Primary dystonia: molecules and mechanisms

Abstract

Primary dystonia is characterized by abnormal, involuntary twisting and turning movements that reflect impaired motor system function. The dystonic brain seems normal, in that it contains no overt lesions or evidence of neurodegeneration, but functional brain imaging has uncovered abnormalities involving the cortex, striatum and cerebellum, and diffusion tensor imaging suggests the presence of microstructural defects in white matter tracts of the cerebellothalamocortical circuit. Clinical electrophysiological studies show that the dystonic CNS exhibits aberrant plasticity--perhaps related to deficient inhibitory neurotransmission--in a range of brain structures, as well as the spinal cord. Dystonia is, therefore, best conceptualized as a motor circuit disorder, rather than an abnormality of a particular brain structure. None of the aforementioned abnormalities can be strictly causal, as they are not limited to regions of the CNS subserving clinically affected body parts, and are found in seemingly healthy patients with dystonia-related mutations. The study of dystonia-related genes will, hopefully, help researchers to unravel the chain of events from molecular to cellular to system abnormalities. DYT1 mutations, for example, cause abnormalities within the endoplasmic reticulum-nuclear envelope endomembrane system. Other dystonia-related gene products traffic through the endoplasmic reticulum, suggesting a potential cell biological theme underlying primary dystonia.

Figure 1

Clinical examples of primary dystonia. a | Writer’s cramp. Abnormal clenching of fingers occurs selectively during writing; patient is otherwise normal. b | Dystonia of arm, neck and face, exacerbated during writing. Patient first developed writer’s cramp, but subsequently developed dystonia of the neck (torticollis) and face. c | Fixed dystonic foot posture. d | Involuntary dystonic flexion of trunk and extension of neck (retrocollis) during gait.

Figure 2

Motor circuit abnormalities associated with DYT1 genotype and clinical symptom manifestation. Left column shows simplified motor circuit diagrams and right column shows cerebellothalamocortical tract reconstructions from fiber tractography data. The DYT1-mutation-positive state is characterized by reduced dopamine D₂ receptor availability, and abnormalities of the cerebellothalamocortical tract, regardless of the presence or absence of symptoms. The site and consequences of decreased D₂ receptor availability are not understood, as striatal D₂ receptors are expressed on cortical, dopaminergic and cholinergic axons, as well as on medium spiny output neurons. Manifesting and non-manifesting DYT1 carriers exhibit similar abnormalities of cerebellothalamic tract microstructure (indicated by broken arrows connecting these structures). Non-manifesting DYT1 carriers show greater abnormalities of thalamocortical microstructure than do symptomatic patients, which could counteract the motor consequences of the cerebellothalamic abnormalcy. The loss of cerebellothalamocortical connectivity is associated with changes in movement-related cerebral blood flow (indicated by coloring of cortex, thalamus and cerebellum). Basal ganglia output (from GPi to thalamus) is reduced or abnormal in hyperkinetic disorders, which is believed to result in disinhibition of the ventral anterior–ventral lateral thalamocortical output. Abbreviations: GPe, globus pallidus externa; GPi, globus pallidus interna; SNpC, substantia nigra pars compacta; STN, subthalamic nucleus.