Preclinical Basal Ganglia Neurodegeneration in Female X Linked Dystonia Parkinsonism Carriers

Abstract

Background and ObjectivesX-linked dystonia-parkinsonism (XDP) is a severe neurodegenerative movement disorder caused by a retrotransposon insertion with a polymorphic hexanucleotide repeat expansion in the TAF1 gene. While the disease predominantly affects males, female carriers may exhibit a variable phenotypic expression. Neurobiological alterations in asymptomatic female mutation carriers (fMC) remain largely unexplored. We aimed to investigate whether fMC exhibit neurodegenerative changes despite the absence of overt clinical manifestations and to assess their clinical, genetic, and longitudinal correlates using multimodal MRI.

MethodsIn this cross-sectional and longitudinal multimodal study, 103 female relatives of XDP patients underwent clinical, genetic, and MRI assessments. Forty-two were identified as fMC and 61 as healthy controls (HC). Structural T1-weighted MRI was analyzed using voxel{-}based morphometry and subcortical volumetry, while susceptibility-weighted imaging assessed iron deposition. Clinical evaluation included standardized motor and cognitive testing. Longitudinal follow-up MRI was available for a subset of participants (20 fMC, 13 HC).

ResultsfMC exhibited significant striatal atrophy compared to HC, with volume reductions in the caudate (-19.4%), putamen (-18.6%), and pallidum (-28.6%) (all p<0.001), despite the absence of overt movement disorders or cognitive deficits, accompanied by relative cerebellar hypertrophy. In fMC striatal volumes decreased with increasing age (putamen: rho=-0.382, p=0.012; caudate: rho=-0.631, p<0.001) and virtual time from genetically determined estimated age at onset (putamen: rho=-0.406, p=0.008; caudate: rho=-0.660, p<0.001). Susceptibility-weighted imaging revealed increased iron deposition in the caudate in fMC, which increased with greater local atrophy (rho=0.718, p<0.001). No significant longitudinal progression was detected over follow-up intervals of up to 25.5 months.

DiscussionAsymptomatic female carriers of the XDP-associated TAF1 variant exhibit significant striatal neurodegeneration and iron accumulation, indicating a dominant-negative effect despite X-linked inheritance. Future longitudinal studies should focus on non-motor features and integrate genetic, imaging, and clinical markers to improve risk stratification and identify the subset of female carriers most likely to benefit from future disease-modifying therapies.

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BibTeX RIS

BibTeX

@misc{hanssen2026preclinical,
  title = {{Preclinical Basal Ganglia Neurodegeneration in Female X Linked Dystonia Parkinsonism Carriers}},
  author = {H. Hanssen and C. C. E. Diesta and M. Heldmann and J. Dy and , J. Tantianpact and J. Uter and M. Brand and B.-H. Laabs and R. R. Rosales and A. Westenberger and C. Klein and J. Q. Oropilla and N. Brüggemann},
  howpublished = {medRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.14.26362974},
  url = {https://www.medrxiv.org/content/10.64898/2026.09.14.26362974v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Preclinical Basal Ganglia Neurodegeneration in Female X Linked Dystonia Parkinsonism Carriers
AU  - H. Hanssen
AU  - C. C. E. Diesta
AU  - M. Heldmann
AU  - J. Dy
AU  - , J. Tantianpact
AU  - J. Uter
AU  - M. Brand
AU  - B.-H. Laabs
AU  - R. R. Rosales
AU  - A. Westenberger
AU  - C. Klein
AU  - J. Q. Oropilla
AU  - N. Brüggemann
PY  - 2026
DA  - 2026/09/14
PB  - medRxiv
DO  - 10.64898/2026.09.14.26362974
UR  - https://www.medrxiv.org/content/10.64898/2026.09.14.26362974v1
AB  - Background and ObjectivesX-linked dystonia-parkinsonism (XDP) is a severe neurodegenerative movement disorder caused by a retrotransposon insertion with a polymorphic hexanucleotide repeat expansion in the TAF1 gene. While the disease predominantly affects males, female carriers may exhibit a variable phenotypic expression. Neurobiological alterations in asymptomatic female mutation carriers (fMC) remain largely unexplored. We aimed to investigate whether fMC exhibit neurodegenerative changes despite the absence of overt clinical manifestations and to assess their clinical, genetic, and longitudinal correlates using multimodal MRI.  MethodsIn this cross-sectional and longitudinal multimodal study, 103 female relatives of XDP patients underwent clinical, genetic, and MRI assessments. Forty-two were identified as fMC and 61 as healthy controls (HC). Structural T1-weighted MRI was analyzed using voxel{-}based morphometry and subcortical volumetry, while susceptibility-weighted imaging assessed iron deposition. Clinical evaluation included standardized motor and cognitive testing. Longitudinal follow-up MRI was available for a subset of participants (20 fMC, 13 HC).  ResultsfMC exhibited significant striatal atrophy compared to HC, with volume reductions in the caudate (-19.4%), putamen (-18.6%), and pallidum (-28.6%) (all p<0.001), despite the absence of overt movement disorders or cognitive deficits, accompanied by relative cerebellar hypertrophy. In fMC striatal volumes decreased with increasing age (putamen: rho=-0.382, p=0.012; caudate: rho=-0.631, p<0.001) and virtual time from genetically determined estimated age at onset (putamen: rho=-0.406, p=0.008; caudate: rho=-0.660, p<0.001). Susceptibility-weighted imaging revealed increased iron deposition in the caudate in fMC, which increased with greater local atrophy (rho=0.718, p<0.001). No significant longitudinal progression was detected over follow-up intervals of up to 25.5 months.  DiscussionAsymptomatic female carriers of the XDP-associated TAF1 variant exhibit significant striatal neurodegeneration and iron accumulation, indicating a dominant-negative effect despite X-linked inheritance. Future longitudinal studies should focus on non-motor features and integrate genetic, imaging, and clinical markers to improve risk stratification and identify the subset of female carriers most likely to benefit from future disease-modifying therapies.
ER  -

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