FUNCTIONAL BRAIN NETWORKS IN DYT1 DYSTONIA

Early-onset idiopathic torsion dystonia (ITD) is an autosomal dominant hyperkinetic movement disorder with incomplete penetrance, associated with a 3 base-pair deletion in the DYT1 gene on chromosome 9q34. To d etermine the metabolic substrates of brain dysfunction in DYT1 dystoni a, we scanned 7 nonmanifesting and 10 affected DYT1 carriers and 14 no rmal volunteers with [F-18] fluorodeoxyglucose and positron emission t omography. We found that DYT1 dystonia is mediated by the expression o f two independent regional metabolic covariance patterns. The first pa ttern, identified in an analysis of nonmanifesting gene carriers was d esignated movement free (MF). This abnormal pattern was characterized by increased metabolic activity in the lentiform nuclei, cerebellum, a nd supplementary motor areas. The MF pattern was present in DYT1 carri ers with and without clinical manifestations and persisted in DYT1 dys tonia patients in whom involuntary movements were suppressed by sleep. The second pattern, identified in an analysis of affected gene carrie rs with sustained contractions at rest, was designated movement relate d (MR). This pattern was characterized by increased metabolic activity in the midbrain, cerebellum, and thalamus. The expression of the MR p attern was increased in waking DYT1 patients with sustained dystonia, compared with DYT1 carriers who were unaffected or who had dystonia on ly on action, as well as normal controls. MR subject scores declined s ignificantly with sleep in affected DYT1 patients but not in normal co ntrols. These findings indicate the penetrance of the DYT1 gene is con siderably greater than previously assumed. ITD is mediated through the interaction of functional brain networks relating separately to gene status and to abnormal movement.