Characterization of the Cerebrospinal Fluid Proteome in Patients with Fragile X-Associated Tremor/Ataxia Syndrome

Cerebellum. 2022 Feb;21(1):86-98. doi: 10.1007/s12311-021-01262-7. Epub 2021 May 27.


Fragile X-associated tremor/ataxia syndrome (FXTAS), first described in 2001, is a neurodegenerative and movement disorder, caused by a premutation in the fragile X mental retardation 1 (FMR1) gene. To date, the biological mechanisms causing this condition are still not well understood, as not all premutation carriers develop FXTAS. To further understand this syndrome, we quantitatively compared the cerebrospinal fluid (CSF) proteome of FXTAS patients with age-matched controls using mass spectrometry. We identified 415 proteins of which 97 were altered in FXTAS patients. These proteins suggest changes in acute phase response signaling, liver X receptor/ retinoid X receptor (LXR/RXR) activation, and farnesoid X receptor (FXR)/RXR activation, which are the main pathways found to be affected. Additionally, we detected changes in many other proteins including amyloid-like protein 2, contactin-1, afamin, cell adhesion molecule 4, NPC intracellular cholesterol transporter 2, and cathepsin B, that had been previously noted to hold important roles in other movement disorders. Specific to RXR pathways, several apolipoproteins (APOA1, APOA2, APOA4, APOC2, and APOD) showed significant changes in the CSF of FXTAS patients. Lastly, CSF parameters were analyzed to investigate abnormalities in blood brain barrier function. Correlations were observed between patient albumin quotient values, a measure of permeability, and CGG repeat length as well as FXTAS rating scale scores.

Keywords: Biomarker; Mass spectrometry; Proteomics.

MeSH terms

  • Ataxia / genetics
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Syndrome*
  • Humans
  • Proteome / genetics
  • Proteome / metabolism
  • Tremor*
  • Trinucleotide Repeat Expansion


  • FMR1 protein, human
  • Proteome
  • Fragile X Mental Retardation Protein

Supplementary concepts

  • Fragile X Tremor Ataxia Syndrome