scholarly journals Plasma metabolic profile delineates roles for neurodegeneration, pro-inflammatory damage and mitochondrial dysfunction in the FMR1 premutation

2016 ◽  
Vol 473 (21) ◽  
pp. 3871-3888 ◽  
Author(s):  
Cecilia Giulivi ◽  
Eleonora Napoli ◽  
Flora Tassone ◽  
Julian Halmai ◽  
Randi Hagerman
Keyword(s):  
Mitochondrial Dysfunction ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Fragile X ◽  
Neurological Diseases ◽  
Plasma Metabolites ◽  
Metabolic Pattern ◽  
Fmr1 Premutation ◽  
Cgg Repeats ◽  
Lactate Levels

Carriers of premutation CGG expansions in the fragile X mental retardation 1 (FMR1) gene are at higher risk of developing a late-onset neurodegenerative disorder named Fragile X-associated tremor ataxia syndrome (FXTAS). Given that mitochondrial dysfunction has been identified in fibroblasts, PBMC and brain samples from carriers as well as in animal models of the premutation and that mitochondria are at the center of intermediary metabolism, the aim of the present study was to provide a complete view of the metabolic pattern by uncovering plasma metabolic perturbations in premutation carriers. To this end, metabolic profiles were evaluated in plasma from 23 premutation individuals and 16 age- and sex-matched controls. Among the affected pathways, mitochondrial dysfunction was associated with a Warburg-like shift with increases in lactate levels and altered Krebs' intermediates, neurotransmitters, markers of neurodegeneration and increases in oxidative stress-mediated damage to biomolecules. The number of CGG repeats correlated with a subset of plasma metabolites, which are implicated not only in mitochondrial disorders but also in other neurological diseases, such as Parkinson's, Alzheimer's and Huntington's diseases. For the first time, the identified pathways shed light on disease mechanisms contributing to morbidity of the premutation, with the potential of assessing metabolites in longitudinal studies as indicators of morbidity or disease progression, especially at the early preclinical stages.

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

2010 ◽  
Vol 429 (3) ◽  
pp. 545-552 ◽  
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.

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

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.

Men with FMR1 premutation alleles of less than 71 CGG repeats have low risk of being affected with fragile X-associated tremor/ataxia syndrome (FXTAS)

2021 ◽  
pp. jmedgenet-2021-107758
Author(s):  
Ellenore M Martin ◽  
Ying Zhu ◽  
Claudine M Kraan ◽  
Kishore R Kumar ◽  
David E Godler ◽  
...  
Keyword(s):  
Late Onset ◽  
Population Control ◽  
Fragile X ◽  
Control Group ◽  
Intention Tremor ◽  
Fmr1 Premutation ◽  
Onset Condition ◽  
Cgg Repeats ◽  
Ataxia Syndrome ◽  
Population Control Group

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset condition characterised by cerebellar ataxia and intention tremor, usually found in individuals with FMR1 premutation alleles (PM—CGG expansion of 55–199 repeats). Population studies estimate that between 1 in 250 and 1 in 1600 men have a PM, with up to 45% of these men suggested to develop FXTAS by age 80. We used a Bayesian approach to compare the probability of finding a specific PM genotype in an ataxia population to a population control group and found an estimated penetrance of <1% (0.031%; CI 0.007% to 0.141%) for men with ≤70 CGGs. These findings suggest that men with a PM of ≤70 CGGs, who comprise the vast majority of those with a PM, have a much lower risk of being affected with FXTAS than previously suggested. This is an issue of growing importance for accurate genetic counselling, as those with a PM of ≤70 CGGs are increasingly detected through community carrier screening or neurodevelopmental assessment programmes.

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

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.

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

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.

scholarly journals Metabolomic Biomarkers Are Associated With Area of the Pons in Fragile X Premutation Carriers at Risk for Developing FXTAS

2021 ◽  
Vol 12 ◽  
Author(s):  
Marwa Zafarullah ◽  
Blythe Durbin-Johnson ◽  
Emily S. Fourie ◽  
David R. Hessl ◽  
Susan M. Rivera ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Fragile X ◽  
Brain Area ◽  
Ultra Performance Liquid Chromatography ◽  
Primary Objective ◽  
Pcr Analysis ◽  
Mass Analyzer ◽  
Cgg Repeat ◽  
Cgg Repeats ◽  
Metabolic Signatures

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late adult-onset neurodegenerative disorder that affects movement and cognition in male and female carriers of a premutation allele (55–200 CGG repeats; PM) in the fragile X mental retardation (FMR1) gene. It is currently unknown how the observed brain changes are associated with metabolic signatures in individuals who develop the disorder over time. The primary objective of this study was to investigate the correlation between longitudinal changes in the brain (area of the pons, midbrain, and MCP width) and the changes in the expression level of metabolic biomarkers of early diagnosis and progression of FXTAS in PM who, as part of an ongoing longitudinal study, emerged into two distinct categories. These included those who developed symptoms of FXTAS (converters, CON) at subsequent visits and those who did not meet the criteria of diagnosis (non-converters, NCON) and were compared to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern Blot and PCR analysis. Magnetic Resonance Imaging (MRIs) acquisition was obtained on a 3T Siemens Trio scanner and metabolomic profile was obtained by ultra-performance liquid chromatography, accurate mass spectrometer, and an Orbitrap mass analyzer. Our findings indicate that differential metabolite levels are linked with the area of the pons between healthy control and premutation groups. More specifically, we observed a significant association of ceramides and mannonate metabolites with a decreased area of the pons, both at visit 1 (V1) and visit 2 (V2) only in the CON as compared to the NCON group suggesting their potential role in the development of the disorder. In addition, we found a significant correlation of these metabolic signatures with the FXTAS stage at V2 indicating their contribution to the progression and pathogenesis of FXTAS. Interestingly, these metabolites, as part of lipid and sphingolipid lipids pathways, provide evidence of the role that their dysregulation plays in the development of FXTAS and inform us as potential targets for personalized therapeutic development.

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

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.

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

2020 ◽  
Vol 21 (12) ◽  
pp. 4391
Author(s):  
Ana Maria Cabal-Herrera ◽  
Nattaporn Tassanakijpanich ◽  
Maria Jimena Salcedo-Arellano ◽  
Randi J. Hagerman
Keyword(s):  
Neurodegenerative Disorder ◽  
Fragile X ◽  
Cgg Repeats ◽  
Mri Features ◽  
Fmr1 Mrna ◽  
Cerebellar Peduncles ◽  
History Of ◽  
Ataxia Syndrome ◽  
Psychiatric Problems ◽  
Female Carriers

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.

scholarly journals The fragile x-associated tremor and ataxia syndrome (FXTAS)

2010 ◽  
Vol 68 (5) ◽  
pp. 791-798 ◽  
Author(s):  
Leonardo Pires Capelli ◽  
Márcia Rúbia Rodrigues Gonçalves ◽  
Claudia C Leite ◽  
Egberto R Barbosa ◽  
Ricardo Nitrini ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Current Knowledge ◽  
Fragile X ◽  
Gait Ataxia ◽  
Intention Tremor ◽  
Full Mutation ◽  
Clinical Genetic ◽  
Diagnostic Aspects ◽  
Ataxia Syndrome

FXTAS (Fragile X-associated tremor and ataxia syndrome) is a late- onset neurodegenerative disorder affecting mainly men, over 50 years of age, who are carriers of the FMR1 gene premutation. The full mutation of this gene causes the fragile X syndrome (FXS), the most common cause of inherited mental retardation. Individuals affected by FXTAS generally present intention tremor and gait ataxia that might be associated to specific radiological and/or neuropathological signs. Other features commonly observed are parkinsonism, cognitive decline, peripheral neuropathy and autonomic dysfunction. Nearly a decade after its clinical characterization, FXTAS is poorly recognized in Brazil. Here we present a review of the current knowledge on the clinical, genetic and diagnostic aspects of the disease.

scholarly journals The quest towards understanding the molecular pathogenesis of triplet repeat disorders: Huntingtons Disease and Fragile X-Associated Tremor and Ataxia Syndrome

2020 ◽  
Author(s):  
Alana Amado ◽  
Alana Amado
Keyword(s):  
Protein Interactions ◽  
Trinucleotide Repeat ◽  
Fragile X ◽  
Neurological Diseases ◽  
Neuronal Loss ◽  
Threshold Effect ◽  
Cag Repeats ◽  
Huntingtin Protein ◽  
Cgg Repeats ◽  
Neuronal Processes

Trinucleotide repeat disorders encompass a group of neurological diseases driven by unstable repeat expansions. Huntingtons disease (HD) is characterized by chorea and brain atrophy. The normal huntingtin protein contains 6-34 CAG repeats; however, upon a threshold effect of >36 repeats, the huntingtin protein acquires toxic mechanisms that are harmful to the cell. Fragile X-Associated Tremor and Ataxia (FXTAS) is characterized by tremor, ataxia and neuronal loss. The normal FMR1 gene contains 5-45 CGG repeats; however, upon a premutation CGG expansion of 55-200, FXTAS arises. A pathological hallmark of these disorders includes aggregate formation within the brain; suggestive of impaired protein and mRNA function. Furthermore, important molecules have been found to be sequestered into these aggregates withdrawing them from their normal roles. In this review, the ways mutant huntingtin and FMR1mRNA aggregates induce intracellular dysfunction in HD and FXTAS is analyzed, specifically in the context of impaired neuronal processes and protein-protein interactions. Analysis revealed that huntingtin and FMR1 mRNA are involved in the regulation of multiple cellular pathways; and whose impaired function results in a detrimental domino-effect that is destructive to the cell. The understanding of these molecular processes hopes to identify potential targets towards the treatment of HD and FXTAS

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