Non-Huntington’s disease chorea: an expanding universe with acquired causes

Huntington's disease phenocopies are conditions characterized by a phenotype similar to Huntington's disease but without a pathogenic repeat expansion in the HTT gene. The percentage of patients who have a Huntington's disease phenotype but subsequently are shown not to carry a repeat expansion ranges from 2% to 40%, depending on the ethnicity and the geographic location of the population studied, as well as the resources available for investigation of the underlying causes. In descending order of frequency, genetic causes are Huntington disease-like 2/JHP3, spinocerebellar ataxia genes (SCA17/TBP, SCA12/PPP2R2B and SCA3/ATXN3, CACNA1A) and frontotemporal dementia genes (C9orf72 and VCP). In addition, it has been established that a growing list of acquired causes may also mimic Huntington's disease, including autoimmune illnesses such as primary antiphospholipid syndrome, paraneoplastic chorea and anti-IGLON5 (immunoglobulin-like cell adhesion molecule 5). Here, we aim to review the epidemiology, aetiology, clinical and laboratory findings of the wide range of conditions associated with Huntington's disease phenocopies, and proceed to suggest a practical diagnostic approach to the investigation of Huntington's disease phenocopies taking into account the age at onset, ethnicity and geographic location of individuals.