After excluding mutations in known primary dystonia genes (TOR1A, THAP1 and CIZ1), whole-exome sequencing identified a GNAL missense mutation (c.682G>T, p.V228F) in an African-American pedigree with clinical phenotypes that include cervical, laryngeal and hand-forearm dystonia.
Altered responses to dopaminergic D2 receptor activation and N-type calcium currents in striatal cholinergic interneurons in a mouse model of DYT1 dystonia.
Although clinically similar to most cohorts with dystonia worldwide, the classical mutation (c.907_909delGAG) in TOR1A (causing DYT1) is absent in our patients.
Although mutations in DYT1 are associated with a rare form of heritable generalized dystonia, the native function of torsinA seems to be cytoprotective in maintaining the cellular threshold to endoplasmic reticulum (ER) stress.
Analysis of 83 published series including 5,057 patients indicated significant differences in the mean age at onset of five phenotypes of PTD (mean age at onset; 95% CI): DYT1dystonia (11.3 years; 10.3 to 12.2), writer's cramp (38.4; 36.9 to 39.9), CD (40.8; 40.3 to 41.3), spasmodic dysphonia (43.0; 42.2 to 43.9), and blepharospasm-oromandibular dystonia (55.7; 55.1 to 56.4).
Based on this evidence, herein we carried out a comprehensive analysis of electrophysiological, behavioral and signaling correlates of D2R transmission in transgenic mice with the DYT1dystonia mutation.
Breakthroughs include the discovery of a genetic modifier that protects against clinical expression in DYT1dystonia and the identification of the gene causing DYT6, THAP1.
Deep brain stimulation (DBS) has been used successfully to treat refractory dystonia, specifically globus pallidus interna (GPi) DBS for DYT1-positive PGD patients.
Diagnostic sensitivity and specificity were evaluated in an additional 8 subjects with known DeltaGAG DYT1 dystonia and 88 subjects with DeltaGAG-negative dystonia.
DYT6 is a primary, early-onset torsion dystonia; however, unlike in DYT1dystonia, the symptoms of DYT6 dystonia frequently involve the craniocervical region.
Early onset in a limb and progression toward a generalized form, but not family history of dystonia, are indicative of DYT1dystonia in Polish dystonic individuals.
Enrollment in this prospective expanded pilot study was limited to adult patients with severely disabling, medically refractory non-DYT1 generalized dystonia or choreoathetosis.
Evidence suggests that TOR1A mutation produces dystonia through an aberrant neuronal signalling within the striatum, where D2 dopamine receptors (D2R) produce an abnormal excitatory response in cholinergic interneurons (ChIs) in different models of DYT1 dystonia.