Brain Advance Access originally published online on November 14, 2006
Brain 2007 130(1):134-142; doi:10.1093/brain/awl283
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Defective temporal processing of sensory stimuli in DYT1 mutation carriers: a new endophenotype of dystonia?
1 Department of Neurological and Vision Sciences, Section of Rehabilitative Neurology, University of Verona Verona 2 Neurology Unit, Borgo Trento Hospital Verona 3 IRCCS CSS, Mendel Institute IRCCS ‘Fondazione Santa Lucia’, Rome 4 Department of Psychology, University of Rome ‘La Sapienza’ and Neuropsychology Research Centre IRCCS ‘Fondazione Santa Lucia’, Rome 5 Neurology Clinic Brescia 6 Neuropsychiatry Department, G. Brotzu Hospital Cagliari 7 Institute of Neurology, University of Bari Italy 8 Sobell Department of Motor Neuroscience and Movement Disorders and Institute of Neurology London, UK
Correspondence to: Mirta Fiorio, Department of Neurological and Vision Sciences, Section of Rehabilitative Neurology, University of Verona, Via Casorati 43, 37131 Verona, Italy E-mail: mirta.fiorio{at}medicina.univr.it
DYT1 primary torsion dystonia is an autosomal dominant movement disorder due to a 3-bp GAG deletion in the TOR1A gene, which becomes manifest in only 30–40% of mutation carriers. Investigating the factors regulating this reduced penetrance might add new insight into the mechanisms underlying the disease. The pathophysiology of dystonia has been related to basal ganglia dysfunctions that lead to the most prominent motor symptoms. However, subclinical sensory deficits have also been reported, particularly in adult-onset focal dystonia. Sensory abnormalities in different forms of sporadic dystonia have been revealed by using a psychophysical method, namely, the temporal discrimination threshold (TDT), quantified as the shortest time interval at which the two stimuli are perceived as separate. Little or no information about the presence of sensory abnormalities in DYT1 gene manifesting and non-manifesting carriers is available. With the aim of disclosing possible associations between sensory deficits and the DYT1 mutation, we assessed TDTs of DYT1 manifesting patients (n = 9); DYT1 non-manifesting relatives (n = 11); non-carrier relatives (n = 9); external control subjects (n = 11). Pairs of tactile, visual or visuo-tactile stimuli were delivered in blocked, counterbalanced order. Intervals between stimuli increased from 0 to 400 ms (in 10 ms steps). On each trial, subjects had to report whether stimuli occurred simultaneously or asynchronously. We measured the first out of three consecutive inter-stimulus intervals at which subjects recognized the two stimuli as temporally separated (TDT) and the first of three consecutive intervals at which they also reported correctly which stimulus in the pair preceded (or followed) the other temporal order judgment (TOJ). Results showed higher tactile and visuo-tactile TDTs and TOJs in DYT1 carriers, both manifesting and non-manifesting, compared with non-carrier relatives and with external control subjects (for all comparisons, P < 0.039). This finding indicates that the DYT1 mutation determines subclinical sensory alterations, which could be disclosed by a psychophysical task. Moreover, these results have the notable implication that sensory deficits in dystonia are not a mere consequence of abnormal movements, but they may even occur before overt clinical manifestations, representing a subclinical phenotype in DYT1 mutation carriers.
Key Words: DYT1 gene; dystonia; sensory systems; temporal discrimination; endophenotype
Abbreviations: ISI, inter-stimulus interval; PTD, primary torsion dystonia; TDT, temporal discrimination threshold; TOJ, temporal order judgement
Received May 18, 2006. Revised August 12, 2006. Accepted September 1, 2006.
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