Interestingly, mutations in the TOR1A gene (the gene encoding torsinA) are associated with DYT1dystonia and with the preferential localization of mutated torsinA at the NE, where it is associated with lamina-associated polypeptide 1.
In children with dystonia; if brain imaging is unremarkable and when there is no history of CNS disorders such as perinatal asphyxia, infections, drug exposure or trauma; genetic analysis for GAG deletion of DYT-1 gene may be performed even if dystonia starts at a very young age or it spreads to involve oromandibular muscles.
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).
Dystonias with known genes include DYT1 and DYT6 dystonia, presenting as isolated torsion dystonia, as well as DYT5 (dopa-responsive dystonia), DYT11 (myoclonus-dystonia), and DYT12 (rapid-onset dystonia-parkinsonism), where dystonia occurs in conjunction with other types of movement disorders.
We used a multidisciplinary approach to investigate the responses to mu activation in 2 mouse models of DYT1dystonia (Tor1a<sup>+/Δgag</sup> mice, Tor1a<sup>+/-</sup> torsinA null mice, and their respective wild-types).
The DeltaGAG deletion mutation in DYT1, causing a loss of a glutamic acid near the carboxyl terminus of torsinA protein (torsinADeltaE), is dominantly inherited and tends to result in a severe generalized form of dystonia with childhood onset.
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.
We report that changes of phosphodiesterase-10A (PDE10A) can map widespread functional imbalance of basal ganglia circuits in a mouse model of DYT1dystonia overexpressing mutant torsinA.
This 18-bp deletion is the first additional mutation, beyond the GAG-deletion (Glu302/303del), to be found in the TOR1A gene, and is associated with a distinct type of early onset dystonia.
Perinatal adversities might modulate the clinical penetrance of DYT1dystonia; their interaction with known genetic factors modifying penetrance of this condition should be investigated in new, larger collaborative studies.
Here, I review the clinical genetics and cell biology of three forms of inherited dystonia for which the causative mutation is known: DYT1 (TOR1A), DYT6 (THAP1), DYT25 (GNAL).
Furthermore, torsinA, that is mutated in DYT1dystonia, a rare type of primary dystonia, binds to and promotes the degradation of epsilon-sarcoglycan mutants when both proteins are co-expressed.
Future study of normal and mutant torsin A, as well as the identification of other primary torsion dystonia genes, should help elucidate the mechanisms underlying dystonia.
The clinical presentations of the DYT1 cases included onset in the limbs that could progress to the generalized dystonia within several years but without cranial involvement.
This observation raises the possibility of genotype-phenotype correlations in DYT1 and indicates that the clinical spectrum of this type of dystonia might be broader then previous classic descriptions.
Linkage of a gene causing classic dystonia in a large non-Jewish kindred (DYT1) and in a group of Ashkenazi Jewish families, to the gelsolin (GSN) and arginino-succinate synthetase (ASS) loci on chromosome 9q32-34, respectively, was recently determined.