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| PMID |
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| TITLE |
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| Relationship Between Neurologic Symptoms and Signs and FMR1 Genotype in Premutation Carriers. |
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| ABSTRACT |
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| BACKGROUND AND OBJECTIVES |
NlmCategory: OBJECTIVE |
| Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is the most severe late-onset condition caused by a premutation in the FMR1 gene, characterized by expanded CGG triplet repeats of 55-200. Clinical presentations of FXTAS, including gait ataxia, kinetic tremor, cognitive decline, and rare Parkinsonism, are linked to white matter degeneration, predominantly in the middle cerebellar peduncles. Underlying pathophysiological mechanisms involve the sequestration of CGG-binding proteins due to elevated FMR1 mRNA and repeat-associated non-AUG (RAN)-initiated translation. Outside of the full presentation of FXTAS, some FMR1 premutation carriers exhibit only isolated clinical changes occurring in this syndrome. This study explored the relationship of molecular predictors of disease, either with these isolated features in patients who did not meet diagnostic criteria for FXTAS or with diagnosable FXTAS. |
| METHODS |
NlmCategory: METHODS |
| Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is the most severe late-onset condition caused by a premutation in the FMR1 gene, characterized by expanded CGG triplet repeats of 55-200. Clinical presentations of FXTAS, including gait ataxia, kinetic tremor, cognitive decline, and rare Parkinsonism, are linked to white matter degeneration, predominantly in the middle cerebellar peduncles. Underlying pathophysiological mechanisms involve the sequestration of CGG-binding proteins due to elevated FMR1 mRNA and repeat-associated non-AUG (RAN)-initiated translation. Outside of the full presentation of FXTAS, some FMR1 premutation carriers exhibit only isolated clinical changes occurring in this syndrome. This study explored the relationship of molecular predictors of disease, either with these isolated features in patients who did not meet diagnostic criteria for FXTAS or with diagnosable FXTAS. 176 male (N = 111) and female (N = 65) premutation carriers were separated into three groups based on neurological/cognitive examination data: asymptomatic, non-syndromic/presenting isolated changes, and syndromic-FXTAS. These categories were then separately correlated with CGG repeat length and FMR1 mRNA expression levels. |
| RESULTS |
NlmCategory: RESULTS |
| Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is the most severe late-onset condition caused by a premutation in the FMR1 gene, characterized by expanded CGG triplet repeats of 55-200. Clinical presentations of FXTAS, including gait ataxia, kinetic tremor, cognitive decline, and rare Parkinsonism, are linked to white matter degeneration, predominantly in the middle cerebellar peduncles. Underlying pathophysiological mechanisms involve the sequestration of CGG-binding proteins due to elevated FMR1 mRNA and repeat-associated non-AUG (RAN)-initiated translation. Outside of the full presentation of FXTAS, some FMR1 premutation carriers exhibit only isolated clinical changes occurring in this syndrome. This study explored the relationship of molecular predictors of disease, either with these isolated features in patients who did not meet diagnostic criteria for FXTAS or with diagnosable FXTAS. 176 male (N = 111) and female (N = 65) premutation carriers were separated into three groups based on neurological/cognitive examination data: asymptomatic, non-syndromic/presenting isolated changes, and syndromic-FXTAS. These categories were then separately correlated with CGG repeat length and FMR1 mRNA expression levels. Regression and distributions' analyses showed that the most consistent associations of both genomic markers were with neurological severity rankings, followed by a binary definition of FXTAS status. Among other minor presentations, Parkinsonism and cognitive impairment were significantly correlated with CGG size in male samples. |
| DISCUSSION |
NlmCategory: CONCLUSIONS |
| Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is the most severe late-onset condition caused by a premutation in the FMR1 gene, characterized by expanded CGG triplet repeats of 55-200. Clinical presentations of FXTAS, including gait ataxia, kinetic tremor, cognitive decline, and rare Parkinsonism, are linked to white matter degeneration, predominantly in the middle cerebellar peduncles. Underlying pathophysiological mechanisms involve the sequestration of CGG-binding proteins due to elevated FMR1 mRNA and repeat-associated non-AUG (RAN)-initiated translation. Outside of the full presentation of FXTAS, some FMR1 premutation carriers exhibit only isolated clinical changes occurring in this syndrome. This study explored the relationship of molecular predictors of disease, either with these isolated features in patients who did not meet diagnostic criteria for FXTAS or with diagnosable FXTAS. 176 male (N = 111) and female (N = 65) premutation carriers were separated into three groups based on neurological/cognitive examination data: asymptomatic, non-syndromic/presenting isolated changes, and syndromic-FXTAS. These categories were then separately correlated with CGG repeat length and FMR1 mRNA expression levels. Regression and distributions' analyses showed that the most consistent associations of both genomic markers were with neurological severity rankings, followed by a binary definition of FXTAS status. Among other minor presentations, Parkinsonism and cognitive impairment were significantly correlated with CGG size in male samples. This data provides evidence for a linear relationship between FMR1 CGG size and mRNA levels, as well as both syndromic and non-syndromic forms of neurological manifestations, which represent aspects of the premutation-linked neurodegenerative process that persist with advancing age. |
| © 2026 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. |
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| DATE PUBLISHED |
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| HISTORY |
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| PUBSTATUS |
PUBSTATUSDATE |
| revised |
2026/02/05 |
| received |
2025/09/29 |
| accepted |
2026/03/06 |
| medline |
2026/04/01 07:04 |
| pubmed |
2026/04/01 07:04 |
| entrez |
2026/04/01 00:43 |
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| AUTHORS |
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| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Tassone F |
|
Tassone |
Flora |
F |
|
School of Medicine and MIND Institute, University of California Davis Medical Center, Davis, California, USA. |
| Chafota F |
|
Chafota |
Freddy |
F |
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Brain and Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
| Rentería ME |
|
Rentería |
Miguel E |
ME |
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School of Biomedical Sciences, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland, Brisbane, Queensland, Australia. |
| Hagerman RJ |
|
Hagerman |
Randi J |
RJ |
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Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis Health, Sacramento, California, USA. |
| Santos E |
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Santos |
Ellery |
E |
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Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis Health, Sacramento, California, USA. |
| Atkinson A |
|
Atkinson |
Anna |
A |
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School of Psychology and Public Health, La Trobe University, Bundoora, Victoria, Australia. |
| Martin NG |
|
Martin |
Nicholas G |
NG |
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Brain and Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
| Storey E |
|
Storey |
Elsdon |
E |
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Department of Medicine (Neuroscience), Monash University, Melbourne, Australia. |
| Loesch DZ |
|
Loesch |
Danuta Z |
DZ |
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School of Psychology and Public Health, La Trobe University, Bundoora, Victoria, Australia. |
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| INVESTIGATORS |
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| JOURNAL |
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| VOLUME: |
| ISSUE: |
| TITLE: Annals of clinical and translational neurology |
| ISOABBREVIATION: Ann Clin Transl Neurol |
| YEAR: 2026 |
| MONTH: Mar |
| DAY: 31 |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 2328-9503 |
| ISSNTYPE: Electronic |
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| MEDLINE JOURNAL |
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| MEDLINETA: Ann Clin Transl Neurol |
| COUNTRY: United States |
| ISSNLINKING: 2328-9503 |
| NLMUNIQUEID: 101623278 |
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| PUBLICATION TYPE |
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| PUBLICATIONTYPE TEXT |
| Journal Article |
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| COMMENTS AND CORRECTIONS |
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| GRANTS |
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| GRANTID |
AGENCY |
COUNTRY |
| CF06/0269 |
National Health and Medical Research Council |
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| F20231230 |
Rebecca L. Cooper Medical Research Foundation through an Al & Val Rosenstrauss Fellowship |
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| APP1172990 |
National Health and Medical Research Council |
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| P50 HD103526 |
NICHD NIH HHS |
United States |
| HD 036071 |
Eunice Kennedy Shriver National Institute of Child Health and Human Development |
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| R01 HD036071 |
NICHD NIH HHS |
United States |
| DDRC P50 HD103526 |
Eunice Kennedy Shriver National Institute of Child Health and Human Development |
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| GENERAL NOTE |
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| KEYWORDS |
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| KEYWORD |
| CGG expansion |
| FMR1 premutation carriers |
| FXTAS |
| mRNA predictors |
| neurological involvement |
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| MESH HEADINGS |
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| SUPPLEMENTARY MESH |
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| GENE SYMBOLS |
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| CHEMICALS |
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