Talk:Fragile X Syndrome

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On this website the Discussion Tab or "talk pages" for a topic has been used for several purposes: References - recent and historic that relates to the topic Additional topic information - currently prepared in draft format Links - to related webpages Topic page - an edit history as used on other Wiki sites Lecture/Practical - student feedback Student Projects - online project discussions. Links: Pubmed Most Recent | Reference Tutorial | Journal Searches Glossary Links Glossary: A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | Numbers | Symbols | Term Link Cite this page: Hill, M.A. (2024, April 30) Embryology Fragile X Syndrome. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Fragile_X_Syndrome

2014

Consistency between research and clinical diagnoses of autism among boys and girls with fragile X syndrome

J Intellect Disabil Res. 2014 Feb 17. doi: 10.1111/jir.12121. [Epub ahead of print]

Klusek J1, Martin GE, Losh M. Author information

Abstract BACKGROUND: Prior research suggests that 60-74% of males and 16-45% of females with fragile X syndrome (FXS) meet criteria for autism spectrum disorder (ASD) in research settings. However, relatively little is known about the rates of clinical diagnoses in FXS and whether such diagnoses are consistent with those performed in a research setting using gold standard diagnostic tools. METHOD: This study explored whether boys and girls with FXS met criteria for ASD in a research setting using the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview-Revised (ADI-R), and then compared these data with the frequency of parent-reported clinical diagnoses. We also examined child and family characteristics as potential diagnostic predictors across settings. Participants included 35 females and 51 males with FXS (mean age: 10 years), who were from Eastern and Midwestern regions of the USA. RESULTS: About half of the children met criteria for ASD on either the ADOS or ADI-R, with ASD occurring three times more frequently in males than females (∼75% vs. ∼25%). In contrast, ∼25% of participants of both genders had received a clinical diagnosis of ASD. While cognitive and language skills predicted diagnostic outcome on the ADOS and ADI-R, these skills did not predict clinical diagnoses. Executive functions predicted clinical diagnoses, but not diagnoses per the ADOS or ADI-R. CONCLUSIONS: ASD in FXS may be under-diagnosed in clinical/educational settings, which raises questions regarding access to ASD-related services. © 2014 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd. KEYWORDS: ADI-R, ADOS, autism, autism spectrum disorder, comorbidity, fragile X syndrome

PMID 24528851

2012

Genetic Counseling and Testing for FMR1 Gene Mutations: Practice Guidelines of the National Society of Genetic Counselors

J Genet Couns. 2012 Jul 14. [Epub ahead of print]

Finucane B, Abrams L, Cronister A, Archibald AD, Bennett RL, McConkie-Rosell A. Source

Genetic Services at Elwyn, Elwyn, PA, USA, brenda_finucane@elwyn.org.

Abstract

Fragile X syndrome (FXS) is one of several clinical disorders associated with mutations in the X-linked Fragile X Mental Retardation-1 (FMR1) gene. With evolving knowledge about the phenotypic consequences of FMR1 transcription and translation, sharp clinical distinctions between pre- and full mutations have become more fluid. The complexity of the issues surrounding genetic testing and management of FMR1-associated disorders has increased; and several aspects of genetic counseling for FMR1 mutations remain challenging, including risk assessment for intermediate alleles and the widely variable clinical prognosis for females with full mutations. FMR1 mutation testing is increasingly being offered to women without known risk factors, and newborn screening for FXS is underway in research-based pilot studies. Each diagnosis of an FMR1 mutation has far-reaching clinical and reproductive implications for the extended family. The interest in large-scale population screening is likely to increase due to patient demand and awareness, and as targeted pharmaceutical treatments for FXS become available over the next decade. Given these developments and the likelihood of more widespread screening, genetic counselors across a variety of healthcare settings will increasingly be called upon to address complex diagnostic, psychosocial, and management issues related to FMR1 gene mutations. The following guidelines are intended to assist genetic counselors in providing accurate risk assessment and appropriate educational and supportive counseling for individuals with positive test results and families affected by FMR1-associated disorders.

PMID 22797890

Mechanism of Repeat-Associated MicroRNAs in Fragile X Syndrome

Neural Plast. 2012;2012:104796. Epub 2012 Jun 20.

Kelley K, Chang SJ, Lin SL. Source

Division of Regenerative Medicine, WJWU & LYNN Institute for Stem Cell Research, 12145 Mora Drive, STE6, Santa Fe Springs, CA 90670, USA.

Abstract

The majority of the human genome is comprised of non-coding DNA, which frequently contains redundant microsatellite-like trinucleotide repeats. Many of these trinucleotide repeats are involved in triplet repeat expansion diseases (TREDs) such as fragile X syndrome (FXS). After transcription, the trinucleotide repeats can fold into RNA hairpins and are further processed by Dicer endoribonuclases to form microRNA (miRNA)-like molecules that are capable of triggering targeted gene-silencing effects in the TREDs. However, the function of these repeat-associated miRNAs (ramRNAs) is unclear. To solve this question, we identified the first native ramRNA in FXS and successfully developed a transgenic zebrafish model for studying its function. Our studies showed that ramRNA-induced DNA methylation of the FMR1 5'-UTR CGG trinucleotide repeat expansion is responsible for both pathological and neurocognitive characteristics linked to the transcriptional FMR1 gene inactivation and the deficiency of its protein product FMRP. FMRP deficiency often causes synapse deformity in the neurons essential for cognition and memory activities, while FMR1 inactivation augments metabotropic glutamate receptor (mGluR)-activated long-term depression (LTD), leading to abnormal neuronal responses in FXS. Using this novel animal model, we may further dissect the etiological mechanisms of TREDs, with the hope of providing insights into new means for therapeutic intervention.

PMID 22779005

http://www.hindawi.com/journals/np/2012/104796/

Synaptic NMDA receptor-mediated currents in anterior piriform cortex are reduced in the adult fragile X mouse

Neuroscience. 2012 Jun 28. [Epub ahead of print]

Gocel J, Larson J. Source Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois, Chicago, IL 60612, United States.

Abstract

Fragile X syndrome is a neurodevelopmental condition caused by the transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene. The Fmr1-KO mouse exhibits age-dependent deficits in long term potentiation (LTP) at association (ASSN) synapses in anterior piriform cortex (APC). To investigate the mechanisms for this, whole-cell voltage-clamp recordings of ASSN stimulation-evoked synaptic currents were made in APC of slices from adult Fmr1-KO and wild-type (WT) mice, using the competitive N-methyl-d-aspartate (NMDA) receptor antagonist, CPP, to distinguish currents mediated by NMDA and AMPA receptors. NMDA/AMPA current ratios were lower in Fmr1-KO mice than in WT mice, at ages ranging from 3-18months. Since amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs) mediated by AMPA receptors were no different in Fmr1-KO and WT mice at these ages, the results suggest that NMDA receptor-mediated currents are selectively reduced in Fmr1-KO mice. Analyses of voltage-dependence and decay kinetics of NMDA receptor-mediated currents did not reveal differences between Fmr1-KO and WT mice, suggesting that reduced NMDA currents in Fmr1-KO mice are due to fewer synaptic receptors rather than differences in receptor subunit composition. Reduced NMDA receptor signaling may help to explain the LTP deficit seen at APC ASSN synapses in Fmr1-KO mice at 6-18months of age, but does not explain normal LTP at these synapses in mice 3-6months old. Evoked currents and mEPSCs were also examined in senescent Fmr1-KO and WT mice at 24-28months of age. NMDA/AMPA ratios were similar in senescent WT and Fmr1-KO mice, due to a decrease in the ratio in the WT mice, without significant change in AMPA receptor-mediated mEPSCs. Copyright © 2012. Published by Elsevier Ltd.

PMID 22750206

2011

Repeat associated non-ATG translation initiation: one DNA, two transcripts, seven reading frames, potentially nine toxic entities!

PLoS Genet. 2011 Mar;7(3):e1002018. Epub 2011 Mar 10.

Pearson CE. Source Program of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. cepearson.sickkids@gmail.com

Abstract

Diseases associated with unstable repetitive elements in the DNA, RNA, and amino acids have consistently revealed scientific surprises. Most diseases are caused by expansions of trinucleotide repeats, which ultimately lead to diseases like Huntington's disease, myotonic dystrophy, fragile X syndrome, and a series of spinocerebellar ataxias. These repeat mutations are dynamic, changing through generations and within an individual, and the repeats can be bi-directionally transcribed. Unsuspected modes of pathogenesis involve aberrant loss of protein expression; aberrant over-expression of non-mutant proteins; toxic-gain-of-protein function through expanded polyglutamine tracts that are encoded by expanded CAG tracts; and RNA-toxic-gain-of-function caused by transcripts harboring expanded CUG, CAG, or CGG tracts. A recent advance reveals that RNA transcripts with expanded CAG repeats can be translated in the complete absence of a starting ATG, and this Repeat Associated Non-ATG translation (RAN-translation) occurs across expanded CAG repeats in all reading frames (CAG, AGC, and GCA) to produce homopolymeric proteins of long polyglutamine, polyserine, and polyalanine tracts. Expanded CTG tracts expressing CUG transcripts also show RAN-translation occurring in all three frames (CUG, UGC, and GCU), to produce polyleucine, polycysteine, and polyalanine. These RAN-translation products can be toxic. Thus, one unstable (CAG)•(CTG) DNA can produce two expanded repeat transcripts and homopolymeric proteins with reading frames (the AUG-directed polyGln and six RAN-translation proteins), yielding a total of potentially nine toxic entities. The occurrence of RAN-translation in patient tissues expands our horizons of modes of disease pathogenesis. Moreover, since RAN-translation counters the canonical requirements of translation initiation, many new questions are now posed that must be addressed. This review covers RAN-translation and some of the pertinent questions.

PMID 21423665

2009

A Mouse Model of the Human Fragile X Syndrome I304N Mutation

PLoS Genet. 2009 Dec;5(12):e1000758. Epub 2009 Dec 11.

Zang JB, Nosyreva ED, Spencer CM, Volk LJ, Musunuru K, Zhong R, Stone EF, Yuva-Paylor LA, Huber KM, Paylor R, Darnell JC, Darnell RB. Source Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York, USA.

Abstract

The mental retardation, autistic features, and behavioral abnormalities characteristic of the Fragile X mental retardation syndrome result from the loss of function of the RNA-binding protein FMRP. The disease is usually caused by a triplet repeat expansion in the 5'UTR of the FMR1 gene. This leads to loss of function through transcriptional gene silencing, pointing to a key function for FMRP, but precluding genetic identification of critical activities within the protein. Moreover, antisense transcripts (FMR4, ASFMR1) in the same locus have been reported to be silenced by the repeat expansion. Missense mutations offer one means of confirming a central role for FMRP in the disease, but to date, only a single such patient has been described. This patient harbors an isoleucine to asparagine mutation (I304N) in the second FMRP KH-type RNA-binding domain, however, this single case report was complicated because the patient harbored a superimposed familial liver disease. To address these issues, we have generated a new Fragile X Syndrome mouse model in which the endogenous Fmr1 gene harbors the I304N mutation. These mice phenocopy the symptoms of Fragile X Syndrome in the existing Fmr1-null mouse, as assessed by testicular size, behavioral phenotyping, and electrophysiological assays of synaptic plasticity. I304N FMRP retains some functions, but has specifically lost RNA binding and polyribosome association; moreover, levels of the mutant protein are markedly reduced in the brain specifically at a time when synapses are forming postnatally. These data suggest that loss of FMRP function, particularly in KH2-mediated RNA binding and in synaptic plasticity, play critical roles in pathogenesis of the Fragile X Syndrome and establish a new model for studying the disorder. PMID: 20011099

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779495

http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000758