Le funzioni sensoriali nella distonia DYT1. Discriminazione temporale e rappresentazione del movimento

DYT1 primary torsion dystonia (PTD) is characterised by prolonged muscular contractions causing abnormal torsion movements and sustained postures (Bressman, 1998). This disorder is due to a 3bp GAG deletion in the TOR1 gene, which manifests in only 33% mutation carriers (Gambarin et al., 2006). Typical of the disease is the early-onset in a limb and rapid generalization (Ozelius et al. 1997). The mechanisms underlying reduced penetrance are poorly understood, although three DYT1 polymorphisms have been recently shown to influence penetrance (Risch et al., 2007). Albeit still largely unknown, the pathophysiology of PTD has been related to basal ganglia dysfunctions leading not only to the most prominent motor symptoms, but also to subclinical sensory deficits. Sensory feedback is crucial for driving motor outputs. Thus, although at first counterintuitive, the impairment of sensory functions may play a fundamental role in the pathophysiology of dystonia (Hallet 1995; Tinazzi 2003). Indeed, defective sensory functions have been demonstrated in several forms of dystonia. Temporal discrimination is a basic aspect of somatosensory processing, essential for a number of functions including kinaesthesia, graphesthesia, vibratory sense and stereognosis. Assessment of this function has been carried out by using temporal discrimination threshold (TDT), defined as the shortest time at witch two stimuli are perceived as separate. Studies converge to indicate that thresholds were much higher in patients with generalised, cervical and focal-hand dystonia than control subjects (Bara-Jimenez et al., 2000; Aglioti et al., 2003; Fiorio et al, 2003; Tinazzi et al., 2004). These deficits have been interpreted in light of the relation between dystonia and dysfunctions of basal ganglia that are implicated not only in motor control but also in temporal processing (Lacrutz et al., 1991; Harrington at al., 1998). Interestingly sensory deficit has been observed in the unaffected hand of patient with unilateral focal-hand dystonia (Fiorio et al., 2003). This would suggest that sensory abnormalities occur before overt manifestation of dystonia (Meunier et al., 2001; Fiorio et al., 2003). Little or no information about the presence of sensory abnormalities in DYT1 gene manifesting and non manifesting carriers is available. The main aim of the first part of our study was to reveal whether any sensory dysfunctions in DYT1 may be related to the abnormal genetic substrate and thus considered a sensory endophenotipic trait of disease. So we applied the same temporal discrimination paradigm (Fiorio et al. 2003) in manifesting and non carrier relatives and in external control subjects. Pairs of tactile, visual or visual-tactile stimuli were delivered in blocked, counter-balanced order. Interval 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 interstimulus intervals at witch subjects recognised the two stimuli as temporally separated (TDT) and the first of the three consecutive intervals at witch they also reported correctly with stimulus in the pair preceded (or followed) the other temporal order judgment (TOJ). We assessed 9 DYT1 manifesting patients, 11 DYT1 non manifesting relatives, 9 non carrier relatives and 9 external control subjects. Results showed hither tactile and visuotactile TDTs and TOJs in DYT1 carriers, both manifesting and non-manifesting, compared with non carrier relatives and with external control subjects (for all comparison, P< 0.039). This finding indicates that the DYT1 mutation determines subclinical sensory alterations, with could be disclosed by a psychophysical task. Moreover the results have notable implication that sensory deficits in dystonia are not mere consequence of abnormal movements, but the may even occur before overt clinical manifestation, representing a subclinical phenotype in DYT1 mutation carriers. An other defective sensory functions, the body movement representation, have been demonstrated in several forms of dystonia. A fundamental mechanism underlying motor control is the ability to predict the correct sequence of movements to be executed and the final position of the body part. A useful tool to investigate movement prediction is the mental rotation paradigm, based on the ability to image a body part or an object in a different perspective from the one in which it actually appears. This process requires an inner simulation of real perceptual and motor performance and, when regarding body parts, it is carried out by simulating actual body movements (Parson, 1994). Cortical and subcortical networks probably underlying mental rotation of body parts and objects include posterior parietal and occipital cortices, motor, premotor and supplementary motor areas, basal ganglia, and cerebellum (Bonda et al., 1995; Pearson et al., 1995). Interestingly, patients with primary non-DYT1, late onset focal-hand and cervical dystonia showed impaired mental rotation of body parts either affected or unaffected by dystonia (Fiorio et al, 2006; 2007), raising the possibility that altered performance represents an endophenotypic trait of primary dystonia. So in the second part of our study we examined whether the mental rotation of body parts was impaired in DYT1 carriers, both manifesting and non-manifesting dystonic symptoms, as compared to normal subjects. DYT1 manifesting patients, DYT1 non manifesting carriers and control subjects were asked to fixate body (hand, foot, face) on non body (car) stimuli on a computer screen. Stimuli were presented at different degrees of orientations and subjects had to mentally rotate them, in order to give a laterality judgement. Reaction times and accuracy were collocated. We founded that DYT1 carriers, manifesting and non manifesting dystonic symptoms, were slower in mentally rotating body parts (but not cars) than control subjects and our conclusion was that DYT1 gene mutation is associated with a slowness in mental simulation of movements, independently from the presence of motor symptoms and than this suggests that the cognitive representation of body movements altered subclinically in dystonia, may be contributing to the endophenotypic trait of the disease. The advances described in the two parts of this study indicate that PTD DYT1 is a complex syndrome in witch abnormal subclinical sensory and perceptual functions may coexist with the most prominent motor symptoms. The subclinical alterations may be related to new evidence and to the concept that basal ganglia come into play only in motor but also in sensory and cognitive functions. The fact that both in temporal discrimination study and in mental rotation, non affected DYT1 gene carriers may also show similar abnormalities suggests the hypothesis that sensory deficits might be independent of motor symptoms and might even pre-exist overt clinical manifestations, constituting subclinical endophenotypic traits of disease. Whether ours paradigms might became a useful tool to diagnose the envelope of dystonia before the starting of the motor symptoms, needs further validation on a larger sample of gene carriers and control subjects.