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.

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 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 Human Cerebral Cortex Proteome of Fragile X-Associated Tremor/Ataxia Syndrome

2021 ◽  
Vol 7 ◽  
Author(s):  
Katharine Nichole Holm ◽  
Anthony W. Herren ◽  
Sandra L. Taylor ◽  
Jamie L. Randol ◽  
Kyoungmi Kim ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Structural Integrity ◽  
Rna Binding ◽  
Neurodegenerative Disorder ◽  
Fragile X ◽  
Protein Abundance ◽  
Cgg Repeat ◽  
Phosphoserine Aminotransferase ◽  
Brain Volume Loss ◽  
Ataxia Syndrome

Background: Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder associated with premutation CGG-repeat expansions (55–200 repeats) in the 5′ non-coding portion of the fragile X mental retardation 1 (FMR1) gene. Core features of FXTAS include progressive tremor/ataxia, cognitive decline, variable brain volume loss, and white matter disease. The principal histopathological feature of FXTAS is the presence of central nervous system (CNS) and non-CNS intranuclear inclusions.Objective: To further elucidate the molecular underpinnings of FXTAS through the proteomic characterization of human FXTAS cortexes.Results: Proteomic analysis of FXTAS brain cortical tissue (n = 8) identified minor differences in protein abundance compared to control brains (n = 6). Significant differences in FXTAS relative to control brain predominantly involved decreased abundance of proteins, with the greatest decreases observed for tenascin-C (TNC), cluster of differentiation 38 (CD38), and phosphoserine aminotransferase 1 (PSAT1); proteins typically increased in other neurodegenerative diseases. Proteins with the greatest increased abundance include potentially novel neurodegeneration-related proteins and small ubiquitin-like modifier 1/2 (SUMO1/2). The FMRpolyG peptide, proposed in models of FXTAS pathogenesis but only identified in trace amounts in the earlier study of FXTAS inclusions, was not identified in any of the FXTAS or control brains in the current study.Discussion: The observed proteomic shifts, while generally relatively modest, do show a bias toward decreased protein abundance with FXTAS. Such shifts in protein abundance also suggest altered RNA binding as well as loss of cell–cell adhesion/structural integrity. Unlike other neurodegenerative diseases, the proteome of end-stage FXTAS does not suggest a strong inflammation-mediated degenerative response.

scholarly journals Abundancy of polymorphic CGG repeats in the human genome suggest a broad involvement in neurological disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dale J. Annear ◽  
Geert Vandeweyer ◽  
Ellen Elinck ◽  
Alba Sanchis-Juan ◽  
Courtney E. French ◽  
...  
Keyword(s):  
Human Disease ◽  
Fragile X ◽  
Disease Genes ◽  
Cgg Repeat ◽  
Neurodevelopmental Disease ◽  
Repeat Units ◽  
Cgg Repeats ◽  
Repeat Expansions ◽  
Ataxia Syndrome ◽  
Strong Candidate

AbstractExpanded CGG-repeats have been linked to neurodevelopmental and neurodegenerative disorders, including the fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS). We hypothesized that as of yet uncharacterised CGG-repeat expansions within the genome contribute to human disease. To catalogue the CGG-repeats, 544 human whole genomes were analyzed. In total, 6101 unique CGG-repeats were detected of which more than 93% were highly variable in repeat length. Repeats with a median size of 12 repeat units or more were always polymorphic but shorter repeats were often polymorphic, suggesting a potential intergenerational instability of the CGG region even for repeats units with a median length of four or less. 410 of the CGG repeats were associated with known neurodevelopmental disease genes or with strong candidate genes. Based on their frequency and genomic location, CGG repeats may thus be a currently overlooked cause of human disease.

scholarly journals Mechanisms of Genome Instability in the Fragile X-Related Disorders

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1633
Author(s):  
Bruce E. Hayward ◽  
Karen Usdin
Keyword(s):  
Genome Instability ◽  
Fragile Site ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Cgg Repeat ◽  
Cgg Repeats ◽  
Large Numbers ◽  
Structural Abnormalities ◽  
Chromosomal Fragility ◽  
Ataxia Syndrome

The Fragile X-related disorders (FXDs), which include the intellectual disability fragile X syndrome (FXS), are disorders caused by expansion of a CGG-repeat tract in the 5′ UTR of the X-linked FMR1 gene. These disorders are named for FRAXA, the folate-sensitive fragile site that localizes with the CGG-repeat in individuals with FXS. Two pathological FMR1 allele size classes are distinguished. Premutation (PM) alleles have 54–200 repeats and confer the risk of fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). PM alleles are prone to both somatic and germline expansion, with female PM carriers being at risk of having a child with >200+ repeats. Inheritance of such full mutation (FM) alleles causes FXS. Contractions of PM and FM alleles can also occur. As a result, many carriers are mosaic for different sized alleles, with the clinical presentation depending on the proportions of these alleles in affected tissues. Furthermore, it has become apparent that the chromosomal fragility of FXS individuals reflects an underlying problem that can lead to chromosomal numerical and structural abnormalities. Thus, large numbers of CGG-repeats in the FMR1 gene predisposes individuals to multiple forms of genome instability. This review will discuss our current understanding of these processes.

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 Neuropathology of RAN translation proteins in Fragile X-associated Tremor/Ataxia Syndrome

2019 ◽  
Author(s):  
Amy Krans ◽  
Geena Skariah ◽  
Yuan Zhang ◽  
Bryana Bayly ◽  
Peter K. Todd
Keyword(s):  
Hippocampal Neurons ◽  
Neurodegenerative Disorder ◽  
Fragile X ◽  
Antisense Strand ◽  
Common Component ◽  
Cgg Repeat ◽  
Neuronal Nuclei ◽  
Sense Strand ◽  
Ataxia Syndrome ◽  
Ran Translation

AbstractCGG repeat expansions in FMR1 cause the neurodegenerative disorder Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). Ubiquitinated neuronal intranuclear inclusions (NIIs) are the neuropathological hallmark of FXTAS. Both sense strand derived CGG repeats and antisense strand derived CCG repeats support non-AUG initiated (RAN) translation of homopolymeric proteins in potentially 6 different reading frames. However, the relative abundance of these proteins in FXTAS brains and their co-localization with each other and NIIs is lacking. Here we describe rater-blinded assessment of immunohistochemical and immunofluorescence staining with newly generated antibodies to different CGG RAN translation products in FXTAS and control brains as well as co-staining with ubiquitin, p62/SQSTM1, and ubiquilin 2. We find that both FMRpolyG and a second CGG repeat derived RAN translation product, FMRpolyA, accumulate in aggregates in FXTAS brains. FMRpolyG is a near-obligate component of both ubiquitin-positive and p62-positive NIIs in FXTAS, with occurrence of aggregates in 20% of all hippocampal neurons and >90% of all inclusions. A subset of these inclusions also stain positive for the ALS/FTD associated protein ubiquilin 2. Ubiquitinated inclusions and FMRpolyG+ aggregates are rarer in cortex and cerebellum. Intriguingly, FMRpolyG staining is also visible in control neuronal nuclei. In contrast to FMRpolyG, staining for FMRpolyA and CCG antisense derived RAN translation products were less abundant and were infrequent components of FMRpolyG+ inclusions. In conclusion, RAN translated FMRpolyG is a common component of ubiquitin and p62 positive inclusions in FXTAS patient brains.

scholarly journals Neuroimaging Insight Into Fragile X-Associated Neuropsychiatric Disorders: Literature Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Andrea Elias-Mas ◽  
Maria Isabel Alvarez-Mora ◽  
Conxita Caro-Benito ◽  
Laia Rodriguez-Revenga
Keyword(s):  
Brain Function ◽  
Psychiatric Symptoms ◽  
Fragile X ◽  
Clinical Manifestations ◽  
Neuropsychiatric Disorders ◽  
Psychiatric Symptomatology ◽  
Cgg Repeat ◽  
Cgg Repeats ◽  
Ataxia Syndrome ◽  
Insight Into

FMR1 premutation is defined by 55–200 CGG repeats in the Fragile X Mental Retardation 1 (FMR1) gene. FMR1 premutation carriers are at risk of developing a neurodegenerative disease called fragile X-associated tremor/ataxia syndrome (FXTAS) and Fragile X-associated primary ovarian insufficiency (FXPOI) in adulthood. In the last years an increasingly board spectrum of clinical manifestations including psychiatric disorders have been described as occurring at a greater frequency among FMR1 premutation carriers. Herein, we reviewed the neuroimaging findings reported in relation with psychiatric symptomatology in adult FMR1 premutation carriers. A structured electronic literature search was conducted on FMR1 premutation and neuroimaging yielding a total of 3,229 articles examined. Of these, 7 articles were analyzed and are included in this review. The results showed that the main radiological findings among adult FMR1 premutation carriers presenting neuropsychiatric disorders were found on the amygdala and hippocampus, being the functional abnormalities more consistent and the volumetric changes more inconsistent among studies. From a molecular perspective, CGG repeat size, FMR1 mRNA and FMRP levels have been investigated in relation with the neuroimaging findings. Based on the published results, FMRP might play a key role in the pathophysiology of the psychiatric symptoms described among FMR1 premutation carriers. However, additional studies including further probes of brain function and a broader scope of psychiatric symptom measurement are required in order to obtain a comprehensive landscape of the neuropsychiatric phenotype associated with the FMR1 premutation.

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.

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