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X-Linked Dystonia-Parkinsonism

recent advances

Bragg, D. Cristopher; Sharma, Nutan; Ozelius, Laurie J.

doi: 10.1097/WCO.0000000000000708
MOVEMENT DISORDERS: Edited by Per Svenningsson and Steven J. Frucht
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Purpose of review Our understanding of X-Linked Dystonia-Parkinsonism (XDP) has advanced considerably in recent years because of a wealth of new data describing its genetic basis, cellular phenotypes, neuroimaging features, and response to deep brain stimulation (DBS). This review provides a concise summary of these studies.

Recent findings XDP is associated with a SINE-VNTR-Alu (SVA)-type retrotransposon insertion within the TAF1 gene. This element includes a hexameric DNA repeat expansion, (CCCTCT)n, the length of which varies among patients and is inversely correlated to age of disease onset. In cell models, the SVA alters TAF1 splicing and reduces levels of full-length transcript. Neuroimaging data have confirmed previous neuropathology studies that XDP involves a progressive striatal atrophy, while further detecting functional alterations in additional brain regions. In patients exhibiting features of both dystonia and parkinsonism, pallidal DBS has resulted in rapid improvement of hyperkinetic movements, but effects on hypokinetic features have been inconsistent.

Summary The discovery that XDP is linked to a polymorphic hexameric sequence suggests that it could share mechanisms with other DNA repeat disorders, whereas the transcriptional defect in cell models raises the possibility that strategies to correct TAF1 splicing could provide therapeutic benefit.

The Collaborative Center for X-linked Dystonia Parkinsonism, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, USA

Correspondence to Laurie J. Ozelius, PhD, Department of Neurology, Massachusetts General Hospital, Building 114, 16th Street, Charlestown, MA 02129, USA. Tel: +1 617 724 2346; fax: +1 617 643 7080; e-mail: lozelius@partners.org

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