The Fragile X Family of Disorders: A Model for Autism and Targeted Treatments

doi:10.2174/157339608783565770

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The Fragile X Family of Disorders: A Model for Autism and Targeted Treatments

Journal Article•DOI•

The Fragile X Family of Disorders: A Model for Autism and Targeted Treatments

Randi J Hagerman, Susan M. Rivera¹, Susan M. Rivera², Paul J. Hagerman¹•Institutions (2)

University of California, Davis¹, University of California, Berkeley²

31 Jan 2008-Current Pediatric Reviews (Bentham Science Publishers B.V.)-Vol. 4, Iss: 1, pp 40-52

TL;DR: The FMR1 gene is causative of a common (autism) phenotype via two entirely different pathogenic mechanisms, RNA toxicity and gene silencing, a paradigm for understanding gene-brain relationships and the means by which diverse genetic mecha- nisms can give rise to a common behavioral phenotype.

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Abstract: CGG-repeat expansion mutations of the fragile X mental retardation 1 (FMR1) gene are the leading known cause of autism and autism spectrum disorders (ASD). Full mutation expansions (>200 CGG repeats) of the gene are gen- erally silenced, resulting in absence of the FMR1 protein and fragile X syndrome. By contrast, smaller expansions in the premutation range (55-200 CGG repeats) result in excess gene activity and RNA toxicity, which is responsible for the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), and likely additional cases of devel- opmental delay and autism. Thus, the FMR1 gene is causative of a common (autism) phenotype via two entirely different pathogenic mechanisms, RNA toxicity and gene silencing. The study of this gene and its pathogenic mechanisms there- fore represents a paradigm for understanding gene-brain relationships and the means by which diverse genetic mecha- nisms can give rise to a common behavioral phenotype.

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Journal Article•DOI•

Advances in the treatment of fragile x Syndrome

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Randi J Hagerman¹, Elizabeth Berry-Kravis², Walter E. Kaufmann³, Michele Y. Ono¹, Nicole Tartaglia⁴, Ave M. Lachiewicz⁵, Rebecca Kronk⁶, Carol Delahunty⁷, David R Hessl, Jeannie Visootsak⁸, Jonathan Picker⁹, Louise W. Gane¹, Michael Tranfaglia - Show less +9 more•Institutions (9)

University of California, Davis¹, Rush University Medical Center², Johns Hopkins University³, University of Colorado Denver⁴, Duke University⁵, University of Pittsburgh⁶, Boston Children's Hospital⁷, Emory University⁸, Harvard University⁹

01 Jan 2009-Pediatrics

TL;DR: The FMR1 mutations can cause a variety of disabilities, including cognitive deficits, attention-deficit/hyperactivity disorder, autism, and other socioemotional problems, in individuals with the full mutation form (fragile X syndrome).

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Abstract: The FMR1 mutations can cause a variety of disabilities, including cognitive deficits, attention-deficit/hyperactivity disorder, autism, and other socioemotional problems, in individuals with the full mutation form (fragile X syndrome) and distinct difficulties, including primary ovarian insufficiency, neuropathy and the fragile X-associated tremor/ataxia syndrome, in some older premutation carriers. Therefore, multigenerational family involvement is commonly encountered when a proband is identified with a FMR1 mutation. Studies of metabotropic glutamate receptor 5 pathway antagonists in animal models of fragile X syndrome have demonstrated benefits in reducing seizures, improving behavior, and enhancing cognition. Trials of metabotropic glutamate receptor 5 antagonists are beginning with individuals with fragile X syndrome. Targeted treatments, medical and behavioral interventions, genetic counseling, and family supports are reviewed here.

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525 citations

Journal Article•DOI•

Autism spectrum disorders—A genetics review

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Judith H. Miles¹•Institutions (1)

University of Missouri¹

01 Apr 2011-Genetics in Medicine

TL;DR: The current emphasis on deciphering autism spectrum disorders has accelerated the field of neuroscience and demonstrated the necessity of multidisciplinary research that must include clinical geneticists both in the clinics and in the design and implementation of basic, clinical, and translational research.

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519 citations

Journal Article•DOI•

The fragile X prevalence paradox

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Paul J. Hagerman¹•Institutions (1)

University of California, Davis¹

01 Aug 2008-Journal of Medical Genetics

TL;DR: Although the numbers of FM alleles in the two studies are too small to attach significance to the difference in frequencies, the trend is consistent with the exclusion of individuals with a family history of FXS, and aspects of this “paradox” are exemplified by two important screening studies of Israeli women.

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Abstract: Although fragile X syndrome (FXS; OMIM 300624) is generally regarded as the most common inherited form of cognitive impairment,1–3 there is little consensus as to its prevalence in the general population or to sex-specific differences in prevalence. Estimates of FXS prevalence (∼1/4000–1/8000) that are based on population projections from cohorts of children with special education needs (SEN) generally underestimate the extent of clinical involvement (for a comprehensive summary, see Song et al 4), as many individuals affected by the behavioural, emotional and/or learning disabilities of FXS have IQs in the normal or borderline range.5 6 The latter may not be included in cohorts that use cognitive impairment as an inclusion criterion, a problem that is particularly marked for girls, with the majority having IQs within the normal range.7 A second difficulty with population studies is the tendency to conflate disease prevalence (projections from SEN cohorts) with allele/carrier frequencies within the general population, as prevalence estimates will only approach carrier frequencies for complete penetrance. Thus, seemingly paradoxical results among studies of prevalence may reflect the effects of selection bias, conflation and differing defining criteria for FXS across studies. Aspects of this “paradox” are exemplified by two important screening studies of Israeli women. Using the same cut-off point (55 CGG repeats) for premutation (PM) carriers, Toledano-Alhadef et al 8 found a higher frequency of carriers (127/14 334 = 1/113) than did Pesso et al 9 (62/9459 = 1/152), despite the fact that Pesso et al reported a higher frequency for full mutation (FM) alleles (4 FM carriers; 1/2365) than did Toledano-Alhadef et al (3 FM carriers; 1/4778). Although the numbers of FM alleles in the two studies are too small to attach significance to the difference in frequencies, the trend is consistent with the exclusion of individuals with a family history of …

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330 citations

Journal Article•DOI•

Fragile X: leading the way for targeted treatments in autism.

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Lulu W. Wang¹, Elizabeth Berry-Kravis², Randi J Hagerman¹•Institutions (2)

University of California, Davis¹, Rush University Medical Center²

01 Jul 2010-Neurotherapeutics

TL;DR: Two different mutations in the FMR1 gene may lead to autism, with the full mutation leading to hypermethylation and transcriptional silencing of FMR 1, resulting in absence or deficiency of the protein product, FMRP, and the premutation (55–200 CGG repeats) may also contribute to the mechanism of autism.

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167 citations

Cites background from "The Fragile X Family of Disorders: ..."

...Instead of these classic Prader-Willi chromosome 15 abnormalities, however, individuals with the Prader-Willi phenotype of FXS have lowered expression of the cytoplasmic interacting FMR1 protein 1 gene (CYFIP1, located in the 15q deletion region of Prader-Willi syndrome), relative both to normal control subjects and to subjects with FXS but without the Prader-Willi phenotype.61 In addition, approximately 70% of those with the Prader-Willi phenotype also have ASD....
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...%) have some symptoms of autism, such as poor eye contact, unusual hand mannerisms, perseverative speech, and other features seen in autism, even though they may not meet the full criteria for an ASD.52-56 In females with FXS, however, the percentage of ASD is lower, at 20–23%.42,57 The fragile X mutation is the leading single-gene mutation known to cause autism and ASD.1 Of those already diagnosed with autism, 3–6% also have FXS.1-3,58-60 Although we do not know why some individuals with FXS also have autism and others do not, it has been suggested there may be secondary gene effects additive to the FMR1 mutation that lead to the development of autism.12 One example of a secondary genetic effect that makes autism more common in FXS is the Prader-Willi phenotype of FXS. Individuals with this phenotype have FXS in addition to hyperphagia, obesity, and a lack of satiation after meals, similar to features seen in Prader- Willi syndrome....
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...The fragile X mutation is the leading single-gene mutation known to cause autism and ASD.(1) Of those already diagnosed with autism, 3–6% also have FXS....
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...Macrocephaly is another common phenotype seen both in children with FXS and in those with idiopathic autism.66,67 The rate of increase in head circumference appears to be faster in children with FXS and ASD than in children with FXS without ASD.66 PTEN, a gene involved in regulation of cell growth, has been hypothesized to be involved in this process, and a mutation in PTEN was found in 18% of individuals with idiopathic autism and macrocephaly.68 The lack of FMRP in FXS also downregulates PTEN expression, and this is thought to contribute to the etiology of macrocephaly in FXS (J.C. Darnell, personal communication)....
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...From studies using these tools, the prevalence of autism in individuals with FXS is reported to be approximately 18%–36%.12,13,42,51 The entire spectrum of autism is represented in children with FXS. Approximately 43%–67% of individuals with FXS have an element of ASD.13,42,51 An even larger percentage of individuals with FXS (i.e., 50%–90...
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Journal Article•DOI•

A review of fragile X premutation disorders: expanding the psychiatric perspective.

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James A. Bourgeois¹, Sarah M. Coffey¹, Susan M. Rivera¹, David R Hessl, Louise W. Gane¹, Flora Tassone¹, Claudia M. Greco¹, Brenda Finucane, Lawrence M. Nelson², Elizabeth Berry-Kravis³, Jim Grigsby⁴, Paul J. Hagerman¹, Randi J Hagerman - Show less +9 more•Institutions (4)

University of California, Davis¹, National Institutes of Health², Rush University Medical Center³, University of Colorado Denver⁴

05 May 2009-The Journal of Clinical Psychiatry

TL;DR: Fragile X-associated psychiatric manifestations serve as a useful model for a molecular genesis of neuropsychiatric illness and genetic testing is confirmatory of the FMR1 premutation and is an essential component of the clinical evaluation.

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Abstract: Objective: Fragile X premutation conditions are associated with a significant degree of psychopathology and thus are of interest to the psychiatrist. Remarkable advances at the molecular level have enhanced our understanding of fragile X premutation disorders.

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167 citations

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Two cortical visual systems

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Leslie G. Ungerleider

01 Jan 1982

4,832 citations

Journal Article•DOI•

Neuroglial activation and neuroinflammation in the brain of patients with autism

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Diana L. Vargas¹, Caterina Nascimbene¹, Caterina Nascimbene², Chitra Krishnan¹, Andrew W. Zimmerman¹, Andrew W. Zimmerman³, Carlos A. Pardo - Show less +3 more•Institutions (3)

Johns Hopkins University School of Medicine¹, University of Milan², Kennedy Krieger Institute³

01 Jan 2005-Annals of Neurology

TL;DR: It is indicated that innate neuroimmune reactions play a pathogenic role in an undefined proportion of autistic patients, suggesting that future therapies might involve modifying neuroglial responses in the brain.

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Abstract: Autism is a neurodevelopmental disorder characterized by impaired communication and social interaction and may be accompanied by mental retardation and epilepsy. Its cause remains unknown, despite evidence that genetic, environmental, and immunological factors may play a role in its pathogenesis. To investigate whether immune-mediated mechanisms are involved in the pathogenesis of autism, we used immunocytochemistry, cytokine protein arrays, and enzyme-linked immunosorbent assays to study brain tissues and cerebrospinal fluid (CSF) from autistic patients and determined the magnitude of neuroglial and inflammatory reactions and their cytokine expression profiles. Brain tissues from cerebellum, midfrontal, and cingulate gyrus obtained at autopsy from 11 patients with autism were used for morphological studies. Fresh-frozen tissues available from seven patients and CSF from six living autistic patients were used for cytokine protein profiling. We demonstrate an active neuroinflammatory process in the cerebral cortex, white matter, and notably in cerebellum of autistic patients. Immunocytochemical studies showed marked activation of microglia and astroglia, and cytokine profiling indicated that macrophage chemoattractant protein (MCP)-1 and tumor growth factor-beta1, derived from neuroglia, were the most prevalent cytokines in brain tissues. CSF showed a unique proinflammatory profile of cytokines, including a marked increase in MCP-1. Our findings indicate that innate neuroimmune reactions play a pathogenic role in an undefined proportion of autistic patients, suggesting that future therapies might involve modifying neuroglial responses in the brain.

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1,845 citations

"The Fragile X Family of Disorders: ..." refers background in this paper

...Recent studies in autism also demonstrate enhanced inflammation in the brain that likely interferes with CNS connectivity leading to autism [166]....
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Journal Article•DOI•

The mGluR theory of fragile X mental retardation

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Mark F. Bear¹, Kimberly M. Huber², Stephen T. Warren³•Institutions (3)

Massachusetts Institute of Technology¹, University of Texas Southwestern Medical Center², Emory University³

01 Jul 2004-Trends in Neurosciences

TL;DR: Loss of fragile X mental retardation protein (FMRP), the defect responsible for fragile X syndrome in humans, increases LTD in mouse hippocampus, consistent with the growing evidence that FMRP normally functions as a repressor of translation of specific mRNAs.

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1,512 citations

"The Fragile X Family of Disorders: ..." refers background in this paper

...The enhanced LTD was mediated by the mGluR5 pathway and FMRP normally inhibits the translation of proteins that internalize the AMPA receptors at the synapse, leading to LTD or weakening of synaptic connections [10]....
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...This phenomenon is thought to be responsible for the mental impairment in FXS [10]....
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...Because of our expanding knowledge of the molecular and neurobiological changes that occur in FXS, new targeted treatments are being developed that may reverse the cognitive and behavioral changes associated with the disorder [10, 11]....
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...Neurobiological studies in the animal models of FXS have demonstrated both glutamate and GABA system abnormalities that are hypothesized to be related to the behavioral and neurological problems in humans with FXS [10, 11, 103-105]....
[...]

Journal Article•DOI•

Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.

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Christelle M. Durand¹, Catalina Betancur², Tobias M. Boeckers³, Juergen Bockmann³, Pauline Chaste¹, Fabien Fauchereau¹, Gudrun Nygren⁴, Maria Råstam⁴, I. Carina Gillberg⁴, Henrik Anckarsäter⁴, Eili Sponheim⁵, Hany Goubran-Botros¹, Richard Delorme¹, Nadia Chabane, Marie-Christine Mouren-Simeoni, Philippe de Mas, Eric Bieth, Bernadette Rogé⁶, Delphine Héron, Lydie Burglen, Christopher Gillberg⁴, Marion Leboyer², Thomas Bourgeron¹ - Show less +19 more•Institutions (6)

Pasteur Institute¹, University of Paris², University of Ulm³, University of Gothenburg⁴, University of Oslo⁵, University of Toulouse⁶

01 Jan 2007-Nature Genetics

TL;DR: It is reported that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders.

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Abstract: SHANK3 (also known as ProSAP2) regulates the structural organization of dendritic spines and is a binding partner of neuroligins; genes encoding neuroligins are mutated in autism and Asperger syndrome. Here, we report that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders. These mutations concern only a small number of individuals, but they shed light on one gene dosage-sensitive synaptic pathway that is involved in autism spectrum disorders.

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1,410 citations

"The Fragile X Family of Disorders: ..." refers background in this paper

...SHANK3 encodes a synaptic protein that is critical for proper brain development; point mutations of this gene cause ASD [21, 24]....
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Journal Article•DOI•

Altered synaptic plasticity in a mouse model of fragile X mental retardation

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Kimberly M. Huber¹, Kimberly M. Huber², Sean M. Gallagher², Stephen T. Warren³, Mark F. Bear² - Show less +1 more•Institutions (3)

University of Texas Southwestern Medical Center¹, Brown University², Emory University³

28 May 2002-Proceedings of the National Academy of Sciences of the United States of America

TL;DR: It is shown that a form of protein synthesis-dependent synaptic plasticity, long-term depression triggered by activation of metabotropic glutamate receptors, is selectively enhanced in the hippocampus of mutant mice lacking FMRP.

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Abstract: Fragile X syndrome, the most common inherited form of human mental retardation, is caused by mutations of the Fmr1 gene that encodes the fragile X mental retardation protein (FMRP). Biochemical evidence indicates that FMRP binds a subset of mRNAs and acts as a regulator of translation. However, the consequences of FMRP loss on neuronal function in mammals remain unknown. Here we show that a form of protein synthesis-dependent synaptic plasticity, long-term depression triggered by activation of metabotropic glutamate receptors, is selectively enhanced in the hippocampus of mutant mice lacking FMRP. This finding indicates that FMRP plays an important functional role in regulating activity-dependent synaptic plasticity in the brain and suggests new therapeutic approaches for fragile X syndrome.

...read moreread less

1,267 citations

"The Fragile X Family of Disorders: ..." refers background in this paper

...[103] demonstrated enhanced long term depression (LTD) in the hippocampus of the KO mouse model of FXS....
[...]
...Neurobiological studies in the animal models of FXS have demonstrated both glutamate and GABA system abnormalities that are hypothesized to be related to the behavioral and neurological problems in humans with FXS [10, 11, 103-105]....
[...]