resource to understand the role of FMRP in neurons, identify cellular treatment targets, and explore effects of proposed diseasemodifying agents. FMRP is an mRNA binding protein involved in the transport, localization and translational regulation of a subset of dendritic mRNAs.79 FMRP functions in a protein complex at the ribosome, where it regulates dendritic protein translation in response to synaptic activation by Group 1 metabotropic glutamate receptors (mGluR1 and mGluR5),80 muscarinic (M1) acetylcholine receptors and probably multiple Gq-linked receptors, including dopamine D1 receptors. Activation of these receptors results in signaling through ERKand mTOR-dependent signaling pathways that ultimately results in loss of FMRP repressor function at the ribosome, and a pulse of new protein synthesis. Translation of a broad array of proteins involved in synaptic functions is regulated by FMRP, such as STEP and Arc, which are linked to AMPA receptor internalization.81 Fragile X mental retardation protein also regulates activity of some pre- and postsynaptic ion channels such as BK and SLACK channels through direct protein–protein interactions.82 These regulatory functions of FMRP appear to be critical for synaptic maturation and strength, as in the absence of FMRP, there is a constitutive elevation of synaptic proteins usually controlled by FMRP, immature elongated morphology of dendritic spines,83 abnormal spine density, abnormal synaptic plasticity including enhanced mGluR-activated hippocampal and cerebellar LTD, and impaired LTP in hippocampus, cortex and amygdala, and proneness to abnormal epileptiform discharges.79,82 The morphological abnormalities and synaptic plasticity deficits found in the fmr1 knockout mouse are associated with numerous cognitive, behavioral, and electrophysiological phenotypes, including abnormal ocular dominance plasticity, olfactory learning deficits, impaired memory formation, decreased motor learning, increased open-field hyperactivity, abnormal marble burying, abnormal social behaviors, abnormal prepulse inhibition (PPI), prolonged epileptiform bursts, neuronal network hyperexcitability, audiogenic seizures, Seminars in Neurology

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Autism and Fragile X Syndrome

Autism and Fragile X Syndrome

Yu, Berry-Kravis

abnormal growth patterns, and increased protein synthesis.79,82 The Drosophila model of FXS, in which there is loss of dfmr1 (homolog of the FMR1 gene in the Drosophila genome), shows defects in circadian rhythms, synaptic branching, courtship behavior, and learning.79,82 The abnormalities observed in the absence of FMRP in the mouse model of FXS has led to identification of treatment targets directed at (1) reduction of excess activity in signal transduction pathways leading from group 1 mGluRs or other Gq-linked receptors to the dendritic translational machinery, (2) reduction of excessive activity of individual proteins normally regulated by FMRP, (3) increasing expression and activation of surface AMPA receptors, (4) modification of activity of GABA and other receptors/proteins that regulate glutamate signaling, and (5) blocking excessive translation of mRNAs normally regulated by FMRP using miRNAs.79,82 Treatments aimed at all of these types of targets have shown success in reversing phenotypes in the Fmr1 knockout mouse84–86 and dfxr fly87 models even in adulthood,88 suggesting that there may not be an absolute developmental requirement for FMRP. Successful preclinical testing in FXS models has led to early proof-of-concept clinical trials and subsequent larger trials for some of the proposed targeted treatments. Lithium, thought to reduce excess mGluR-dependent activation of translation by attenuating GSK3β activity and possibly phosphatidyl inositol (PI) turnover, resulted in significant improvement in behavioral scales, verbal memory, and abnormal ERK phosphorylation rates in lymphocytes in a 2month pilot open-label proof-of-concept trial in children and young adults with FXS.89 A pilot placebo-controlled crossover trial of minocycline, an antibiotic that inhibits overexpressed synaptic MMP9 in FXS models, conducted in children with FXS showed mild global clinical improvement and reduction of blood MMP9 levels in responders.90 GABA-B agonist arbaclofen presumably lowers presynaptic glutamate release with resultant reduction of group 1 mGluR signaling. In a phase II double-blind placebo-controlled crossover trial,91 arbaclofen showed improvement over placebo in the entire per protocol group for parent-nominated problem behaviors and social withdrawal. However, a large-phase III placebo-controlled trial in adolescents and adults with FXS did not show benefits for arbaclofen over placebo in the primary outcome of social withdrawal. An additional phase III trial in children with FXS is pending. Acamprosate, currently approved by the U.S. Food and Drug Administration (FDA) for alcohol withdrawal, with agonist properties at both GABA-A and GABA-B receptors, has shown promise for hyperactivity and social functioning in FXS in an open-label trial.92 Acamprosate and GABA-A agonist ganaxolone are being tested in small placebo-controlled trials in FXS (clinicaltrials.gov). Multiple negative modulators of the mGluR5 receptor (group 1 mGluR expressed throughout the brain) have been in trials in FXS. A single oral dose of fenobam93 resulted in a significant improvement in abnormal PPI compared with untreated control subjects with FXS. A phase II double-blind placebo-controlled, crossover trial of AFQ056 in 30 adult Seminars in Neurology

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males with FXS treated for 28 days each with AFQ and placebo,94 suggested improvement in maladaptive behavior in a post hoc analysis in the subgroup with full methylation of FMR1. Larger multinational trials have not supported this behavioral outcome, but have not addressed cognitive outcomes. RO4917523, another mGluR5 negative modulator is also in large multinational trials in FXS (clinicaltrials.gov). Although many neuronal targets for treating the underlying disorder in FXS have emerged, and early translational work has begun, there have been problems with demonstrating disease modification in early trials because there are still many uncertainties about how to optimally demonstrate treatment effects in a clinical trial setting.78,79,95 Major trial design issues in FXS trials potentially include variable but narrow dosing windows; timing (age) and length of treatment necessary; potential need for cognitive or behavioral interventions to see drug effects on learning; large placebo effects; and lack of validated, sensitive biomarkers and functional outcome measures in FXS.95 These trial design issues will need to be resolved to be able to demonstrate disease modification in FXS, but it is hoped that in the future treatment to reverse the underlying disorder will replace or complement supportive treatment. There is significant overlap in molecular and cellular pathways involving FMRP and those that include gene products associated with ASD.75,79 This overlap falls into three broad categories: (1) defects in proteins in the signaling cascade for activation of FMRP-regulated translation, such as SHANK, mTOR, PAK, and PTEN; (2) defects in proteins regulated directly by FMRP, such as PSD95 and Arc; and (3) defects in proteins that regulate the balance of activity in brain glutamate and GABA systems. Indeed, this pathway overlap has been recently supported by the findings that (1) FMRP binds to one-third to one-half of all genes identified as associated with ASD in a meta-analysis of exome screening studies47; (2) FMRP target genes are more likely than other genes with similar expression patterns to contribute to ASD64; and (3) common variants in genes involved in postsynaptic regulation of FMRP (CAMK4, GRM1, CYFIP1) are risk factors for ASD.96 Treatments directed at mechanisms involving all of these overlap areas are becoming available in FXS trials and if successful, progress in development of targeted treatments for FXS is likely to result in targeted treatments to reverse central nervous system defects and clinical manifestations of ASD, other NDDs, and intellectual disability.

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