Phenotypes and genetic architecture of focal primary torsion dystonia

Groen, Justus L.; Kallen, Marlot C.; Warrenburg, B.P.C. van de; Speelman, Johannes D.; Hilten, Jacobus J. van; Aramideh, M.; Boon, Agnita J.W.; Klein, Christine; Koelman, Johannes H. T. M.; Langeveld, Ton P. M.; Baas, Frank; Tijssen, Marina A. J.

doi:10.1136/jnnp-2012-302729

Cited by 22 publications

(23 citation statements)

References 40 publications

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“…The reported prevalence of sensory tricks was similar to that found in previous studies [28,46]. The physiology of such alleviating manoeuvres in dystonia has been suggested to involve modulation of abnormally increased facilitation [47,48]; detailed characterization of the neurophysiological mechanisms of such alleviating manoeuvres would contribute to increased understanding of sensorimotor integration in dystonia.…”

Section: Sensory Trickssupporting

confidence: 83%

“…A family history of dystonia in these remaining 19 patients cannot be confirmed; Leube and colleagues suggest that patient report is likely to significantly underestimate actual rates of dystonia amongst family members [6]. Reported rates of family history of dystonia in seemingly sporadic AOIFD vary from 26.1% [53], 18% [6] to 9.1% [28]. The patterns of inheritance observed in this study would support an autosomal dominant transmission of genes predisposing to dystonia, with reduced penetrance.…”

Section: Genetic Aspectsmentioning

confidence: 60%

“…Genetic heterogeneity and variation in environmental exposures are possible explanations for this wide range [24,25]. Blepharospasm, for example, is more prevalent in studies from lower latitudes with high solar insolation [23,24,[26][27][28][29][30][31]. Environmental exposures, sex and age at onset may interact with as yet unidentified genetic variants to influence phenotype and penetrance [32][33][34].…”

Section: Introductionmentioning

confidence: 99%

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Epidemiological, clinical and genetic aspects of adult onset isolated focal dystonia in Ireland

Williams

McGovern

Kimmich

et al. 2016

Euro J of Neurology

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The prevalence of adult onset idiopathic isolated focal dystonia in Ireland is higher than that recorded in many similar service-based epidemiological studies but is still likely to be an underestimate. The low proportion of individuals with blepharospasm may reflect reduced environmental exposure to sunlight in Ireland. This study will serve as a resource for international comparative studies of environmental and genetic factors in the pathogenesis of the disorder.

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Section: Sensory Trickssupporting

confidence: 83%

Section: Genetic Aspectsmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

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Epidemiological, clinical and genetic aspects of adult onset isolated focal dystonia in Ireland

Williams

McGovern

Kimmich

et al. 2016

Euro J of Neurology

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“…The expression of the phenotype depends on other, as yet unknown factors, some of which may be environmental . Except for writer's cramp, women are more frequently affected in all AOPTD phenotypes . It has been suggested that (1) higher awareness of symptoms among women, (2) genetic factors, and (3) increased exposure to environmental factors are possible factors leading to the higher prevalence of focal dystonia in women .…”

Section: Discussionmentioning

confidence: 99%

Temporal discrimination, a cervical dystonia endophenotype: Penetrance and functional correlates

et al. 2014

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The pathogenesis of adult-onset primary dystonia remains poorly understood. There is variable age-related and gender-related expression of the phenotype, the commonest of which is cervical dystonia. Endophenotypes may provide insight into underlying genetic and pathophysiological mechanisms of dystonia. The temporal discrimination threshold (TDT)-the shortest time interval at which two separate stimuli can be detected as being asynchronous-is abnormal both in patients with cervical dystonia and in their unaffected first-degree relatives. Functional magnetic resonance imaging (fMRI) studies have shown that putaminal activation positively correlates with the ease of temporal discrimination between two stimuli in healthy individuals. We hypothesized that abnormal temporal discrimination would exhibit similar age-related and gender-related penetrance as cervical dystonia and that unaffected relatives with an abnormal TDT would have reduced putaminal activation during a temporal discrimination task. TDTs were examined in a group of 192 healthy controls and in 158 unaffected first-degree relatives of 84 patients with cervical dystonia. In 24 unaffected first-degree relatives, fMRI scanning was performed during a temporal discrimination task. The prevalence of abnormal TDTs in unaffected female relatives reached 50% after age 48 years; whereas, in male relatives, penetrance of the endophenotype was reduced. By fMRI, relatives who had abnormal TDTs, compared with relatives who had normal TDTs, had significantly less activation in the putamina and in the middle frontal and precentral gyri. Only the degree of reduction of putaminal activity correlated significantly with worsening of temporal discrimination. These findings further support abnormal temporal discrimination as an endophenotype of cervical dystonia involving disordered basal ganglia circuits.

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“…The latter group of dystonias includes cervical dystonia, writer's cramp, blepharospasm, and spasmodic dysphonia, as well as segmental forms of dystonia. It often appears sporadic but still has relatively high heritability, for which genetic susceptibility factors or even dominantly acting genes with very low penetrance are being discussed …”

Section: What Is the Contribution Of Genetics To Dystonia?mentioning

confidence: 99%

Genetics of dystonia: What's known? What's new? What's next?

Lohmann

Klein

2013

Movement Disorders

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Although all forms of dystonia share the core clinical features of involuntary dystonic dyskinesia, there is not only marked phenotypic but also etiologic heterogeneity. Isolated dystonia can be caused by mutations in TOR1A (DYT1), TUBB4 (DYT4), THAP1 (DYT6), CIZ1 (DYT23), ANO3 (DYT24), and GNAL (DYT25). Combined dystonias (with parkinsonism or myoclonus) are further subdivided into persistent (TAF1 [DYT3], GCHI [DYT5], SGCE [DYT11], ATP1A3 [DYT12]), PRKRA (DYT16), and paroxysmal (MR-1 [DYT8], PRRT2 [DYT10], SLC2A1 [DYT18]. With the advent of next-generation sequencing, an unprecedented number of new dystonia genes have recently been described, including 4 in the past 12 months. Despite the need for independent confirmation, these recent findings raise 2 important questions regarding (1) the role of genetics in dystonia overall and (2) the role of different molecular mechanisms in dystonia pathogenesis. The genetic contribution to dystonia represents a continuum ranging from genetic susceptibility factors of small effect to causative genes with markedly reduced penetrance to those with full penetrance. Equally diverse and complex are the pathways and neuronal function(s) putatively involved in dystonia pathogenesis including dopamine signaling, intracellular transport, cytoskeletal dynamics, transcriptional regulation, cell-cycle control, ion channel function, energy metabolism, signal transduction, and detoxification mechanisms. In the next decade of dystonia research, we expect to see the discovery of additional dystonia genes and susceptibility factors. In this context, it will be of great interest to explore whether the diverse cellular functions of the known dystonia proteins may be linked to shared pathways and thus complete the complex puzzle of dystonia pathogenesis. © 2013 Movement Disorder Society.

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Phenotypes and genetic architecture of focal primary torsion dystonia

Cited by 22 publications

References 40 publications

Epidemiological, clinical and genetic aspects of adult onset isolated focal dystonia in Ireland

Epidemiological, clinical and genetic aspects of adult onset isolated focal dystonia in Ireland

Temporal discrimination, a cervical dystonia endophenotype: Penetrance and functional correlates

Genetics of dystonia: What's known? What's new? What's next?

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