Hereditary dystonia as a neurodevelopmental circuit disorder: Evidence from neuroimaging

Abstract

Primary dystonia has traditionally been viewed as a basal ganglia disorder, but recent studies suggest that the cerebellum plays a crucial role in the disease. Primary dystonia is associated with several genotypes. Among those, DYT1 and DYT6 are inherited in autosomal dominant fashion with reduced penetrance. Extensive structural and functional imaging studies have been performed on manifesting and non-manifesting carriers of these mutations. The results suggest that primary dystonia can be viewed as a neurodevelopmental circuit disorder, involving the cortico-striatopallido-thalamo-cortical and cerebello-thalamo-cortical pathways. Anatomical disruption of the cerebellar outflow is found in non-manifesting and manifesting mutation carriers, and a second downstream disruption in thalamo-cortical projections appears clinically protective in nonmanifesting carriers. The microstructural deficits in cerebellar outflow are linked to an abnormally elevated sensorimotor network (NMRP) in dystonia patients. Abnormal expression of this network is reduced by successful treatment with deep brain stimulation.

Recent Advances in the Molecular Pathogenesis of Dystonia-Plus Syndromes and Heredodegenerative Dystonias

“…The neuroanatomy underlying dystonic movements reported in this review also highlights the importance of cerebellar pathways, as well as the basal ganglia, which also reflects functional imaging studies in primary dystonia [87]. This suggests that at least some types of dystonia are caused not only by localised dysfunction of the basal ganglia but by the mis-concerted activity of more wide-spread neuronal networks spanning multiple brain regions.…”

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

“…1). Thus, it appears that both the basal ganglia and cerebellum participate and interact under normal conductions in motor and nonmotor functions, and that they share pathologic activity in certain movement disorders, such as parkinsonian tremor and some types of dystonia [95][96][97][98].…”

“…For instance, gene carriers of the autosomal dominant DYT1 and DYT6 dystonias show functional disturbances of cerebellar connections. DYT1 has a relatively low penetrance (about 30 %) that may result from an additional abnormality in thalamocortical projections, which may be protective in these cases [97,[211][212][213]. Subtle structural cerebellar pathology is suspected to occur in some forms of dystonia [214].…”

Dystonia - new advances in classification, genetics, pathophysiology and treatment

“…Extensive structural and functional imaging studies have been performed on manifesting and non-manifesting carriers of DYT1-and DYT6-mutations, and were recently reviewed. The results suggest that primary dystonia can be viewed as a neurodevelopmental circuit disorder, involving the corticostriato-pallido-thalamo-cortical and cerebellothalamo-cortical pathways (28). Aberrant plasticity in various forms of primary dystonia has been reported from several groups.…”

“…Five descriptors are utilized to specify the clinical features axis: age at onset, body distribution, temporal pattern, coexistence of other movement disorders, and coexistence of other neurological or systemic manifestations. Age at onset is divided into infancy (0-2 years), childhood (3-12 years), adolescence (13-20 years), early adulthood (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40), and late adulthood (>40 years). Body distribution is, as in earlier classifications, divided into focal, segmental, multifocal, generalized, and hemidystonia.…”