There are well-known monogenic forms of isolated dystonia with pediatric onset such as DYT1 and DYT6 transmitted with autosomal dominant inheritance and low penetrance.
We tested if OCS/OCD is a clinical manifestation of the DYT1dystonia mutation by interviewing members of families with an identified DYT1 mutation, and classifying by manifesting carriers (MC), non-manifesting carriers (NMC), and non-carriers (NC).
While a 3-bp deletion in the DYT1 gene is the most frequent cause of early limb-onset, generalized dystonia, it has also been found in non-generalized forms of sporadic dystonia.
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.
To evaluate the contribution of these genetic loci to other families with familial "non-DYT1" dystonia five large families with dystonia were studied using genetic markers spanning the DYT6 and DYT7 regions.
No difference in regional mean 11C-diprenorphine binding was found between DYT1-PTD and controls, and no correlation between the severity of dystonia and opioid binding was seen.
These findings provide functional evidence for the potential pathogenic nature of these rare sequence variants in the TOR1A gene, thus implicating these pathologies in the development of dystonia.
Inherited dystonia designated by DYT locus symbols can be separated into three broad phenotypic categories: primary torsion dystonia (PTD), where dystonia is the only clinical sign (except for tremor) (DYT1, 2, 4, 6, 7, 13, 17, and 21); dystonia plus loci, where other phenotypes in addition to dystonia, including parkinsonism or myoclonus, are present (DYT3, 5/14, 11, 12, 15, and 16); and paroxysmal forms of dystonia/dyskinesia (DYT8, 9, 10, 18, 19, and 20).
In conclusion, multiple cell types appear to utilize torsin AAA+ proteins and differential expression of torsinB may contribute to both the neuronal specific importance of torsinA and the symptom specificity of DYT1dystonia.
We tested DYT1 GAG-deletion carriers with (n=119) and without (n=113) clinical signs of dystonia and control individuals (n=197) and found the frequency of the 216H allele to be increased in GAG-deletion carriers without dystonia and to be decreased in carriers with dystonia, compared with the control individuals.
We conclude that marked phenotypic heterogeneity characterizes some families with DYT1dystonia, suggesting a role for genetic, environmental, or other modifiers.
Six patients aged 7 to 16 years and diagnosed with isolated dystonia ( DYT1 negative) (3 patients), choreo-dystonia related to PDE2A mutation (1 patient), or myoclonus-dystonia syndrome SGCE mutations (2 patients) were evaluated during a period of 6 to 19 months.
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.
1.The prevalence of DYT1 mutation among patients with early-onset (<or= 24 years) dystonia was 20.8% and it was similar to that found in other European populations.2.
In conclusion, our results argue against the hypothesis of transcriptional dysregulation in DYT1dystonia, suggesting potential alternative pathogenic pathways.