title: Defective temporal processing of sensory stimuli in DYT1 mutation carriers: a new endophenotype of dystonia?
abstract: 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.
authors.affiliation: Department of Neurological and Vision Sciences, Section of Rehabilitative Neurology, University of Verona, Verona, Italy. mirta.fiorio@medicina.univr.it
authors.forename: Mirta
authors.initials: M
authors.lastname: Fiorio
authors.forename: Mattia
authors.initials: M
authors.lastname: Gambarin
authors.forename: Enza Maria
authors.initials: EM
authors.lastname: Valente
authors.forename: Paolo
authors.initials: P
authors.lastname: Liberini
authors.forename: Mario
authors.initials: M
authors.lastname: Loi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cossu
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Moretto
authors.forename: Kailash P
authors.initials: KP
authors.lastname: Bhatia
authors.forename: Giovanni
authors.initials: G
authors.lastname: Defazio
authors.forename: Salvatore M
authors.initials: SM
authors.lastname: Aglioti
authors.forename: Antonio
authors.initials: A
authors.lastname: Fiaschi
authors.forename: Michele
authors.initials: M
authors.lastname: Tinazzi
mesh_terms: D000328:Adult; D000368:Aged; D004192:Discrimination, Psychological; D004422:Dystonia Musculorum Deformans / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D005192:Family Health; D005260:Female; D006579:Heterozygote; D006801:Humans; D007600:Judgment; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011601:Psychophysics; D012678:Sensation Disorders / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D012684:Sensory Thresholds / Q000502:physiology; D013997:Time Factors; D014110:Touch / Q000502:physiology; D014786:Vision Disorders / Q000150:complications / Q000235:genetics / Q000503:physiopathology
chemical_list: D018832:Molecular Chaperones; C108175:TOR1A protein, human