Comparing endophenotypes in adult‐onset primary torsion dystonia

Abstract

Adult-onset primary torsion dystonia (AOPTD) has an autosomal dominant pattern of inheritance with markedly reduced penetrance; the genetic causes of most forms of AOPTD remain unknown. Endophenotypes, markers of subclinical gene carriage, may be of use detecting non-manifesting gene carriers in relatives of AOPTD patients. The aim of this study was to compare the utility of the spatial discrimination threshold (SDT) and temporal discrimination threshold (TDT) as potential endophenotypes in AOPTD. Data on other published candidate endophenotypes are also considered. Both SDT and TDT testing were performed in 24 AOPTD patients and 34 of their unaffected first degree relatives; results were compared with normal values from a control population. Of the 24 AOPTD patients 5 (21%) had abnormal SDTs and 20 (83%) had abnormal TDTs. Of the 34 first degree relatives 17 (50%) had abnormal SDTs and 14 (41%) had abnormal TDTs. Discordant results on SDT and TDT testing were found in 16 (67%) AOPTD patients and 21 (62%) first degree relatives. TDT testing has superior sensitivity compared to SDT testing in AOPTD patients; although false positive TDTs are recognised, the specificity of TDT testing in unaffected relatives is not determinable. The high level of discordance between the two tests probably relates methodological difficulties with SDT testing. The SDT is an unreliable AOPTD endophenotype; TDT testing fulfils criteria for a reliable endophenotype with a high sensitivity.2009 Movement Disorder Society

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 …”

Structural, functional and molecular imaging of the brain in primary focal dystonia—A review

“…It has been proposed as an endophenotype of these disorders. Therefore, it is possible that abnormal TDT is an indicator of abnormal basal ganglia function (Bradley et al, 2010). Interestingly, also relatives of patients with different types of focal dystonia that had abnormal TDT had an increase in putaminal gray matter, in contrast to relatives with normal TDT (Bradley et al, 2009).…”

Temporal discrimination thresholds in adult-onset primary torsion dystonia: an analysis by task type and by dystonia phenotype

“…The temporal discrimination threshold (TDT) is defined as the shortest time interval at which two stimuli can be determined to be asynchronous and is a promising AOPTD endophenotype [13]. This sensory testing modality may be used to demonstrate abnormal temporal processing in AOPTD patients and relatives [14], and is probably a marker of basal ganglia (putaminal) dysfunction [14,15] and possibly of dopaminergic pathway dysfunction in particular [16].…”