Temporal Discrimination, a Cervical Dystonia Endophenotype: Penetrance and Functional Correlates Okka Kimmich, MB, 1,2 Anna Molloy, MRCPI, 1,2 Robert Whelan, PhD, 3 Laura Williams, MRCPI, 1,2 David Bradley, PhD, 1,3 Joshua Balsters, PhD, 4 Fiona Molloy, FRCPI, 5 Tim Lynch, FRCPI, 6 Daniel G. Healy, PhD, 7 Cathal Walsh, PhD, 8 Se an O’Riordan, FRCPI, 1,2 Richard B. Reilly, PhD, 3 and Michael Hutchinson, FRCP 1,2 * 1 Department of Neurology, St. Vincent’s University Hospital, Dublin, Ireland 2 School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland 3 Trinity Centre for Bioengineering, Trinity College Dublin, Ireland 4 Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland 5 Department of Neurophysiology, Beaumont Hospital, Dublin, Ireland 6 Department of Neurology, Mater Misericordiae University Hospital, Dublin, Ireland 7 Department of Neurology, Beaumont Hospital, Dublin, Ireland 8 Department of Statistics, Trinity College Dublin, Dublin, Ireland ABSTRACT: The pathogenesis of adult-onset pri- mary dystonia remains poorly understood. There is vari- able age-related and gender-related expression of the phenotype, the commonest of which is cervical dystonia. Endophenotypes may provide insight into underlying genetic and pathophysiological mechanisms of dystonia. The temporal discrimination threshold (TDT)—the shortest time interval at which two separate stimuli can be detected as being asynchronous—is abnormal both in patients with cervical dystonia and in their unaffected first-degree relatives. Functional magnetic resonance imaging (fMRI) studies have shown that putaminal activa- tion positively correlates with the ease of temporal dis- crimination between two stimuli in healthy individuals. We hypothesized that abnormal temporal discrimination would exhibit similar age-related and gender-related pen- etrance as cervical dystonia and that unaffected relatives with an abnormal TDT would have reduced putaminal activation during a temporal discrimination task. TDTs were examined in a group of 192 healthy controls and in 158 unaffected first-degree relatives of 84 patients with cervical dystonia. In 24 unaffected first-degree relatives, fMRI scanning was performed during a temporal discrimi- nation task. The prevalence of abnormal TDTs in unaf- fected female relatives reached 50% after age 48 years; whereas, in male relatives, penetrance of the endopheno- type was reduced. By fMRI, relatives who had abnormal TDTs, compared with relatives who had normal TDTs, had significantly less activation in the putamina and in the middle frontal and precentral gyri. Only the degree of reduction of putaminal activity correlated significantly with worsening of temporal discrimination. These findings further support abnormal temporal discrimination as an endophenotype of cervical dystonia involving disordered basal ganglia circuits. V C 2014 International Parkinson and Movement Disorder Society Key Words: cervical dystonia; temporal discrimina- tion; functional magnetic resonance imaging; putamen; endophenotype Cervical dystonia is the commonest form of adult- onset primary torsion dystonia (AOPTD) with a female preponderance. It is believed that manifestation of the disease results from a combination of suscepti- bility genes with reduced penetrance, 1-4 individual genetic and environmental risk factors, and a likely effect of age of onset on the expression of the pheno- type. 5 To date, apart from the protein-coding THAP domain containing, apoptosis associated protein 1 gene (THAP1), 6 no genes other than those affecting single families have been identified. 7,8 ------------------------------------------------------------ Additional Supporting Information may be found in the online version of this article. *Correspondence to: Dr. Michael Hutchinson, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland; mhutchin2@mac.com Funding agencies: This work was supported by grants from Dystonia Ireland, a non-profit patient information and support organization, and the Health Research Board, Ireland (CSA-2012/5). Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online ver- sion of this article. Received: 2 May 2013; Revised: 3 December 2013; Accepted: 9 December 2013 Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25822 RESEARCH ARTICLE Movement Disorders, Vol. 00, No. 00, 2014 1