Journal
CURRENT OPINION IN NEUROLOGY
Volume 29, Issue 4, Pages 486-495Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/WCO.0000000000000352
Keywords
chorea; genetics; Huntington's disease; medium spiny neurons; next-generation sequencing
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Funding
- Medical Research Council/Wellcome Trust Strategic Award [WT089698/Z/09/Z]
- Department of Health's National Institute for Health Research (NIHR) Biomedical Research Centres
- Pierfranco and Luisa Mariani Foundation
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Purpose of review Chorea presenting in childhood and adulthood encompasses several neurological disorders, both degenerative and nonprogressive, often with a genetic basis. In this review, we discuss how modern genomic technologies are expanding our knowledge of monogenic choreic syndromes and advancing our insight into the molecular mechanisms responsible for chorea. Recent findings A genome-wide association study in Huntington's disease identified genetic disease modifiers involved in controlling DNA repair mechanisms and stability of the HTT trinucleotide repeat expansion. Chorea is the cardinal feature of newly recognized genetic entities, ADCY5 and PDE10A-related choreas, with onset in infancy and childhood. A phenotypic overlap between chorea, ataxia, epilepsy, and neurodevelopmental disorders is becoming increasingly evident. Summary The differential diagnosis of genetic conditions presenting with chorea has considerably widened, permitting a molecular diagnosis and an improved prognostic definition in an expanding number of cases. The identification of Huntington's disease genetic modifiers and new chorea-causing gene mutations has allowed the initial recognition of converging molecular pathways underlying medium spiny neurons degeneration and dysregulation of normal development and activity of basal ganglia circuits. Signalling downstream of dopamine receptors and control of cAMP levels represent a very promising target for the development of new aetiology-based treatments for chorea and other hyperkinetic disorders.
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