Basal Ganglia Atrophy as a Marker for Prodromal X-Linked Dystonia-Parkinsonism

Henrike Hanssen, Cid C.E. Diesta, Marcus Heldmann, Jackson Dy, Jeffrey Tantianpact, Julia Steinhardt, Rosanna Sauza, Hans T.S. Manalo, Andreas Sprenger, Charles Jourdan Reyes, Raphael Tuazon, Björn Hergen Laabs, Aloysius Domingo, Raymond L. Rosales, Christine Klein, Thomas F. Münte, Ana Westenberger, Jean Q. Oropilla, Norbert Brüggemann*

*Corresponding author for this work
3 Citations (Scopus)


In neurodegenerative diseases, the characterization of the prodromal phase is essential for the future application of disease-modifying therapies. X-linked dystonia-parkinsonism is a hereditary neurodegenerative movement disorder characterized by severe adult-onset dystonia accompanied by parkinsonism. Distinct striatal and pallidal atrophy is present already in early disease stages indicating a long-lasting presymptomatic degenerative process. To gain insight into the prodromal phase of X-linked dystonia-parkinsonism, structural and iron-sensitive magnetic resonance imaging (MRI) was performed in 10 non-manifesting carriers and 24 healthy controls in a double-blind fashion. Seventeen patients with X-linked dystonia-parkinsonism were recruited to replicate previous findings of basal ganglia pathology and iron accumulation. Age at onset was estimated in non-manifesting carriers and patients using the repeat length of the hexanucleotide expansion and 3 single-nucleotide polymorphisms associated with age at onset. Voxel-based morphometry and subcortical volumetry showed striatal and pallidal atrophy in non-manifesting carriers (~10%) and patients (~40%). Substantia nigra volume was similarly reduced in patients (~40%). Caudate volume correlated with time to estimated onset in non-manifesting carriers. Susceptibility-weighted imaging confirmed iron deposition in the anteromedial putamen in patients. Non-manifesting carriers also showed small clusters of iron accumulation in the same area after lowering the statistical threshold. In conclusion, basal ganglia atrophy and iron accumulation precede the clinical onset of X-linked dystonia-parkinsonism and can be detected years before the estimated disease manifestation. It thereby highlights the potential of multimodal imaging to identify clinically unaffected mutation carriers with incipient neurodegeneration and to monitor disease progression independent of clinical measures. Longitudinal studies are needed to further elucidate the onset and progression rate of neurodegeneration in prodromal X-linked dystonia-parkinsonism. ANN NEUROL 2023;93:999–1011.

Original languageEnglish
JournalAnnals of Neurology
Issue number5
Pages (from-to)999-1011
Number of pages13
Publication statusPublished - 05.2023

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)
  • Research Area: Medical Genetics
  • Academic Focus: Biomedical Engineering

DFG Research Classification Scheme

  • 206-06 Molecular and Cellular Neurology and Neuropathology
  • 206-07 Clinical Neurology Neurosurgery and Neuroradiology
  • 205-32 Medical Physics, Biomedical Engineering

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