Sporadic adult onset primary torsion dystonia is a genetic disorder by the temporal discrimination test

Abstract

Adult-onset primary torsion dystonia is an autosomal dominant disorder with markedly reduced penetrance; patients with sporadic adult-onset primary torsion dystonia are much more prevalent than familial. The temporal discrimination threshold is the shortest time interval at which two stimuli are detected to be asynchronous and has been shown to be abnormal in adult-onset primary torsion dystonia. The aim was to determine the frequency of abnormal temporal discrimination thresholds in patients with sporadic adult-onset primary torsion dystonia and their first-degree relatives. We hypothesized that abnormal temporal discrimination thresholds in first relatives would be compatible with an autosomal dominant endophenotype. Temporal discrimination thresholds were examined in 61 control subjects (39 subjects <50 years of age; 22 subjects >50 years of age), 32 patients with sporadic adult-onset primary torsion dystonia (cervical dystonia n = 30, spasmodic dysphonia n = 1 and Meige's syndrome n = 1) and 73 unaffected first-degree relatives (36 siblings, 36 offspring and one parent) using visual and tactile stimuli. Z-scores were calculated for all subjects; a Z > 2.5 was considered abnormal. Abnormal temporal discrimination thresholds were found in 1/61 (2%) control subjects, 27/32 (84%) patients with adult-onset primary torsion dystonia and 32/73 (44%) unaffected relatives [siblings (20/36; 56%), offspring (11/36; 31%) and one parent]. When two or more relatives were tested in any one family, 22 of 24 families had at least one first-degree relative with an abnormal temporal discrimination threshold. The frequency of abnormal temporal discrimination thresholds in first-degree relatives of patients with sporadic adult-onset primary torsion dystonia is compatible with an autosomal dominant disorder and supports the hypothesis that apparently sporadic adult-onset primary torsion dystonia is genetic in origin.

Sensory aspects of movement disorders

“…107–112 Abnormalities in temporal cutaneous discrimination have been noted not only in the affected limb but also in the unaffected limb of patients with unilateral focal dystonia, and in patients with blepharospasm and cervical dystonia and their unaffected relatives, which suggests a common underlying genetic endophenotype. 110,113–115 The presence of these non-elemental sensory abnormalities, coupled with evidence of impaired sensory and motor processing and loss of so-called surround inhibition, provide strong support for the idea that dystonia is not only a motor but also a sensory disorder. 7,116–118 …”

Temporal discrimination threshold with healthy aging

“…Even higher TDTs, sufficient to differentiate from Parkinson patients, were reported in multiple system atrophy (Rocchi et al, 2013). In dystonia, increased TDT (Conte et al, 2014b, Bradley et al, 2012, Scontrini et al, 2009, Fiorio et al, 2008a, Fiorio et al, 2003, Sanger, et al, 2001, Bara-Jimenez, et al, 2000, Tinazzi et al, 1999) is not only prevalent, but considered to be an endophenotype in autosomal dominant primary torsion dystonia, seen even in unaffected carriers (Kimmich et al, 2011, Bradley et al, 2009, Fiorio et al, 2007). That TDT is highly associated with particular gene mutations has led to interest in developing TDT as a useful tool in performing genetic studies.…”

Spatial Discrimination Threshold Abnormalities are not Detected in a Pilot Study of DYT6 Dystonia Mutation Carriers

“…Studies indicate that such thresholds are higher in patients with DYT1 dystonia,29 and cervical and focal-hand dystonia30 than in healthy controls. Abnormalities in the TDT may represent a reliable endophenotype in those predisposed family members who have not manifested with adult-onset focal dystonia 30, 31. As TDT testing is more sensitive than SDT in adult-onset focal dystonia,16 it may demonstrate changes in sensory integration abnormalities in DYT6 dystonia, and should be tested in this population.…”