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

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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Family history of FXTAS is associated with age-related cognitive-linguistic decline among mothers with the FMR1 premutation

Journal of Neurodevelopmental Disorders ◽

10.1186/s11689-022-09415-3 ◽

2022 ◽

Vol 14 (1) ◽

Author(s):

Jessica Klusek ◽

Amanda Fairchild ◽

Carly Moser ◽

Marsha R. Mailick ◽

Angela John Thurman ◽

...

Keyword(s):

Family History ◽

Neurodegenerative Disease ◽

Cognitive Skills ◽

Fragile X ◽

Repeat Length ◽

Syntactic Complexity ◽

Cgg Repeat ◽

Age Related ◽

Increased Risk ◽

History Of

Abstract Background Women who carry a premutation allele of the FMR1 gene are at increased vulnerability to an array of age-related symptoms and disorders, including age-related decline in select cognitive skills. However, the risk factors for age-related decline are poorly understood, including the potential role of family history and genetic factors. In other forms of pathological aging, early decline in syntactic complexity is observed and predicts the later onset of neurodegenerative disease. To shed light on the earliest signs of degeneration, the present study characterized longitudinal changes in the syntactic complexity of women with the FMR1 premutation across midlife, and associations with family history of fragile X-associated tremor/ataxia syndrome (FXTAS) and CGG repeat length. Methods Forty-five women with the FMR1 premutation aged 35–64 years at study entry participated in 1–5 longitudinal assessments spaced approximately a year apart (130 observations total). All participants were mothers of children with confirmed fragile X syndrome. Language samples were analyzed for syntactic complexity and participants provided information on family history of FXTAS. CGG repeat length was determined via molecular genetic testing. Results Hierarchical linear models indicated that women who reported a family history of FXTAS exhibited faster age-related decline in syntactic complexity than those without a family history, with that difference emerging as the women reached their mid-50 s. CGG repeat length was not a significant predictor of age-related change. Conclusions Results suggest that women with the FMR1 premutation who have a family history of FXTAS may be at increased risk for neurodegenerative disease, as indicated by age-related loss of syntactic complexity. Thus, family history of FXTAS may represent a personalized risk factor for age-related disease. Follow-up study is needed to determine whether syntactic decline is an early indicator of FXTAS specifically, as opposed to being a more general age-related cognitive decline associated with the FMR1 premutation.

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

Neuron ◽

10.1016/j.neuron.2013.07.008 ◽

2013 ◽

Vol 79 (2) ◽

pp. 402 ◽

Cited By ~ 1

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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Adult Female Fragile X Premutation Carriers Exhibit Age- and CGG Repeat Length-Related Impairments on an Attentionally Based Enumeration Task

Frontiers in Human Neuroscience ◽

10.3389/fnhum.2011.00063 ◽

2011 ◽

Vol 5 ◽

Cited By ~ 38

Author(s):

Naomi J. Goodrich-Hunsaker ◽

Ling M. Wong ◽

Yingratana McLennan ◽

Flora Tassone ◽

Danielle Harvey ◽

...

Keyword(s):

Adult Female ◽

Fragile X ◽

Repeat Length ◽

Cgg Repeat ◽

Fragile X Premutation ◽

Enumeration Task

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Fragile X-associated tremor/ataxia syndrome: Intrafamilial variability and the size of theFMR1 premutation CGG repeat

Movement Disorders ◽

10.1002/mds.21347 ◽

2007 ◽

Vol 22 (6) ◽

pp. 866-870 ◽

Cited By ~ 13

Author(s):

Leonardo P. Capelli ◽

Márcia R. R. Gonçalves ◽

Fernando Kok ◽

Cláudia C. Leite ◽

Ricardo Nitrini ◽

...

Keyword(s):

Fragile X ◽

Cgg Repeat ◽

Intrafamilial Variability ◽

Ataxia Syndrome

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

Neuron ◽

10.1016/j.neuron.2013.03.026 ◽

2013 ◽

Vol 78 (3) ◽

pp. 440-455 ◽

Cited By ~ 257

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

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.600840 ◽

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.

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