Dystonia: diagnosis and management

Albanese, Alberto; Giovanni, Mario Di; Lalli, Stefania

doi:10.1111/ene.13762

Cited by 91 publications

(88 citation statements)

References 90 publications

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“…Dystonia is a common movement disorder affecting at least half a million individuals in the United States. Current treatments are generally insufficient to address symptoms, which cause substantial pain, disability, and even death (Albanese et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Diverse Mechanisms Lead to Common Dysfunction of Striatal Cholinergic Interneurons in Distinct Genetic Mouse Models of Dystonia

Jaunarajs¹,

Scarduzio²,

Ehrlich

et al. 2019

J. Neurosci.

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Clinical and experimental data indicate striatal cholinergic dysfunction in dystonia, a movement disorder typically resulting in twisted postures via abnormal muscle contraction. Three forms of isolated human dystonia result from mutations in the TOR1A (DYT1), THAP1 (DYT6), and GNAL (DYT25) genes. Experimental models carrying these mutations facilitate identification of possible shared cellular mechanisms. Recently, we reported elevated extracellular striatal acetylcholine by in vivo microdialysis and paradoxical excitation of cholinergic interneurons (ChIs) by dopamine D2 receptor (D2R) agonism using ex vivo slice electrophysiology in Dyt1 ⌬ GAG/ϩ mice. The paradoxical excitation was caused by overactive muscarinic receptors (mAChRs), leading to a switch in D2R coupling from canonical G i/o to noncanonical ␤-arrestin signaling. We sought to determine whether these mechanisms in Dyt1 ⌬ GAG/ϩ mice are shared with Thap1 C54Y/ϩ knock-in and Gnal ϩ/ Ϫ knockout dystonia models and to determine the impact of sex. We found Thap1 C54Y/ϩ mice of both sexes have elevated extracellular striatal acetylcholine and D2R-induced paradoxical ChI excitation, which was reversed by mAChR inhibition. Elevated extracellular acetylcholine was absent in male and female Gnal ϩ/ Ϫ mice, but the paradoxical D2R-mediated ChI excitation was retained and only reversed by inhibition of adenosine A2ARs. The G i/o-preferring D2R agonist failed to increase ChI excitability, suggesting a possible switch in coupling of D2Rs to ␤-arrestin, as seen previously in a DYT1 model. These data show that, whereas elevated extracellular acetylcholine levels are not always detected across these genetic models of human dystonia, the D2Rmediated paradoxical excitation of ChIs is shared and is caused by altered function of distinct G-protein-coupled receptors.

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Section: Introductionmentioning

confidence: 99%

Diverse Mechanisms Lead to Common Dysfunction of Striatal Cholinergic Interneurons in Distinct Genetic Mouse Models of Dystonia

Jaunarajs¹,

Scarduzio²,

Ehrlich

et al. 2019

J. Neurosci.

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“…Standard neuroimaging such as computed tomography (CT) and magnetic resonance imaging (MRI) are typically normal in subjects with primary dystonia [ 69 , 70 , 71 , 72 ]. In rare cases, however, focal lesions can produce a clinical picture nearly identical to idiopathic dystonia [ 73 , 74 , 75 ].…”

Section: Current Understanding Of Dystonia Pathophysiologymentioning

confidence: 99%

Olfaction as a Marker for Dystonia: Background, Current State and Directions

et al. 2020

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Dystonia is a heterogeneous group of hyperkinetic movement disorders. The unifying descriptor of dystonia is the motor manifestation, characterized by continuous or intermittent contractions of muscles that cause abnormal movements and postures. Additionally, there are psychiatric, cognitive, and sensory alterations that are possible or putative non-motor manifestations of dystonia. The pathophysiology of dystonia is incompletely understood. A better understanding of dystonia pathophysiology is highly relevant in the amelioration of significant disability associated with motor and non-motor manifestations of dystonia. Recently, diminished olfaction was found to be a potential non-motor manifestation that may worsen the situation of subjects with dystonia. Yet, this finding may also shed light into dystonia pathophysiology and yield novel treatment options. This article aims to provide background information on dystonia and the current understanding of its pathophysiology, including the key structures involved, namely, the basal ganglia, cerebellum, and sensorimotor cortex. Additionally, involvement of these structures in the chemical senses are reviewed to provide an overview on how olfactory (and gustatory) deficits may occur in dystonia. Finally, we describe the present findings on altered chemical senses in dystonia and discuss directions of research on olfactory dysfunction as a marker in dystonia.

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“…Isolated dystonia is a heterogeneous group of underdiagnosed movement disorders [1]. The main clinical findings are the dystonic movements and postures, defined by "sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both" [1,2]. Depending on the body distribution, isolated dystonia is classifiable as focal, segmental, multifocal, generalized, and unilateral [2].…”

Section: Introductionmentioning

confidence: 99%

CACNA1B gene variants in adult-onset isolated focal dystonia

et al. 2020

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Background Isolated focal dystonia (IFD) is a heterogeneous group of potentially invalidating movement disorders. The etiopathogenesis is complex, both genetic and environmental factors playing a role, but remains elusive. The CACNA1B gene codes for the N-type neuronal voltage-gated calcium channels CaV2.2, which may play a role in the development of some IFD. Methods We analyzed samples from the GENDYS cohort for mutations in CACNA1B gene, using targeted next-generation sequencing (NGS). Results The GENDYS cohort consists of 120 people with adult-onset IFD (cervical dystonia 47.5%, blepharospasm 47.2%, others 8.3%). Of these, 35% had subsequent topographical extension. Average age at onset was 42 and average disease durations 8 years. Targeted NGS revealed a novel frameshift mutation c.2291AGG > A, in exon 19, and a previously reported variant, c.6834T > G, in exon 47. Conclusion Our findings suggest that disease-causing mutations in CACNA1B gene may be involved in the development of some adult-onset IFD. To our knowledge, this is the first study that identified a disease-causing CACNA1B gene mutation in association with adult-onset IFD.

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Dystonia: diagnosis and management

Cited by 91 publications

References 90 publications

Diverse Mechanisms Lead to Common Dysfunction of Striatal Cholinergic Interneurons in Distinct Genetic Mouse Models of Dystonia

Diverse Mechanisms Lead to Common Dysfunction of Striatal Cholinergic Interneurons in Distinct Genetic Mouse Models of Dystonia

Olfaction as a Marker for Dystonia: Background, Current State and Directions

CACNA1B gene variants in adult-onset isolated focal dystonia

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