Intrafamilial variability in fragile X-associated tremor/ataxia syndrome

Both RNA-binding proteins (RBPs) and translation are increasingly implicated in several neurodegenerative diseases, but their specific roles in promoting disease are not yet fully defined. This chapter critically evaluates the evidence that altered translation of specific mRNAs mediated by RNA-binding proteins plays an important role in driving specific neurodegenerative diseases. First, diseases are discussed where a causal role for RNA-binding proteins in disease appears solid, but whether this involves altered translation is less clear. The main foci here are TAR DNA-binding protein (TDP-43) and fused in sarcoma (FUS) in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Subsequently, diseases are presented where altered translation is believed to contribute, but involvement of RNA-binding proteins is less clear. These include Huntington’s and other repeat expansion disorders such as fragile X tremor/ataxia syndrome (FXTAS), where repeat-induced non-AUG-initiated (RAN) translation is a focus. The potential contribution of both canonical and non-canonical RBPs to altered translation in Parkinson’s disease is discussed. The chapter closes by proposing key research frontiers for the field to explore and outlining methodological advances that could help to address them.

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Cerebral Microbleeds in Fragile X–Associated Tremor/Ataxia Syndrome

Movement Disorders ◽

10.1002/mds.28559 ◽

2021 ◽

Author(s):

María Jimena Salcedo‐Arellano ◽

Jun Yi Wang ◽

Yingratana A. McLennan ◽

Mai Doan ◽

Ana Maria Cabal‐Herrera ◽

...

Keyword(s):

Fragile X ◽

Cerebral Microbleeds ◽

Ataxia Syndrome

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Fragile-X-Associated Tremor/Ataxia Syndrome or Alcohol-Induced Cerebellar Degeneration? A Case Report

Case Reports in Neurology ◽

10.1159/000511954 ◽

2020 ◽

Vol 12 (3) ◽

pp. 466-471

Author(s):

Giulia Grigioni ◽

Christian Saleh ◽

Phillip Jaszczuk ◽

Dorothea Wand ◽

Stefanie Wilmes ◽

...

Keyword(s):

Cognitive Impairment ◽

Case Report ◽

Neurodegenerative Disorder ◽

Fragile X ◽

Disease Diagnosis ◽

Cerebellar Degeneration ◽

Gait Ataxia ◽

Intention Tremor ◽

Triplet Expansion ◽

Ataxia Syndrome

Fragile-X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that manifests with intention tremor, progressive gait ataxia, and cognitive impairment. The disease is genetically characterized by a premutation of the <i>FMR1</i>gene on the X-chromosome manifesting with a CGG triplet expansion between 55 and 200. Given the phenotypical variety of this disease, diagnosis is frequently delayed. We present and discuss a male patient whose diagnosis of FXTAS was delayed due to his concomitant alcohol abuse.

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Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

International Journal of Molecular Sciences ◽

10.3390/ijms22168368 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8368

Author(s):

Luis M. Valor ◽

Jorge C. Morales ◽

Irati Hervás-Corpión ◽

Rosario Marín

Keyword(s):

Neurodegenerative Disorder ◽

Late Onset ◽

Fragile X ◽

Endocrine System ◽

Molecular Pathogenesis ◽

Adult Women ◽

Adult Men ◽

Cgg Repeats ◽

Reproductive Impairment ◽

Ataxia Syndrome

Abnormal trinucleotide expansions cause rare disorders that compromise quality of life and, in some cases, lifespan. In particular, the expansions of the CGG-repeats stretch at the 5’-UTR of the Fragile X Mental Retardation 1 (FMR1) gene have pleiotropic effects that lead to a variety of Fragile X-associated syndromes: the neurodevelopmental Fragile X syndrome (FXS) in children, the late-onset neurodegenerative disorder Fragile X-associated tremor-ataxia syndrome (FXTAS) that mainly affects adult men, the Fragile X-associated primary ovarian insufficiency (FXPOI) in adult women, and a variety of psychiatric and affective disorders that are under the term of Fragile X-associated neuropsychiatric disorders (FXAND). In this review, we will describe the pathological mechanisms of the adult “gain-of-function” syndromes that are mainly caused by the toxic actions of CGG RNA and FMRpolyG peptide. There have been intensive attempts to identify reliable peripheral biomarkers to assess disease progression and onset of specific pathological traits. Mitochondrial dysfunction, altered miRNA expression, endocrine system failure, and impairment of the GABAergic transmission are some of the affectations that are susceptible to be tracked using peripheral blood for monitoring of the motor, cognitive, psychiatric and reproductive impairment of the CGG-expansion carriers. We provided some illustrative examples from our own cohort. Understanding the association between molecular pathogenesis and biomarkers dynamics will improve effective prognosis and clinical management of CGG-expansion carriers.

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CGG repeat length correlates with age of onset of motor signs of the fragile X-associated tremor/ataxia syndrome (FXTAS)

American Journal of Medical Genetics Part B Neuropsychiatric Genetics ◽

10.1002/ajmg.b.30482 ◽

2007 ◽

Vol 144B (4) ◽

pp. 566-569 ◽

Cited By ~ 95

Author(s):

Flora Tassone ◽

John Adams ◽

Elizabeth M. Berry-Kravis ◽

Susannah S. Cohen ◽

Alfredo Brusco ◽

...

Keyword(s):

Age Of Onset ◽

Fragile X ◽

Repeat Length ◽

Cgg Repeat ◽

Ataxia Syndrome

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CGG repeats in RNA modulate expression of TDP-43 in mouse and fly models of fragile X tremor ataxia syndrome

Human Molecular Genetics ◽

10.1093/hmg/ddu314 ◽

2014 ◽

Vol 23 (22) ◽

pp. 5906-5915 ◽

Cited By ~ 14

Author(s):

Jocelyn N. Galloway ◽

Chad Shaw ◽

Peng Yu ◽

Deena Parghi ◽

Mickael Poidevin ◽

...

Keyword(s):

Fragile X ◽

Cgg Repeats ◽

Ataxia Syndrome

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ASFMR1splice variant

Neurology Genetics ◽

10.1212/nxg.0000000000000246 ◽

2018 ◽

Vol 4 (4) ◽

pp. e246 ◽

Cited By ~ 6

Author(s):

Padmaja Vittal ◽

Shrikant Pandya ◽

Kevin Sharp ◽

Elizabeth Berry-Kravis ◽

Lili Zhou ◽

...

Keyword(s):

Mental Retardation ◽

Splice Variant ◽

Messenger Rna ◽

Clinical Symptoms ◽

Fragile X ◽

Cgg Repeat ◽

Men And Women ◽

Fragile X Mental Retardation ◽

Repeat Size ◽

Ataxia Syndrome

ObjectiveTo explore the association of a splice variant of theantisense fragile X mental retardation 1(ASFMR1) gene, loss offragile X mental retardation 1(FMR1) AGG interspersions andFMR1CGG repeat size with manifestation, and severity of clinical symptoms of fragile X-associated tremor/ataxia syndrome (FXTAS).MethodsPremutation carriers (PMCs) with FXTAS, without FXTAS, and normal controls (NCs) had a neurologic evaluation and collection of skin and blood samples. Expression ofASFMR1transcript/splice variant 2 (ASFMR1-TV2), nonsplicedASFMR1, totalASFMR1, andFMR1messenger RNA were quantified and compared using analysis of variance. Least absolute shrinkage and selection operator (LASSO) logistic regression and receiver operating characteristic analyses were performed.ResultsPremutation men and women both with and without FXTAS had higherASFMR1-TV2 levels compared with NC men and women (n = 135,135,p< 0.0001), andASFMR1-TV2 had good discriminating power for FXTAS compared with NCs but not for FXTAS from PMC. After adjusting for age, loss of AGG, larger CGG repeat size (in men), and elevatedASFMR1-TV2 level (in women) were strongly associated with FXTAS compared with NC and PMC (combined).ConclusionsThis study found elevated levels ofASFMR1-TV2and loss of AGG interruptions in both men and women with FXTAS. Future studies will be needed to determine whether these variables can provide useful diagnostic or predictive information.

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