statdx/docs_md/articles/fragile-x-associated-tremor-ataxia-fxtas_4778fafe-9873-4c28-8f4f-299c00c72b50.md

---
title: "Fragile X-Associated Tremor/Ataxia (FXTAS)"
docid: "4778fafe-9873-4c28-8f4f-299c00c72b50"
authors:
  - key: "a25c450b-3d34-4f64-bba3-cc0834813df6"
    value: "Miral D. Jhaveri, MD, MBA"
breadcrumbs:
  -
    name: "Brain"
    slug: "brain"
    treeNodeId: "6d8829f1-14d7-45af-8675-255189aa526a"
  -
    name: "Diagnosis"
    slug: "diagnosis"
    treeNodeId: "51c00394-446e-4a38-94af-d3b1d14d34e8"
  -
    name: "Pathology-Based Diagnoses"
    slug: "pathology-based-diagnoses"
    treeNodeId: "d9d3a8ed-f21b-4831-8c77-591a3500ef77"
  -
    name: "Acquired Toxic/Metabolic/Degenerative Disorders"
    slug: "acquired-toxicmetabolicdegenerativ-"
    treeNodeId: "ba3cfeaf-64d9-4117-91e8-d2ce58783fc5"
  -
    name: "Dementias and Degenerative Disorders"
    slug: "dementias-and-degenerative-disorde-"
    treeNodeId: "6381104d-7a4c-4be5-bb19-3cd90837d547"
  -
    name: "Fragile X-Associated Tremor/Ataxia (FXTAS)"
    slug: "fragile-x-associated-tremorataxia--"
    treeNodeId: null
category: "Brain"
documentVersionId: "19e8e928-1533-4e9f-8293-80f21fba4e0a"
imageCount: 4
lastUpdated: "08/05/20"
pageDescription: "Fragile X-Associated Tremor/Ataxia (FXTAS)"
pageKeywords: "Brain, Diagnosis, Pathology-Based Diagnoses, Acquired Toxic/Metabolic/Degenerative Disorders, Dementias and Degenerative Disorders, Fragile X-Associated Tremor/Ataxia (FXTAS)"
pageTitle: "Fragile X-Associated Tremor/Ataxia (FXTAS) | STATdx"
enhancedTitle: "Fragile X-Associated Tremor/Ataxia (FXTAS)"
type: "DX"
references: true
breadcrumbs:
  - "Brain"
  - "Diagnosis"
  - "Pathology-Based Diagnoses"
  - "Acquired Toxic/Metabolic/Degenerative Disorders"
  - "Dementias and Degenerative Disorders"
  - "Fragile X-Associated Tremor/Ataxia (FXTAS)"
---
# KEY FACTS

- ## Terminology
  
  
    - Fragile X-associated tremor/ataxia syndrome (FXTAS)
    - X-linked progressive neurodegenerative disorder characterized by 55-200 CGG trinucleotide repeats in *FMR1* gene
- ## Imaging
  
  
    - Ventricular and sulcal prominence: Global volume loss
    - WM and brainstem hyperintensities
    - MCP atrophy with symmetric hyperintensities: MCP sign
          - Decreased MCP width may be first notable sign
    - Splenium of corpus callosum atrophy with hyperintensity: Corpus callosum splenium sign
          - High sensitivity but lower specificity than MCP sign
- ## Top Differential Diagnoses
  
  
    - **Middle cerebellar peduncle sign**
          - Neurodegenerative, metabolic, cerebrovascular, inflammatory and demyelinating disorders
    - **Corpus callosum splenium sign**
          - Normal aging, radiation therapy
          - Cytotoxic/transient splenial lesions
- ## Pathology
  
  
    - Premutation expansions (55-200 CGG repeats) in 5' untranslated region of *FMR1* gene, located on X-chromosome
    - **Radiological criteria**
          - Major: White matter lesions in brainstem or MCP sign
          - Minor: Cerebral white matter lesions, moderate to severe generalized brain atrophy
- ## Clinical Issues
  
  
    - Kinetic tremor, cerebellar gait ataxia, cognitive dysfunction
    - Usually > age 50
    - Diagnosis confirmed by molecular genetic testing
    - Progressive and severe neurodegenerative disease

# TERMINOLOGY

- ## Abbreviations
  
  
    - Fragile X-associated tremor/ataxia syndrome (FXTAS)
- ## Definitions
  
  
    - X-linked progressive neurodegenerative disorder characterized by 55-200 CGG trinucleotide repeats in *FMR1* gene

# IMAGING

- ## General Features
  
  
    - ### Best diagnostic clue
      
      
          - Generalized brain atrophy with hyperintensities in brainstem or middle cerebellar peduncle (MCP)
    - ### Location
      
      
          - Brainstem and middle cerebellar peduncles
          - Cerebral white matter (WM), corpus callosum
    - ### Size
      
      
          - MCP atrophy, global atrophy
- ## CT Findings
  
  
    - ### NECT
      
      
          - Moderate to severe generalized brain atrophy
          - MCP atrophy with subtle hypodensities
- ## MR Findings
  
  
    - ### T1WI
      
      
          - Subtle hypointensity in MCP with atrophy
          - Corpus callosum splenium hypointensity
    - ### FLAIR
      
      
          - Ventricular and sulcal prominence: Global volume loss
          - WM and brainstem hyperintensities
          - Putaminal rim hyperintensity
          - MCP atrophy with symmetric hyperintensities: MCP sign
                  - Decreased MCP width may be first notable sign
          - Splenium of corpus callosum atrophy with hyperintensity: Corpus callosum splenium sign
                  - High sensitivity but lower specificity than MCP sign
    - ### T2* GRE
      
      
          - No hemorrhage
    - ### T1WI C+
      
      
          - No enhancement
    - ### MRS
      
      
          - Decreased NAA/Cr and Ch/Cr in MCP
    - DTI
          - Reduced fractional anisotropy (FA) in corpus callosum
                  - Associated with increasing FXTAS symptom severity
          - Reduced FA in MCP
- ## Imaging Recommendations
  
  
    - ### Best imaging tool
      
      
          - Brain MR without contrast
    - ### Protocol advice
      
      
          - Add coronal T2/FLAIR MR

# DIFFERENTIAL DIAGNOSIS

- ## Middle Cerebellar Peduncle Sign
  
  
    - **Neurodegenerative**
          - Multiple systemic atrophy (MSA), olivopontocerebellar atrophy, spinocerebellar ataxia
    - **Metabolic**
          - Adrenoleukodystrophy, Wilson disease, hypoglycemia
    - **Cerebrovascular**
          - Infarcts, PRES, pontine infarct with wallerian degeneration of MCPs
    - **Inflammatory and demyelinating**
          - Multiple sclerosis, ADEM, Behçet disease
- ## Corpus Callosum Splenium Sign
  
  
    - Normal aging, radiation therapy
    - Cytotoxic /transient splenial lesions
          - Seizure- &/or drug-related, viral encephalitis, metabolic derangement

# PATHOLOGY

- ## General Features
  
  
    - ### Genetics
      
      
          - Premutation expansions (55-200 CGG repeats) in untranslated region of *FMR1* gene, located on X-chromosome
          - Full mutation (> 200 CGG repeats) leads to neurodevelopmental disease fragile X syndrome (FXS)
    - 2 main molecular mechanisms
          - Toxic gain of function of expanded CGG-repeat *FMR1*mRNA → binding/sequestration of CGG-binding proteins
          - CGG repeat-associated non-AUG-initiated (RAN) translation → polyglycine peptide toxic to cells
- ## Staging, Grading, & Classification
  
  
    - Diagnostic criteria for FXTAS: Clinical, radiological, and pathological
    - **Radiological criteria**
          - Major criteria: WM lesions in brainstem or MCP sign
          - Minor criteria: Cerebral WM lesions, moderate to severe generalized brain atrophy
- ## Microscopic Features
  
  
    - Diffuse, spongy degeneration of WM
    - Eosinophilic intranuclear inclusions in neurons and astrocytes with cortex and cerebellum

# CLINICAL ISSUES

- ## Presentation
  
  
    - ### Most common signs/symptoms
      
      
          - Kinetic tremor, cerebellar gait ataxia, cognitive dysfunction
    - ### Other signs/symptoms
      
      
          - Psychiatric disorders common
- ## Demographics
  
  
    - Usually > age 50
    - More common among male patients who are hemizygous for premutation (40%) than female patients who are heterozygous for premutation (8-16%)
- ## Natural History & Prognosis
  
  
    - Diagnosis confirmed by molecular genetic testing
    - Progressive and severe neurodegenerative disease
- ## Treatment
  
  
    - Symptomatic and supportive

# DIAGNOSTIC CHECKLIST

- ## Consider
  
  
    - Patient presenting with ataxia and tremor with symmetric middle cerebellar peduncle hyperintensities (MCP sign)

 863ab378-3ef7-4994-a374-6fc4bb8249e5

## References

# Selected References

1. [Cvejic RC et al: Reduced caudate volume and cognitive slowing in men at risk of fragile X-associated tremor ataxia syndrome. Brain Imaging Behav. ePub, 2018](http://www.ncbi.nlm.nih.gov/pubmed/?term=30046972%5Bpmid%5D)
1. [Famula JL et al: Presence of middle cerebellar peduncle sign in FMR1 premutation carriers without tremor and ataxia. Front Neurol. 9:695, 2018](http://www.ncbi.nlm.nih.gov/pubmed/?term=30186228%5Bpmid%5D)
1. [Mascalchi M et al: Neuroimaging Applications in Chronic Ataxias. Int Rev Neurobiol. 143:109-162, 2018](http://www.ncbi.nlm.nih.gov/pubmed/?term=30473193%5Bpmid%5D)
1. [Hall DA et al: The corpus callosum splenium sign in fragile X-associated tremor ataxia syndrome. Mov Disord Clin Pract. 4(3):383-8, 2017](http://www.ncbi.nlm.nih.gov/pubmed/?term=30363360%5Bpmid%5D)
1. [Fasano A et al: MRI-guided focused ultrasound thalamotomy in fragile X-associated tremor/ataxia syndrome. Neurology. 87(7):736-8, 2016](http://www.ncbi.nlm.nih.gov/pubmed/?term=27440151%5Bpmid%5D)
1. [Filley CM: Fragile X tremor ataxia syndrome and white matter dementia. Clin Neuropsychol. 30(6):901-12, 2016](http://www.ncbi.nlm.nih.gov/pubmed/?term=27356088%5Bpmid%5D)


## Images


### Selected Images

![Sagittal T1 MR in a 56-year-old man with fragile X-associated tremor/ataxia syndrome (FXTAS) demonstrates atrophy of the corpus callosum <img src='img/arrows/CS.png'/>, brainstem <img src='img/arrows/CC.png'/>, and cerebellum  <img src='img/arrows/CO.png'/>.](images/app.statdx.com_image_thumbnail_bd354cab-3b2c-4a44-834d-8a782f46ee4d_size_168_quality_85_ce881543_20251014T204705Z.jpg)
*Sagittal T1 MR in a 56-year-old man with fragile X-associated tremor/ataxia syndrome (FXTAS) demonstrates atrophy of the corpus callosum <img src='img/arrows/CS.png'/>, brainstem <img src='img/arrows/CC.png'/>, and cerebellum  <img src='img/arrows/CO.png'/>.*

![Axial FLAIR MR in the same patient shows decreased width of the middle cerebellar peduncles with symmetric hyperintensities <img src='img/arrows/CC.png'/>, consistent with the MCP sign. This sign can be seen in a number of conditions, particularly neurodegenerative diseases, and is most commonly associated with FXTAS.](images/app.statdx.com_image_thumbnail_6e85ed35-5fce-4b42-8e4b-e22ad8384616_size_168_quality_85_6c416419_20251014T204705Z.jpg)
*Axial FLAIR MR in the same patient shows decreased width of the middle cerebellar peduncles with symmetric hyperintensities <img src='img/arrows/CC.png'/>, consistent with the MCP sign. This sign can be seen in a number of conditions, particularly neurodegenerative diseases, and is most commonly associated with FXTAS.*

![Axial FLAIR MR in a patient with tremor, cerebellar ataxia, and cognitive decline shows diffuse parenchymal volume loss, WM hyperintensities <img src='img/arrows/CC.png'/>, and hyperintensity in the splenium of the corpus callosum <img src='img/arrows/CS.png'/>  (corpus callosum splenium sign).](images/app.statdx.com_image_thumbnail_139d26cb-4438-4af5-b15f-e814163805de_size_168_quality_85_ca5b409b_20251014T204705Z.jpg)
*Axial FLAIR MR in a patient with tremor, cerebellar ataxia, and cognitive decline shows diffuse parenchymal volume loss, WM hyperintensities <img src='img/arrows/CC.png'/>, and hyperintensity in the splenium of the corpus callosum <img src='img/arrows/CS.png'/>  (corpus callosum splenium sign).*

![Axial T2 MR in the same patient shows atrophy of the middle cerebellar peduncles with symmetric hyperintensities <img src='img/arrows/CC.png'/>  (MCP sign). The patient was diagnosed with definite FXTAS and had 166 CGG repeats on molecular genetic testing.](images/app.statdx.com_image_thumbnail_163bf33d-0795-49b8-ac7b-393d1289a00e_size_168_quality_85_e69bac40_20251014T204705Z.jpg)
*Axial T2 MR in the same patient shows atrophy of the middle cerebellar peduncles with symmetric hyperintensities <img src='img/arrows/CC.png'/>  (MCP sign). The patient was diagnosed with definite FXTAS and had 166 CGG repeats on molecular genetic testing.*