DOCSLIB.ORG

Developmental Studies in Fragile X Syndrome Khaleel A

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Developmental Studies in Fragile X Syndrome Khaleel A Razak et al. Journal of Neurodevelopmental Disorders (2020) 12:13 https://doi.org/10.1186/s11689-020-09310-9 REVIEW Open Access Developmental studies in fragile X syndrome Khaleel A. Razak1, Kelli C. Dominick2,3 and Craig A. Erickson2,3* Abstract Fragile X syndrome (FXS) is the most common single gene cause of autism and intellectual disabilities. Humans with FXS exhibit increased anxiety, sensory hypersensitivity, seizures, repetitive behaviors, cognitive inflexibility, and social behavioral impairments. The main purpose of this review is to summarize developmental studies of FXS in humans and in the mouse model, the Fmr1 knockout mouse. The literature presents considerable evidence that a number of early developmental deficits can be identified and that these early deficits chart a course of altered developmental experience leading to symptoms well characterized in adolescents and adults. Nevertheless, a number of critical issues remain unclear or untested regarding the development of symptomology and underlying mechanisms. First, what is the role of FMRP, the protein product of Fmr1 gene, during different developmental ages? Does the absence of FMRP during early development lead to irreversible changes, or could reintroduction of FMRP or therapeutics aimed at FMRP-interacting proteins/pathways hold promise when provided in adults? These questions have implications for clinical trial designs in terms of optimal treatment windows, but few studies have systematically addressed these issues in preclinical and clinical work. Published studies also point to complex trajectories of symptom development, leading to the conclusion that single developmental time point studies are unlikely to disambiguate effects of genetic mutation from effects of altered developmental experience and compensatory plasticity. We conclude by suggesting a number of experiments needed to address these major gaps in the field. Introduction affecting synthesis of many proteins including those Fragile X syndrome (FXS) is the most common inher- involved in synaptic pruning during development. ited cause of intellectual disability and most common Additional functions such as modulation of ion chan- single gene cause of autism. Common symptoms of nels have also been proposed [15, 29, 39]. A recent FXS include hyperactivity, repetitive behaviors and meta-analysis estimates the frequencies of individuals cognitive inflexibility, hypersensitivity to sensory stim- with the full mutation FXS allele to be approximately uli and seizures, social and language impairments, in- 1 in 7000 males and 1 in 11,000 females [75]. As an tellectual disability, and increased anxiety. FXS occurs X-linked disorder, the phenotypic expression is quite as a result of Fmr1 gene hypermethylation due to an variable in females because of random inactivation unstable CGG triplet repeat expansion (> 200 repeats) and potential compensation by the normal X chromo- in the 5′ untranslated region of the Fmr1 gene some [108]. Therefore, the prevalence of females who located on the X chromosome, which leads to gene carry the full mutation allele and display the pheno- methylation, inactivation, and resultant loss of fragile typic features of FXS is less than 1 in 11,000 [75]. X mental retardation protein expression (FMRP; The Fmr1 knockout (KO) mouse has been the most [147]). FMRP functions as a translational regulator, widely studied animal model of FXS, but other model systems such as drosophila and Fmr1 KO rats have also contributed valuable information regarding basic bio- * Correspondence: [email protected] 2Department of Psychiatry and Behavioral Neuroscience, University of logical functions of FMRP and mechanisms of patho- Cincinnati, Cincinnati, OH, USA physiology when FMRP is removed. Over the past two 3 ’ Division of Child and Adolescent Psychiatry, Cincinnati Children s Hospital decades, considerable progress has been made in terms Medical Center, 3333 Burnet Avenue MLC 4002, Cincinnati, OH 45229, USA Full list of author information is available at the end of the article of our understanding of symptomology and underlying © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Razak et al. Journal of Neurodevelopmental Disorders (2020) 12:13 Page 2 of 15 neurobiology in humans with FXS and animal models. literature on animal models. The major point made Because of the monogenic origin of the disorder and sig- bythesestudiesisthatmanyofthephenotypicdiffer- nificant overlap with autism, the interest in FXS is at ences between KO and WT mice are developmentally least partly due to the potential for discoveries about transient, suggesting the importance of studying tra- FXS to serve as a paradigm for studies of neurodevelop- jectories. This is all the more relevant if altered brain mental disorders more broadly. responses attributed to an imbalance in excitatory While several potential therapeutics show efficacy in and inhibitory function reflects compensatory plasti- reversing symptoms in the Fmr1 KO mice, they have city, and is not necessarily the primary defect driven failed clinical trials [12]. A number of reasons may by the genetic mutation causing neurodevelopmental explain these failures including the validity of the pre- disorders [4, 102, 136]. clinical models, validity of outcome measures, insuffi- cient stratification of patients, optimality of dose and Developmental regulation of FMRP expression duration, and finally, appropriate treatment age. To FMRP levels are developmentally regulated [46] in the address optimal treatment ages, we focused on devel- mouse brain. Peak FMRP expression during develop- opmental studies of both humans and mice to gener- ment occurs between P3 and P12 in different brain re- ate hypotheses based on published data. FXS is a gions and is reduced in adulthood. This age coincides neurodevelopmental disorder. However, there is little with the onset of sensory stimulation and developmental understanding of whether and how functions of critical period plasticity windows, suggesting an import- FMRP change during development. Only a few studies ant role for FMRP in experience-dependent plasticity. In have systematically examined the roles of this protein the auditory and somatosensory cortex, peak FMRP for normal brain development over time. The devel- levels are seen between P7 and P12. In the hippocampus, opmental trajectories of symptoms and their relation- cerebellum, striatum, and brainstem, the peak FMRP ex- ship to changes in underlying mechanisms are only pression is between P3 and P7. FMRP is expressed beginning to be understood. In human work, only a across cell types in multiple brain regions in adults. handful of studies have examined early childhood de- Whether different cell types in these regions show differ- velopment (age < 5). Only a few longitudinal studies ent developmental profiles of FMRP expression has not with large sample sizes have examined trajectories of been studied. developmental change in FXS phenotypes. There is Such consistently high levels of FMRP expression in little data-driven guidance on optimal time points in early development suggest that the function of FMRP is development for clinical tests of potential therapeu- essential during this time period. FMRP regulates pro- tics. While studies point to early detection of many tein translation by association with a vast array of phenotypes, whether developmental treatment has mRNAs [16, 148]. A well-known phenotype in the Fmr1 longer lasting benefits than adult treatments remains KO mouse brain is increased protein synthesis [93, 109]. unknown. In the following sections, we summarize However, it remains unclear if this phenotype is ob- the animal and human studies that have bearing on served across development and if different brain regions these issues and suggest a number of future experi- have similar changes in protein synthesis across develop- mental approaches that are needed to fill major gaps ment. Most studies examine a single or a few time in our knowledge of FXS development. points in specific brain regions. This issue is further complicated in that different cell types may show dif- Animal Models ferent proteins whose levels are increased or de- Development of mechanisms and phenotypes in animal creased. Recent studies of protein synthesis in models of FXS humans with FXS show that at least some of the pa- There is an extensive literature on preclinical animal tients show decreased protein synthesis [81, 114], op- models of FXS, mostly in mice. Many of these studies posite to that seen in the mouse model. While this have examined phenotypes during early development naturally leads to questions on the utility of the either due to convenience of methodology (e.g., mouse model, this paradox can be potentially resolved in vitro slices are easier to record from in very young if developmental profiles of protein synthesis in FXS mice) or to examine developmental trajectory. Almost in different brain regions are
Load more

Recommended publications
  • Autism Guideline Jan2018.Pdf
    DATE: January 2018 TEXAS CHILDREN’S HOSPITAL EVIDENCE-BASED OUTCOMES CENTER Screening and Diagnosis of Autism Spectrum Disorder (ASD) Evidence-Based Guideline Definition: (1) Autism Spectrum Disorder (ASD) per the DSM-5 Early Signs (2,5,6) encompasses four previously separate disorders that are Social Skills Deficits actually a single condition with different levels of symptom Early years severity in two core domains. These four disorders are the - Do not appear to seek connectedness DSM-IV Autistic Disorder (autism), Asperger’s Disorder, - Contentbeingalone Childhood Disintegrative Disorder, and Pervasive - Ignore parents’ bids for attention Developmental Disorder Not Otherwise Specified (PDD-NOS). - Seldom make eye contact or bid for others’ attention ASD is characterized in early childhood by 1) deficits in social with gestures or vocalizations communication and social interaction and 2) restricted - Deficits in joint attention repetitive behaviors, interests, and activities (RRBs). - Fail to follow a point and/or share expression - Failto point to “comment” Etiology: (2) Although ASDs are heritable neurodevelopmental - Failtorespondtoname conditions with strong genetic underpinnings, their exact - Selective hearing etiology is unknown. The etiology is multifactorial with a variety - Less imitation of genetic and, to a lesser extent, environmental factors Later years playing a role. ASDs can be either idiopathic or associated with - Difficulty sharing the emotional state of others in other diagnoses; most are idiopathic. cooperative
    [Show full text]
  • Retted Q&A: Epilepsy Incidence, Treatments and Research Dr. Eric
    RettEd Q&A: Epilepsy Incidence, Treatments and Research Dr. Eric Marsh, MD PhD, Medical Director Rett Clinic, NHS Investigator, and Basic Scientist, Children’s Hospital of Philadelphia Webcast 09/11/2018 Facilitator: Paige Nues, Rettsyndrome.org Recording link: https://attendee.gotowebinar.com/recording/2303318923907771398 ATTENDEE QUESTIONS RESPONSE REFERENCES AED Questions: Treatments and Triggers I want to know what about relation between Stressors are anecdotally reported to lower the seizure pain, digestive pain, apnea and seizure threshold- these would all be stressful features that could discharge. lower seizure threshold and theoretically increase seizure frequency. Any opinions on fycompa? Very limited experience so far to make a clear judgment. I have tried it in 2 Rett patients without great success, both in patients with very severe seizures. Is there a way to tell the difference between There is a slide in the talk that goes over some features, such a seizure and a “Rett spell” other than EEG? as retained awareness, repetitive nature of the events, that can give some hints as to the nature of the event, but only EEG can definitively discern the difference. My daughter has epilepsy and always has Without knowing all of her clinical details, it is hard for me to seizures. She takes medication Onfi and give recommendations. Depending on seizure types, EEG, Keppra and still have seizures. What should and previous medications tried, I would suggest other meds I do? I need help and ideas thanks. such as Rufinamide, valproic acid or trying the ketogenic diet. Do you see seizures connected to puberty or You can look at Jane Lane’s RettEd about puberty.
    [Show full text]
  • Communication Intervention in Rett Syndrome: a Systematic Review Research in Autism Spectrum Disorders
    Research in Autism Spectrum Disorders 3 (2009) 304–318 Contents lists available at ScienceDirect Research in Autism Spectrum Disorders Journal homepage: http://ees.elsevier.com/RASD/default.asp Review Communication intervention in Rett syndrome: A systematic review Jeff Sigafoos a,*, Vanessa A. Green a, Ralf Schlosser b, Mark F. O’eilly c, Giulio E. Lancioni d, Mandy Rispoli c, Russell Lang c a Victoria University of Wellington, New Zealand b Northeastern University, Boston and Childrens Hospital Boston at Waltham, MA, USA c Meadows Center for Preventing Educational Risk, The University of Texas at Austin, Austin, TX, USA d University of Bari, Bari, Italy ARTICLE INFO ABSTRACT Article history: We reviewed communication intervention studies involving people Received 25 September 2008 with Rett syndrome. Systematic searches of five electronic databases, Accepted 26 September 2008 selected journals, and reference lists identified nine studies meeting the inclusion criteria. These studies were evaluated in terms of: (a) Keywords: participant characteristics, (b) target skills, (c) procedures, (d) main Communication intervention findings, and (e) certainty of evidence. Across the nine studies, Rett syndrome intervention was provided to a total of 31 participants aged 2:7–17:0 Systematic review (years:months). Communication modes included speech, gestures, communication boards, and computer-based systems. Targeted communication functions included imitative speech, requesting, naming/commenting, and various receptive language skills (e.g., respond to requests, answer questions, receptively identify symbols). Intervention approaches included early intensive behavioral inter- vention, systematic instruction, and music therapy. Positive out- comes were reported for 26 (84%) of the 31 participants. However, these outcomes must be interpreted with caution because the certainty of evidence was inconclusive for all but one of the studies.
    [Show full text]
  • Epilepsy and Rett Syndrome
    EPILEPSY AND RETT SYNDROME Liisa Metsähonkala, Pediatric Neurologist Epilepsia-Helsinki, Helsinki University Hospital HUS Helsinki University Hospital RETT Epilepsy -syndrome Epilepsy in Epilepsy in Rett Rett syndrome syndrome Epilepsy may be a major or minor problem for people with Rett syndrome and their families 2 28.9.19 HUS Helsinki University Hospital EPILEPSY AND RETT SYNDROME - Some general aspects of epilepsy - Epilepsy in Rett syndrome (focus on children) - Diversity of epileptic seizures - Diversity of nonepileptic paroxysmal attacks - How to make the diagnosis? - Treatment of epilepsy 3 28.9.19 HUS Helsinki University Hospital WHAT IS EPILEPSY ? International - epilepsy is not one disease but a large group of different League disorders Against Epilepsy - an epileptic seizure is a transient occurrence of signs and/ or symptoms due to abnormal and certain kind of neuronal activity (excessive or synchronous) in the brain - versus nonepileptic symptoms - epilepsy is a disease characterized by an enduring predisposition to generate epileptic seizures – versus seizures that anyone can have because of an acute provoking factor 4 28.9.19 HUS Helsinki University Hospital Seizure types Etiology Focal Generalized Unknown onset onset onset Structural Genetic Epilepsy types Infectious Combined FocalFocal Generalized Unknown Generalized Metabolic & Focal Immune Co-morbidities Unknown Epilepsy Syndromes HUS Helsinki University Hospital Generalized seizures Focal seizures • Originate at some point within • Originate within networks and rapidly
    [Show full text]
  • Whole-Genome Sequencing Reveals Principles of Brain Retrotransposition in Neurodevelopmental Disorders
    Cell Research (2018) 28:187-203. © 2018 IBCB, SIBS, CAS All rights reserved 1001-0602/18 $ 32.00 ORIGINAL ARTICLE www.nature.com/cr Whole-genome sequencing reveals principles of brain retrotransposition in neurodevelopmental disorders Jasmine Jacob-Hirsch1, 2, Eran Eyal1, Binyamin A Knisbacher2, Jonathan Roth3, 5, Karen Cesarkas1, Chen Dor1, Sarit Farage-Barhom1, Vered Kunik1, Amos J Simon1, Moran Gal2, Michal Yalon4, Sharon Moshitch-Moshkovitz1, Rick Tearle6, Shlomi Constantini3, 5, Erez Y Levanon2, Ninette Amariglio1, 2, Gideon Rechavi1, 5 1Cancer Research Center and the Wohl Institute of Translational Medicine, the Chaim Sheba Medical Center, Tel Hashomer, Is- rael; 2Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Israel; 3Department of Pediatric Neurosurgery, Dana Children’s Hospital, Tel Aviv Medical Center, Israel; 4Department of Pediatric Hematology-Oncology, Edmond and Lily Sa- fra Children’s Hospital, The Chaim Sheba Medical Center, Tel Hashomer, Israel; 5Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 6Complete Genomics, 2071 Stierlin Court, Mountain View, CA 94043, USA Neural progenitor cells undergo somatic retrotransposition events, mainly involving L1 elements, which can be potentially deleterious. Here, we analyze the whole genomes of 20 brain samples and 80 non-brain samples, and char- acterized the retrotransposition landscape of patients affected by a variety of neurodevelopmental disorders including Rett syndrome, tuberous sclerosis, ataxia-telangiectasia and autism. We report that the number of retrotranspositions in brain tissues is higher than that observed in non-brain samples and even higher in pathologic vs normal brains. The majority of somatic brain retrotransposons integrate into pre-existing repetitive elements, preferentially A/T rich L1 sequences, resulting in nested insertions.
    [Show full text]
  • Fragile X Syndrome
    AUCD Annual Conference Research Symposium The Rapidly Changing Landscape of Fragile X Elizabeth Berry-Kravis MD PhD Rush University Medical Center Disclosures: EBK has received funding from Neuropharm LTD, Seaside Therapeutics , Novartis and Roche Pharmaceuticals to consult on trial design and conduct clinical trials in FXS Features of Fragile X Syndrome • Physical: large prominent ears, long face, large head, prominent jaw and forehead, midfacial hypoplasia hyperflexible joints, large testis • Intellectual Disability or LD • Behavior problems: hyperactivity distractibility, anxiety, perseveration • Autism: 18-36% AD, 43-67% ASD • Seizures – 15% • Strabismus – 30% • Medical: otitis, sinus, MVP, reflux, sleep apnea, loose stools, allergies FXS Treatment in Clinic - Rush FXS Clinic since 1992 > 450 patients Supportive • Aggressive tx of otitis – • Early intervention tubes/audiology • Intensive speech therapy • Manage sleep apnea – • OT with sensory integration T&A • Inclusion in school as much • Treat sleep dysregulation as possible – melatonin/medications • Educational curriculum, • Yearly eye exams – environment, teaching style patching, surgery, glasses matched to FXS cognitive • Control seizures profile • Orthopedics if needed • Socialization program • Monitor for MVP/heart • Behavior plan • Genetic counseling • Behavior medications for • Discuss reproductive ADD/anxiety options Seizures in Fragile X Syndrome – Recent and Largest Study National Fragile X Survey 1394 FXS full mutation (1090 M, 304 F) 173 (12%) seizures: 154 (14%)
    [Show full text]
  • The Fragile X Syndrome and Infantile Autism: a Prevalence Study Brian Herb Annex Yale University
    Yale University EliScholar – A Digital Platform for Scholarly Publishing at Yale Yale Medicine Thesis Digital Library School of Medicine 1985 The fragile X syndrome and infantile autism: a prevalence study Brian Herb Annex Yale University Follow this and additional works at: http://elischolar.library.yale.edu/ymtdl Recommended Citation Annex, Brian Herb, "The fragile X syndrome and infantile autism: a prevalence study" (1985). Yale Medicine Thesis Digital Library. 2345. http://elischolar.library.yale.edu/ymtdl/2345 This Open Access Thesis is brought to you for free and open access by the School of Medicine at EliScholar – A Digital Platform for Scholarly Publishing at Yale. It has been accepted for inclusion in Yale Medicine Thesis Digital Library by an authorized administrator of EliScholar – A Digital Platform for Scholarly Publishing at Yale. For more information, please contact [email protected]. YALE MEDICAL LIBRARY Permission for photocopying or microfilming of " TU (title of thesis) tr for the purpose of individual scholarly consultation or refer¬ ence is hereby granted by the author. This permission is not to be interpreted as affecting publication of this work, or otherwise placing it in the public domain, and the author re¬ serves all rights of ownership guaranteed under common law protection of unpublished manuscripts. (Signature of author) (Printed name) (Date) Digitized by the Internet Archive in 2017 with funding from The National Endowment for the Humanities and the Arcadia Fund https://archive.org/details/fragilexsyndromeOOanne The Fragile X Syndrome and Infantile Autism A Prevalence Study A Thesis Submitted to the Yale University School of Medicine in Partial Fulfillment of the Requirements for the degree of Doctor of Medicine by Brian Herb Annex 1985 Acknowledgments I would like to express my sincere appreciation to all those who advised and assisted me in this thesis project.
    [Show full text]
  • Epilepsy & Behavior
    Epilepsy & Behavior 66 (2017) 27–33 Contents lists available at ScienceDirect Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh Effectiveness and tolerability of antiepileptic drugs in 104 girls with Rett syndrome Aglaia Vignoli, Miriam Nella Savini ⁎, Maria Sonia Nowbut, Angela Peron, Katherine Turner, Francesca La Briola, Maria Paola Canevini Epilepsy Center, San Paolo Hospital, Department of Health Sciences, Università degli Studi di Milano, Italy article info abstract Article history: Approximately 60–80% of girls with Rett Syndrome (RTT) have epilepsy, which represents one of the most severe Received 29 July 2016 problems clinicians have to deal with, especially when patients are 7–12 years old. Revised 6 October 2016 The aim of this study was to analyze the antiepileptic drugs (AEDs) prescribed in RTT, and to assess their effec- Accepted 8 October 2016 tiveness and tolerability in different age groups from early infancy to adulthood. Available online xxxx We included in this study 104 girls, aged 2–42 years (mean age 13.9 years): 89 had a mutation in MECP2,5in Keywords: CDKL5,2inFOXG1, and the mutational status was unknown in the remaining 8. Rett syndrome Epilepsy was present in 82 patients (79%). Mean age at epilepsy onset was 4.1 years. Epilepsy We divided the girls into 5 groups according to age: b5, 5–9, 10–14, 15–19, 20 years and older. Antiepileptic drugs Valproic acid (VPA) was the most prescribed single therapy in young patients (b15 years), whereas carbamaze- Age-dependency pine (CBZ) was preferred by clinicians in older patients. The most frequently adopted AED combination in the pa- tients younger than 10 years and older than 15 was VPA and lamotrigine (LTG).
    [Show full text]
  • The Fragile X Syndrome–Autism Comorbidity: What Do We Really Know?
    REVIEW ARTICLE published: 16 October 2014 doi: 10.3389/fgene.2014.00355 The fragile X syndrome–autism comorbidity: what do we really know? Leonard Abbeduto 1,2*, Andrea McDuffie 1,2 and Angela John Thurman 1,2 1 MIND Institute, University of California, Davis, Sacramento, CA, USA 2 Department of Psychiatry and Behavioral Sciences, University of California, Davis, Sacramento, CA, USA Edited by: Autism spectrum disorder (ASD) is a common comorbid condition in people with fragile Anne C. Wheeler, Carolina Institute X syndrome (FXS). It has been assumed that ASD symptoms reflect the same underlying for Developmental Disabilities; University of North Carolina at psychological and neurobiological impairments in both FXS and non-syndromic ASD, which Chapel Hill, USA has led to the claim that targeted pharmaceutical treatments that are efficacious for core Reviewed by: symptoms of FXS are likely to be beneficial for non-syndromic ASD as well. In contrast, we Molly Losh, Northwestern present evidence from a variety of sources suggesting that there are important differences University, USA in ASD symptoms, behavioral and psychiatric correlates, and developmental trajectories Dejan Budimirovic, Kennedy Krieger Institute/The Johns Hopkins between individuals with comorbid FXS and ASD and those with non-syndromic ASD. We University, USA also present evidence suggesting that social impairments may not distinguish individuals *Correspondence: with FXS with and without ASD. Finally, we present data that demonstrate that the Leonard Abbeduto, MIND Institute, neurobiological substrates of the behavioral impairments, including those reflecting core University of California, Davis, 2825 ASD symptoms, are different in FXS and non-syndromic ASD. Together, these data suggest 50th Street, Sacramento, CA 95817, USA that there are clinically important differences between FXS and non-syndromic ASD e-mail: leonard.abbeduto@ucdmc.
    [Show full text]
  • Clinical Report—Health Supervision for Children with Fragile X Syndrome
    Guidance for the Clinician in Rendering Pediatric Care Clinical Report—Health Supervision for Children With Fragile X Syndrome Joseph H. Hersh, MD, Robert A. Saul, MD, and COMMITTEE abstract ON GENETICS Fragile X syndrome (an FMR1–related disorder) is the most commonly KEY WORDS fragile X syndrome, FMR1–related conditions, mental inherited form of mental retardation. Early physical recognition is dif- retardation, health guidelines ficult, so boys with developmental delay should be strongly considered ABBREVIATIONS for molecular testing. The characteristic adult phenotype usually does FMR1—fragile X mental retardation 1 gene not develop until the second decade of life. Girls can also be affected CGG—cytosine-guanine-guanine FMRP—fragile X mental retardation 1 protein with developmental delay. Because multiple family members can be mGluR—metabotropic glutamate receptor affected with mental retardation and other conditions (premature POI—primary ovarian insufficiency ovarian failure and tremor/ataxia), family history information is of FXTAS—fragile X–associated tremor/ataxia syndrome critical importance for the diagnosis and management of affected pa- This document is copyrighted and is property of the American tients and their families. This report summarizes issues for fragile X Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American syndrome regarding clinical diagnosis, laboratory diagnosis, genetic Academy of Pediatrics. Any conflicts have been resolved through counseling, related health problems, behavior management, and age- a process approved by the Board of Directors. The American related health supervision guidelines. The diagnosis of fragile X syn- Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of drome not only involves the affected children but also potentially has this publication.
    [Show full text]
  • Fragile X Syndrome
    Fragile X syndrome What is fragile X syndrome? Fragile X syndrome is an X-linked disease of intellectual disability with variable severity.1 Expansions of CGG repeat sequences in the FMR1 gene account for 99% of mutations causing fragile X syndrome. Interpretation of CGG repeat expansion results is based on the following ranges: Negative: <45 repeats; intermediate: 45-54 repeats; premutation: 55-200 repeats; full mutation: >200 repeats. Greater than 99% of males and approximately 50% of females with the full mutation are intellectually disabled.2 What are the symptoms of fragile X syndrome and what treatment is available? Fragile X syndrome is associated with a range of symptoms. Early signs include delayed speech and language skills.1 Intellectual problems vary from mild learning disabilities to severe intellectual disability.3 Behavioral characteristics include autism and hyperactivity.1 Physical features, such as a long face and large or prominent ears, are usually more noticeable in adults than in children, and in males more than females.3 There is no cure for fragile X syndrome. Treatment is supportive and focuses on educational and behavioral support and management of symptoms.2 Individuals with a premutation do not have fragile X syndrome, but may have an increased risk for fragile X-related disorders. Females may have fragile X-associated primary ovarian insufficiency (FXPOI), which can cause infertility or early menopause. Most males with a premutation and some females are at risk for fragile X-associated tremor and ataxia syndrome
    [Show full text]
  • A Functional MRI Study of Facial Emotion-Processing
    G C A T T A C G G C A T genes Article Autism in Fragile X Syndrome; A Functional MRI Study of Facial Emotion-Processing Andrew G. McKechanie 1,2,* , Sonya Campbell 1, Sarah E. A. Eley 1 and Andrew C. Stanfield 1,2 1 The Patrick Wild Centre, The University of Edinburgh, Edinburgh EH10 5HF, UK; [email protected] (S.C.); [email protected] (S.E.A.E.); andrew.stanfi[email protected] (A.C.S.) 2 NHS Lothian, Edinburgh EH1 3EG, UK * Correspondence: [email protected]; Tel.: +44-131-537-6000 Received: 1 November 2019; Accepted: 13 December 2019; Published: 17 December 2019 Abstract: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder, and among those with fragile X syndrome, approximately 1/3rd meet a threshold for an autism spectrum disorder (ASD) diagnosis. Previous functional imaging studies of fragile X syndrome have typically focused on those with fragile X syndrome compared to either neurotypical or autism spectrum disorder control groups. Further, the majority of previous studies have tended to focus on those who are more intellectually able than is typical for fragile X syndrome. In this study, we examine the impact of autistic traits in individuals with fragile X syndrome on a paradigm looking at facial emotion processing. The study included 17 individuals with fragile X syndrome, of whom 10 met criteria for autism as measured by the Autism Diagnostic Observation Schedule (ADOS). Prior to the scan, participants rehearsed on a mock scanner to help acclimatize to the scanner environment and thus allow more severely affected individuals to participate.
    [Show full text]