The authors screened 197 patients with dystonia (generalized: n = 5; focal/segmental: n = 126; myoclonus-dystonia: n = 34; neuroleptic-induced: n = 32), 435 with PD, and 42 with various other movement disorders, along with 812 healthy controls, for small deletions in exon 5 of DYT1 and tested for exon rearrangements by quantitative, duplex PCR in 51 GAG deletion-negative dystonia cases.
Two other non-Jewish families with atypical ITD (later onset and/or cranial or cervical involvement) are not linked to DYT1, which indicates involvement of other genes in dystonia.
Finally, recent studies using DYT1dystonia worm and mouse models led to a potential novel therapeutic agent, which is currently undergoing clinical trials.
Subsequently, DYT1dystonia is used as an example of how genetics can aid in the evaluation of patients presenting with this group of heritable diseases.
Abnormal processing, transport, or entrapment of VMAT2 within the mutant torsinA membranous inclusions, therefore, may affect cellular dopamine release, providing a potential pathogenic mechanism for the DYT1-dependent dystonia.
The DYT1 mutation was also detected in 2 patients with multifocal dystonia, 1 of them presenting with involvement of cranial and cervical muscles, and in 2 patients with writer's cramp of both hands with only slight progression.
Twelve dystonia patients manifesting the disease, seven nonmanifesting dystonia mutation carriers (DYT1 and DYT6 gene mutations), and eight age-matched normal control subjects were imaged for a previous study.
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.
We identified a de novo delGAG mutation in the TOR1A gene in a patient with a typical DYT1 phenotype and a novel c.1A > G (p.Met1?) mutation in THAP1 in a patient with early onset generalized dystonia with speech involvement.
These results indicate that the cysteine-containing sensor II plays a critical role in redox sensing and the nucleotide and partner binding functions of torsinA and suggest that loss of this function of torsinA contributes to the development of DYT1dystonia.
Although clinically similar to most cohorts with dystonia worldwide, the classical mutation (c.907_909delGAG) in TOR1A (causing DYT1) is absent in our patients.
Diagnostic sensitivity and specificity were evaluated in an additional 8 subjects with known DeltaGAG DYT1 dystonia and 88 subjects with DeltaGAG-negative dystonia.