Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in older premutation (55–200 CGG repeats) carriers of FMR1. The premutation has excessive levels of FMR1 mRNA that lead to toxicity and mitochondrial dysfunction. The clinical features usually begin in the 60 s with an action or intention tremor followed by cerebellar ataxia, although 20% have only ataxia. MRI features include brain atrophy and white matter disease, especially in the middle cerebellar peduncles, periventricular areas, and splenium of the corpus callosum. Neurocognitive problems include memory and executive function deficits, although 50% of males can develop dementia. Females can be less affected by FXTAS because of a second X chromosome that does not carry the premutation. Approximately 40% of males and 16% of female carriers develop FXTAS. Since the premutation can occur in less than 1 in 200 women and 1 in 400 men, the FXTAS diagnosis should be considered in patients that present with tremor, ataxia, parkinsonian symptoms, neuropathy, and psychiatric problems. If a family history of a fragile X mutation is known, then FMR1 DNA testing is essential in patients with these symptoms.

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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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Delineating the Relationships Between Motor, Cognitive-Executive and Psychiatric Symptoms in Female FMR1 Premutation Carriers

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.742929 ◽

2021 ◽

Vol 12 ◽

Author(s):

Darren R. Hocking ◽

Danuta Z. Loesch ◽

Paige Stimpson ◽

Flora Tassone ◽

Anna Atkinson ◽

...

Keyword(s):

Executive Functioning ◽

Response Inhibition ◽

Rating Scales ◽

Psychiatric Symptoms ◽

Fragile X ◽

Fmr1 Premutation ◽

Symptom Dimensions ◽

Cgg Repeats ◽

Cerebellar Peduncles ◽

Ataxia Syndrome

Introduction: Premutation expansions (55–200 CGG repeats) of the Fragile X Mental Retardation 1 (FMR1) gene on the X chromosome are associated with a range of clinical features. Apart from the most severe - Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) - where the most typical white matter changes affect cerebellar peduncles, more subtle changes may include impairment of executive functioning, affective disorders and/or subtle motor changes. Here we aimed to examine whether performance in selected components of executive functioning is associated with subclinical psychiatric symptoms in non-FXTAS, adult females carrying the FMR1 premutation.Methods and Sample: A total of 47 female premutation carriers (sub-symptomatic for FXTAS) of wide age range (26–77 years; M = 50.3; SD = 10.9) were assessed using standard neuropsychological tests, three motor rating scales and self-reported measures of psychiatric symptoms using the Symptom Checklist-90-Revised (SCL-90-R).Results: After adjusting for age and educational level where appropriate, both non-verbal reasoning and response inhibition as assessed on the Stroop task (i.e., the ability to resolve cognitive interference) were associated with a range of primary psychiatric symptom dimensions, and response inhibition uniquely predicted some primary symptoms and global psychiatric features. Importantly, lower scores (worse performance) in response inhibition were also strongly correlated with higher (worse) scores on standard motor rating scales for tremor-ataxia and for parkinsonism.Conclusion: These results provide evidence for the importance of response inhibition in the manifestation of psychiatric symptoms and subtle tremor-ataxia motor features, suggestive of the presence of early cerebellar changes in female premutation carriers.

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Genetic and Pathological Characteristic Patterns of a Family With Neuronal Intranuclear Inclusion Disease

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlaa142 ◽

2020 ◽

Vol 79 (12) ◽

pp. 1293-1302

Author(s):

Shugang Zhang ◽

Qixing Gong ◽

Di Wu ◽

Yun Tian ◽

Lu Shen ◽

...

Keyword(s):

Neurodegenerative Disorder ◽

Fragile X ◽

Cerebrovascular Diseases ◽

Pathological Examination ◽

Positive Staining ◽

Intranuclear Inclusion ◽

Cgg Repeats ◽

Genetic Features ◽

Neuronal Intranuclear Inclusion ◽

Ataxia Syndrome

Abstract Neuronal intranuclear inclusion disease (NIID) is a rare, progressive neurodegenerative disorder. This study aimed to investigate clinical, imaging, genetic, and dermatopathological characteristics of a family with adult-onset NIID. The proband was a 62-year-old woman with 3 brothers and 2 sisters. Of these, 4 had symptoms of paroxysmal visual field defect, extrapyramidal symptoms, dysautonomia, emotional changes, and cognitive dysfunction. Genetic examination revealed no abnormality related to cerebrovascular diseases. More than 200 CGG repeats of FMR1 gene cause fragile X-associated tremor/ataxia syndrome (FXTAS) whereas repeats of the proband were found 29 times, which excluded FXTAS. Quantitative reverse transcription polymerase chain reaction (PCR) and GC-rich-PCR identified an expanded GGC repeat (with ∼100 repeats) in the 5′ region of NOTCH2NLC in the patient and her 2 younger brothers. Pathological examination found eosinophilic intranuclear inclusions inside adipocytes, fibrocytes, and sweat gland cells. Immunohistochemistry and immunofluorescence staining revealed positive staining for ubiquitin and p62. The detailed pathological and genetic features of this NIID family provide a valuable contribution to the existing knowledge base of this rare disorder.

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Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome

Biochemical Journal ◽

10.1042/bj20091960 ◽

2010 ◽

Vol 429 (3) ◽

pp. 545-552 ◽

Cited By ~ 104

Author(s):

Catherine Ross-Inta ◽

Alicja Omanska-Klusek ◽

Sarah Wong ◽

Cedrick Barrow ◽

Dolores Garcia-Arocena ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Fragile X ◽

Mitochondrial Protein ◽

Additional Treatment ◽

Cgg Repeat ◽

Cgg Repeats ◽

Nitrative Stress ◽

Ataxia Syndrome

FXTAS (fragile X-associated tremor/ataxia syndrome) is a late-onset neurodegenerative disorder that affects individuals who are carriers of premutation expansions (55–200 CGG repeats) in the 5′ untranslated region of the FMR1 (fragile X mental retardation 1) gene. The role of MD (mitochondrial dysfunction) in FXTAS was evaluated in fibroblasts and brain samples from premutation carriers with and without FXTAS symptoms, with a range of CGG repeats. This study resulted in several important conclusions: (i) decreased NAD- and FAD-linked oxygen uptake rates and uncoupling between electron transport and synthesis of ATP were observed in fibroblasts from premutation carriers; (ii) a lower expression of mitochondrial proteins preceded both in age and in CGG repeats the appearance of overt clinical involvement; (iii) the CGG repeat size required for altered mitochondrial protein expression was also smaller than that required to produce brain intranuclear inclusions from individuals with the premutation who died, suggesting that MD is an incipient pathological process occurring in individuals who do not display overt features of FXTAS; and (iv) on the basis of the CGG repeats, MD preceded the increase in oxidative/nitrative stress damage, indicating that the latter is a late event. MD in carriers of small CGG repeats, even when the allele size is not sufficient to produce FXTAS, may predispose them to other disorders (e.g. Parkinson's disease) that are likely to involve MD, and to environmental stressors, which may trigger the development of FXTAS symptoms. Detection of MD is of critical importance to the management of FXTAS, since it opens up additional treatment options for this disorder.

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Dementia in Fragile X-associated Tremor/Ataxia Syndrome

Dementia & Neuropsychologia ◽

10.1590/s1980-57642010dn40100014 ◽

2010 ◽

Vol 4 (1) ◽

pp. 79-83 ◽

Cited By ~ 1

Author(s):

Ricardo Nitrini ◽

Márcia Rúbia R. Gonçalves ◽

Leonardo P. Capelli ◽

Egberto Reis Barbosa ◽

Cláudia Sellitto Porto ◽

...

Keyword(s):

Cognitive Decline ◽

Fragile X ◽

Gait Ataxia ◽

Action Tremor ◽

Fmr1 Premutation ◽

Cerebellar Peduncles ◽

History Of ◽

Diagnostic Hypothesis ◽

Ataxia Syndrome ◽

Lateral Sclerosis

Abstract Fragile X-associated tremor/ataxia syndrome (FXTAS) is a cause of movement disorders and cognitive decline which has probably been underdiagnosed, especially if its prevalence proves similar to those of progressive supranuclear palsy and amyotrophic lateral sclerosis. We report a case of a 74-year-old man who presented with action tremor, gait ataxia and forgetfulness. There was a family history of tremor and dementia, and one of the patient's grandsons was mentally deficient. Neuropsychological evaluation disclosed a frontal network syndrome. MRI showed hyperintensity of both middle cerebellar peduncles, a major diagnostic hallmark of FXTAS. Genetic testing revealed premutation of the FMR1 gene with an expanded (CGG)90 repeat. The diagnosis of FXTAS is important for genetic counseling because the daughters of the affected individuals are at high risk of having offspring with fragile X syndrome. Tremors and cognitive decline should raise the diagnostic hypothesis of FXTAS, which MRI may subsequently reinforce, while the detection of the FMR1 premutation can confirm the condition.

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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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Short antisense oligonucleotides alleviate the pleiotropic toxicity of RNA harboring expanded CGG repeats

Nature Communications ◽

10.1038/s41467-021-21021-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Magdalena Derbis ◽

Emre Kul ◽

Daria Niewiadomska ◽

Michał Sekrecki ◽

Agnieszka Piasecka ◽

...

Keyword(s):

Motor Behavior ◽

Neurodegenerative Disorder ◽

Therapeutic Potential ◽

Cell Damage ◽

Fragile X ◽

Nuclear Proteins ◽

Mirna Biogenesis ◽

Loop Formation ◽

Cgg Repeats ◽

Initiation Of Translation

AbstractFragile X-associated tremor/ataxia syndrome (FXTAS) is an incurable neurodegenerative disorder caused by expansion of CGG repeats in the FMR1 5’UTR. The RNA containing expanded CGG repeats (rCGGexp) causes cell damage by interaction with complementary DNA, forming R-loop structures, sequestration of nuclear proteins involved in RNA metabolism and initiation of translation of polyglycine-containing protein (FMRpolyG), which forms nuclear insoluble inclusions. Here we show the therapeutic potential of short antisense oligonucleotide steric blockers (ASOs) targeting directly the rCGGexp. In nuclei of FXTAS cells ASOs affect R-loop formation and correct miRNA biogenesis and alternative splicing, indicating that nuclear proteins are released from toxic sequestration. In cytoplasm, ASOs significantly decrease the biosynthesis and accumulation of FMRpolyG. Delivery of ASO into a brain of FXTAS mouse model reduces formation of inclusions, improves motor behavior and corrects gene expression profile with marginal signs of toxicity after a few weeks from a treatment.

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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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FMRP Levels in Human Peripheral Blood Leukocytes Correlates with Intellectual Disability

Diagnostics ◽

10.3390/diagnostics11101780 ◽

2021 ◽

Vol 11 (10) ◽

pp. 1780

Author(s):

Mark Roth ◽

Lucienne Ronco ◽

Diego Cadavid ◽

Blythe Durbin-Johnson ◽

Randi J. Hagerman ◽

...

Keyword(s):

Mental Retardation ◽

Intellectual Disability ◽

Peripheral Blood ◽

Fragile X ◽

Repeat Expansion ◽

Repeat Number ◽

Cgg Repeat ◽

Fragile X Mental Retardation ◽

Cgg Repeats ◽

Fmr1 Mrna

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. FXS is an X-linked, neurodevelopmental disorder caused by a CGG trinucleotide repeat expansion in the 5′ untranslated region (UTR) of the Fragile X Mental Retardation gene, FMR1. Greater than 200 CGG repeats results in epigenetic silencing of the gene leading to the deficiency or absence of Fragile X mental retardation protein (FMRP). The loss of FMRP is considered the root cause of FXS. The relationship between neurological function and FMRP expression in peripheral blood mononuclear cells (PBMCs) has not been well established. Assays to detect and measure FMR1 and FMRP have been described; however, none are sufficiently sensitive, precise, or quantitative to properly characterize the relationships between cognitive ability and CGG repeat number, FMR1 mRNA expression, or FMRP expression measured in PBMCs. To address these limitations, two novel immunoassays were developed and optimized, an electro-chemiluminescence immunoassay and a multiparameter flow cytometry assay. Both assays were performed on PMBCs isolated from 27 study participants with FMR1 CGG repeats ranging from normal to full mutation. After correcting for methylation, a significant positive correlation between CGG repeat number and FMR1 mRNA expression levels and a significant negative correlation between FMRP levels and CGG repeat expansion was observed. Importantly, a high positive correlation was observed between intellectual quotient (IQ) and FMRP expression measured in PBMCs.

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