Summary
A medRxiv preprint reports striatal atrophy and increased caudate iron accumulation in asymptomatic female carriers of the genetic variant associated with X-linked dystonia-parkinsonism. The findings came from multimodal MRI in 42 carriers compared with 61 healthy controls.
A medRxiv preprint reports structural changes in the basal ganglia of female carriers of the genetic variant associated with X-linked dystonia-parkinsonism (XDP), even though the carriers had no overt movement disorder or cognitive deficit. The findings came from a cross-sectional and longitudinal multimodal MRI study of 103 female relatives of people with XDP.
The researchers identified 42 female mutation carriers (fMC) and compared them with 61 healthy controls. The preprint was posted on September 15, 2026, and has not yet undergone peer review.
MRI showed changes in the striatum
XDP is a severe neurodegenerative movement disorder associated with a retrotransposon insertion and polymorphic hexanucleotide repeat expansion in the TAF1 gene. The striatum—comprising the caudate and putamen—is a major part of the basal ganglia, brain circuits involved in movement control.
The study used structural T1-weighted MRI to measure regional brain volume and susceptibility-weighted imaging to assess iron deposition. Participants also underwent standardized motor and cognitive testing, alongside genetic and clinical assessments.
Compared with healthy controls, female carriers had lower volumes in several striatal structures:
- caudate volume was reduced by 19.4%;
- putamen volume was reduced by 18.6%;
- pallidum volume was reduced by 28.6%.
All three differences had p<0.001. The carriers also showed relative enlargement of the cerebellum.
Within the carrier group, smaller striatal volumes were associated with increasing age and with increasing time from the genetically estimated age at onset. The age relationship was particularly strong for the caudate, with rho=-0.631, p<0.001, while the putamen showed rho=-0.382, p=0.012.
Susceptibility-weighted MRI also found increased iron deposition in the caudate. Greater local atrophy was associated with greater caudate iron accumulation, with rho=0.718, p<0.001.
A possible preclinical stage of XDP
The combination of volume loss and iron accumulation suggests that some female carriers may undergo biological changes in vulnerable basal-ganglia regions before recognizable clinical symptoms appear. The authors interpret the findings as evidence of significant striatal neurodegeneration in asymptomatic carriers and propose that the pattern may reflect a dominant-negative effect despite X-linked inheritance.
The longitudinal component included 20 female carriers and 13 controls, with follow-up intervals of up to 25.5 months. No significant progression was detected during that period. This short follow-up and the smaller longitudinal subgroup mean the cross-sectional comparison provides the main evidence in the preprint.
The findings could help guide future studies of non-motor features and risk markers in female carriers. The authors propose combining genetic information with imaging and clinical measures to identify which carriers are most likely to develop clinically relevant disease and which might eventually benefit from disease-modifying treatment. The current study itself assessed brain structure, iron deposition and clinical measures; it did not test a treatment or establish that the MRI changes predict future symptoms.