Novel insights into the pathogenesis of DYT1 dystonia from induced patient-derived neurons

AbstractBackgroundDYT1 dystonia is a neurological movement disorder characterized by painful sustained muscle contractions resulting in abnormal twisting and postures. In a subset of patients, it is caused by a loss-of-function mutation (ΔE302/303; or ΔE) in the luminal ATPases associated with various cellular activities (AAA+) protein torsinA encoded by the TOR1A gene. The low penetrance of the ΔE mutation (∼30-40%) suggests the existence of unknown genetic modifiers of DYT1 dystonia.MethodsTo identify these modifiers, we performed whole exome sequencing of blood leukocyte DNA isolated from two DYT1 dystonia patients, three asymptomatic carriers of the ΔE mutation, and an unaffected adult relative.ResultsA total of 264 DYT1 dystonia-associated variants (DYT1 variants) were identified in 195 genes. Consistent with the emerging view of torsinA as an important regulator of the cytoskeleton, endoplasmic reticulum homeostasis, and lipid metabolism, we found DYT1 variants in genes that encode proteins implicated in these processes. Moreover, 40 DYT1 variants were detected in 32 genes associated with neuromuscular and neuropsychiatric disorders.ConclusionThe DYT1 variants described in this work represent exciting new targets for future studies designed to increase our understanding of the pathophysiology and pathogenesis of DYT1 dystonia.

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Subtle microstructural changes of the cerebellum in a knock-in mouse model of DYT1 dystonia

Neurobiology of Disease ◽

10.1016/j.nbd.2013.10.003 ◽

2014 ◽

Vol 62 ◽

pp. 372-380 ◽

Cited By ~ 26

Author(s):

Chang-Hyun Song ◽

Doug Bernhard ◽

Ellen J. Hess ◽

H.A. Jinnah

Keyword(s):

Mouse Model ◽

Microstructural Changes ◽

Dyt1 Dystonia

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Stimulation-Induced Dyskinesia, Interleaving Settings, and Management of Subthalamic Nucleus Deep Brain Stimulation in DYT1 Dystonia

Deep Brain Stimulation ◽

10.1093/med/9780190647209.003.0038 ◽

2020 ◽

pp. 201-204

Author(s):

Kyle T. Mitchell ◽

Kristen A. Dodenhoff ◽

Philip A. Starr ◽

Jill L. Ostrem

Keyword(s):

Deep Brain Stimulation ◽

Subthalamic Nucleus ◽

Brain Stimulation ◽

Complete Resolution ◽

Symptomatic Improvement ◽

Zona Incerta ◽

Dyt1 Dystonia ◽

Primary Dystonia ◽

Stn Dbs ◽

Deep Brain

DYT1 dystonia is a primary dystonia with potential for significant symptomatic improvement after bilateral deep brain stimulation (DBS) of the globus pallidus interna (GPi). GPi is the historical target of choice for this disease. This chapter presents a case of an adolescent with disabling generalized DYT1 dystonia who underwent bilateral subthalamic nucleus (STN) DBS as part of a prospective clinical trial. While limb and cervical dystonia dramatically improved with DBS, programming was limited by stimulation-induced bilateral limb dyskinesia, including in the left arm, which was previously unaffected by dystonia. After years of evolving symptoms and complex programming, bilateral interleaved settings using both a contact in motor STN and the most dorsal DBS contact in the zona incerta resulted in sustained, near-complete resolution of dystonia without side effects. This case illustrates the use of the STN as an effective DBS target for primary dystonia, although complex programming was necessary to mitigate stimulation-induced dyskinesia.

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