scholarly journals Neuropathology of FMR1-premutation carriers presenting with dementia and neuropsychiatric symptoms

2021 ◽  
Author(s):  
Anke A Dijkstra ◽  
Saif Haify ◽  
Niek A Verwey ◽  
Niels D Prins ◽  
Esmay C van der Toorn ◽  
...  
Keyword(s):  
Fragile X ◽  
Neuropsychiatric Symptoms ◽  
White Matter Lesions ◽  
Neuropsychiatric Disorders ◽  
Vascular Lesions ◽  
Intranuclear Inclusions ◽  
Cgg Repeat ◽  
Fmr1 Premutation ◽  
Ataxia Syndrome ◽  
The Brain

Abstract CGG repeat expansions within the premutation range (55-200) of the FMR1 gene can lead to Fragile-X associated tremor/ataxia syndrome and Fragile-X associated neuropsychiatric disorders. These CGG repeats are translated into a toxic polyglycine-containing protein, FMRpolyG. Pathology of Fragile-X associated tremor/ataxia syndrome and Fragile-X associated neuropsychiatric disorders comprise FMRpolyG- and p62-positive intranuclear inclusions. Diagnosing a FMR1-premutation carrier remains challenging, as the clinical features overlap with other neurodegenerative diseases. Here, we describe two male cases with Fragile-X associated neuropsychiatric disorders related symptoms and mild movement disturbances and novel pathological features that can attribute to the variable phenotype. Macroscopically, both donors did not show characteristic white matter lesions on MRI, however, vascular infarcts in cortical- and subcortical regions were identified. Immunohistochemistry analyses revealed a high number of FMRpolyG intranuclear inclusions throughout the brain, which were also positive for p62. Importantly, we identified a novel pathological vascular phenotype with inclusions present in pericytes and endothelial cells. Although these results need to be confirmed in more cases, we propose that these vascular lesions in the brain could contribute to the complex symptomology of FMR1-premutation carriers. Overall, our report suggests that Fragile-X associated tremor/ataxia syndrome and Fragile-X associated neuropsychiatric disorders may present diverse clinical involvements resembling other types of dementia, and in the absence of genetic testing, FMRpolyG can be used post-mortem to identify premutation carriers.

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.

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

2007 ◽  
Vol 144B (4) ◽  
pp. 566-569 ◽  
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

scholarly journals ASFMR1splice variant

2018 ◽  
Vol 4 (4) ◽  
pp. e246 ◽  
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.

scholarly journals CGG-repeat length and neuropathological and molecular correlates in a mouse model for fragile X-associated tremor/ataxia syndrome

2008 ◽  
Vol 107 (6) ◽  
pp. 1671-1682 ◽  
Author(s):  
Judith R. Brouwer ◽  
Karin Huizer ◽  
Lies-Anne Severijnen ◽  
Renate K. Hukema ◽  
Robert F. Berman ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X ◽  
Repeat Length ◽  
Cgg Repeat ◽  
Ataxia Syndrome

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.

P–514 RAN-Translation in Fragile X associated Premature Ovarian Insufficiency (FXPOI): FMRpolyG as a predictive tool

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
X P Nguyen ◽  
B Messmer ◽  
J E Dietrich ◽  
K Hinderhofer ◽  
T Strowitzki ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Fragile X ◽  
Human Lymphocytes ◽  
Predictive Tool ◽  
Ovarian Insufficiency ◽  
Glass Coverslip ◽  
Cgg Repeat ◽  
Fmr1 Premutation ◽  
The Impact ◽  
Ran Translation

Abstract Study question Does repeat-associated non-AUG (RAN) translation lead to accumulation of polyglycine- containing protein (FMRpolyG) in human lymphocytes and mural granulosa cells of FMR1 premutation carriers? Summary answer Lymphocytes and granulosa cells from FMR1 premutation carriers contain intracellular inclusions that stain positive for both FMRpolyG and ubiquitin. What is known already: Fragile-X-associated-Primary-Ovarian-Insufficiency (FXPOI) is characterized by oligo/amenorrhea and hypergonadotropic hypogonadism associated with the expansion of CGG-repeats in the 5’UTR of FMR1, called premutation (PM) (n: 55–200). Approximately 20% of women carrying a FMR1-premutation (PM) allele develop FXPOI. RAN-translation dependent on variable CGG-repeat length is hypothesized to cause FXPOI due to the production of a polyglycine-containing FMR1-protein, FMRpolyG. Recently, FMRpolyG inclusions were found in neuronal brain cells of FXTAS patients and stromal cells of the ovary of an FXPOI patient. Study design, size, duration: Lymphocytes and granulosa cells (GCs) from women with PM (6) and women without PM (10) (controls) were analyzed by immunofluorescence (IF) staining for the presence of inclusions positive for ubiquitin and FMRpolyG. Cell lysis and protein extraction samples were subjected to Fluorescent Western Blot (WB) analysis to detect FMRP and FMRpolyG Participants/materials, setting, methods Human GCs were obtained from follicular fluid after oocyte retrieval and lymphocytes were isolated from peripheral blood using Ficoll-Paque. Cells suspended in PBS were adhered to a glass-coverslip placed at the bottom of the 6-well culture plate, via gravity sedimentation. Adhered cells were fixed, IF staining for FMRpolyG and ubiquitin was performed and analyzed by fluorescence microscopy. Fluorescent WB was used to demonstrate the expression of FMRP, FMRpolyG in extracted protein from lymphocytes and GCs. Main results and the role of chance FMRP was successfully detected by fluorescence WB in both lymphocytes and GCs. FMRP is mainly present in cytoplasm and was expressed in greater amount in GCs than in leukocytes. Moreover, FMRP expression was significantly decreased in GCs from FMR1-PM compared with controls. Lymphocytes from PM-carriers and controls were immunostained for FMRpolyG and ubiquitin. In PM-carriers, FMRpolyG was present as aggregates, whereas in controls only a weak signal without inclusions was detectable. The expression pattern of FMRpolyG in GCs was similar to that in lymphocytes with a significant increase in PM-carriers. There, the FMRpolyG-aggregates additionally demonstrated as ubiquitin-positive inclusions. These may resemble the toxic potential of these protein fractions involved the ovarian damage in developing FXPOI. Limitations, reasons for caution More patients are needed to support the present findings. Further investigation into the possible consequences of these FMRpolyG-positive inclusions in PM-carriers is also advisable. Wider implications of the findings: We found for the first time FMRpolyG-accumulation in lymphocytes and GCs from FMR1-PM-carriers in ubiquitin-positive inclusions. Future experiments evaluating consistency in more patients and elucidating the impact on fertility and prospective value for individual ovarian reserve are therefore in preparation. Trial registration number Not applicable

scholarly journals Lack of a Clear Behavioral Phenotype in an Inducible FXTAS Mouse Model Despite the Presence of Neuronal FMRpolyG-Positive Aggregates

2020 ◽  
Vol 7 ◽  
Author(s):  
Saif N. Haify ◽  
Ruchira S. D. Mankoe ◽  
Valerie Boumeester ◽  
Esmay C. van der Toorn ◽  
Rob F. M. Verhagen ◽  
...  
Keyword(s):  
Mouse Model ◽  
Rna Binding ◽  
Neurodegenerative Disorder ◽  
Rna Binding Proteins ◽  
Fragile X ◽  
Brain Regions ◽  
Intranuclear Inclusions ◽  
Behavioral Deficits ◽  
Cgg Repeat ◽  
Progressive Cerebellar Ataxia

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a rare neurodegenerative disorder caused by a 55–200 CGG repeat expansion in the 5′ untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene. FXTAS is characterized by progressive cerebellar ataxia, Parkinsonism, intention tremors and cognitive decline. The main neuropathological hallmark of FXTAS is the presence of ubiquitin-positive intranuclear inclusions in neurons and astrocytes throughout the brain. The molecular pathology of FXTAS involves the presence of 2 to 8-fold elevated levels of FMR1 mRNA, and of a repeat-associated non-AUG (RAN) translated polyglycine peptide (FMRpolyG). Increased levels of FMR1 mRNA containing an expanded CGG repeat can result in cellular toxicity by an RNA gain-of-function mechanism. The increased levels of CGG repeat-expanded FMR1 transcripts may create RNA foci that sequester important cellular proteins, including RNA-binding proteins and FMRpolyG, in intranuclear inclusions. To date, it is unclear whether the FMRpolyG-positive intranuclear inclusions are a cause or a consequence of FXTAS disease pathology. In this report we studied the relation between the presence of neuronal intranuclear inclusions and behavioral deficits using an inducible mouse model for FXTAS. Neuronal intranuclear inclusions were observed 4 weeks after dox-induction. After 12 weeks, high numbers of FMRpolyG-positive intranuclear inclusions could be detected in the hippocampus and striatum, but no clear signs of behavioral deficits related to these specific brain regions were found. In conclusion, the observations in our inducible mouse model for FXTAS suggest a lack of correlation between the presence of intranuclear FMRpolyG-positive aggregates in brain regions and specific behavioral phenotypes.

scholarly journals CGG Repeat-Associated Translation Mediates Neurodegeneration in Fragile X Tremor Ataxia Syndrome

Neuron ◽  
2013 ◽  
Vol 79 (2) ◽  
pp. 402 ◽  
Author(s):  
Peter K. Todd ◽  
Seok Yoon Oh ◽  
Amy Krans ◽  
Fang He ◽  
Chantal Sellier ◽  
...  
Keyword(s):  
Fragile X ◽  
Cgg Repeat ◽  
Ataxia Syndrome
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