Genetic Risk Factors in Isolated Dystonia Escape Genome-Wide Association Studies.

BACKGROUND: Despite considerable heritability, previous smaller genome-wide association studies (GWASs) have not identified any robust genetic risk factors for isolated dystonia. OBJECTIVE: The objective of this study was to perform a large-scale GWAS in a well-characterized, multicenter sample of >6000 individuals to identify genetic risk factors for isolated dystonia. METHODS: Array-based GWASs were performed on autosomes for 4303 dystonia participants and 2362 healthy control subjects of European ancestry with subgroup analysis based on age at onset, affected body regions, and a newly developed clinical score. Another 736 individuals were used for validation. RESULTS: This GWAS identified no common genome-wide significant loci that could be replicated despite sufficient power to detect meaningful effects. Power analyses imply that the effects of individual variants are likely very small. CONCLUSIONS: Moderate single-nucleotide polymorphism-based heritability indicates that common variants do not contribute to isolated dystonia in this cohort. Sequence-based GWASs (eg, by whole-genome sequencing) might help to better understand the genetic basis. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Sex Differences in Dystonia.

BACKGROUND: Prior studies have indicated that female individuals outnumber male individuals for certain types of dystonia. Few studies have addressed factors impacting these sex differences or their potential biological mechanisms. OBJECTIVES: To evaluate factors underlying sex differences in the dystonias and explore potential mechanisms for these differences. METHODS: Data from individuals with various types of dystonia were analyzed in relation to sex. Data came from two different sources. One source was the Dystonia Coalition database, which contains predominantly idiopathic adult-onset focal and segmental dystonias. The second source was the MDSGene database, which contains predominantly early-onset monogenic dystonias. RESULTS: The 3222 individuals from the Dystonia Coalition included 71% female participants and 29% male participants for an overall female-to-male ratio (F:M) of 2.4. This ratio varied according to body region affected and whether dystonia was task-specific. The female predominance was age-dependent. Sex did not have a significant impact on co-existing tremor, geste antagoniste, depression or anxiety. In the 1377 individuals from the MDSGene database, female participants outnumbered male participants for some genes (GNAL, GCH1, and ANO3) but not for other genes (THAP1, TH, and TOR1A). CONCLUSIONS: These results are in keeping with prior studies that have indicated female individuals outnumber male individuals for both adult-onset idiopathic and early onset monogenic dystonias. These results extend prior observations by revealing that sex ratios depend on the type of dystonia, age, and underlying genetics.

An Empirical Comparison of Commonly Used Universal Rating Scales for Dystonia.

Background: There are several widely used clinical rating scales for documenting the severity and distribution of various types of dystonia. Objectives: The goal of this study was to evaluate the performance of the most commonly used scales in a large group of adults with the most common types of isolated dystonia. Methods: Global Dystonia Rating Scale (GDRS) and the Burke-Fahn-Marsden Dystonia Rating Scale (BFM) scores were obtained for 3067 participants. Most had focal or segmental dystonia, with smaller numbers of multifocal or generalized dystonia. These scales were also compared for 209 adults with cervical dystonia that had Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) scores and 210 adults with blepharospasm that had Blepharospasm Severity Scale (BSRS) scores. Results: There were strong correlations between the GDRS and BFM total scores (r = 0.79) and moderate correlations for their sub scores (r > 0.5). Scores for both scales showed positive skew, with an overabundance of low scores. BFM sub-scores were not normally distributed, due to artifacts caused by the provoking factor. Relevant sub-scores of the GDRS and BFM also showed moderate correlations with the TWSTRS (r > 0.5) for cervical dystonia and the BSRS (r > 0.5) for blepharospasm. Conclusions: The BFM is more widely used than the GDRS, but these results suggest the GDRS may be preferable for focal and segmental dystonias. The overabundance of very low scores for both scales highlights challenges associated with discriminating very mild dystonia from other abnormal movements or variants of normal behavior.

REM Behavior Disorder: Implications for PD Therapeutics.

PURPOSE: Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia that occurs during REM sleep, characterized by REM sleep without atonia (RSWA) and dream enactment behavior (DEB). RBD is associated with several diseases and medications but most notably is a prodromal feature of synucleinopathies, including Parkinson's disease (PD). This article reviews RBD, its treatments, and implications for PD therapeutics. RECENT FINDINGS: Recent research recognizes RBD as a prodromal marker of PD, resulting in expansion of basic science and clinical investigations of RBD. Current basic science research investigates the pathophysiology of RBD and explores animal models to allow therapeutic development. Clinical research has focused on natural history observation, as well as potential RBD treatments and their impact on sleep and phenoconversion to neurodegenerative disease. RBD serves as a fresh access point to develop both neuroprotective and symptomatic therapies in PD. These types of investigations are novel and will benefit from the more established basic science infrastructure to develop new interventions.

Clinical Features and Evolution of Blepharospasm: A Multicenter International Cohort and Systematic Literature Review.

Objective: Blepharospasm is a type of dystonia where the diagnosis is often delayed because its varied clinical manifestations are not well recognized. The purpose of this study was to provide a comprehensive picture of its clinical features including presenting features, motor features, and non-motor features. Methods: This was a two-part study. The first part involved a systematic literature review that summarized clinical features for 10,324 cases taken from 41 prior reports. The second part involved a summary of clinical features for 884 cases enrolled in a large multicenter cohort collected by the Dystonia Coalition investigators, along with an analysis of the factors that contribute to the spread of dystonia beyond the periocular region. Results: For cases in the literature and the Dystonia Coalition, blepharospasm emerged in the 50s and was more frequent in women. Many presented with non-specific motor symptoms such as increased blinking (51.9%) or non-motor sensory features such as eye soreness or pain (38.7%), photophobia (35.5%), or dry eyes (10.7%). Non-motor psychiatric features were also common including anxiety disorders (34-40%) and depression (21-24%). Among cases presenting with blepharospasm in the Dystonia Coalition cohort, 61% experienced spread of dystonia to other regions, most commonly the oromandibular region and neck. Features associated with spread included severity of blepharospasm, family history of dystonia, depression, and anxiety. Conclusions: This study provides a comprehensive summary of motor and non-motor features of blepharospasm, along with novel insights into factors that may be responsible for its poor diagnostic recognition and natural history.

Executive functions in premanifest Huntington's disease.

BACKGROUND: We investigated the viability of psychometrically robust executive function measures as markers for premanifest Huntington's disease (HD). METHODS: Fifteen premanifest HD subjects and 42 controls were compared on the NIH EXAMINER executive function battery. This battery yields an overall executive composite score, plus working memory, cognitive control, and fluency scores that are measured on psychometrically matched scales. The scores were correlated with two disease markers, disease burden and striatal volumes, in the premanifest HD subjects. RESULTS: The premanifest HD subjects scored significantly lower on the working memory score. The executive composite positively correlated with striatal volumes, and the working memory score negatively correlated with disease burden. The cognitive control and fluency scores did not differ between the groups or correlate significantly with the disease markers. CONCLUSIONS: The NIH EXAMINER executive composite and working memory scores are sensitive markers of cognitive dysfunction, striatal volume, and disease burden in premanifest HD.

Blood supply and vascular reactivity of the spinal cord under normal and pathological conditions.

The authors present a review of spinal cord blood supply, discussing the anatomy of the vascular system and physiological aspects of blood flow regulation in normal and injured spinal cords. Unique anatomical functional properties of vessels and blood supply determine the susceptibility of the spinal cord to damage, especially ischemia. Spinal cord injury (SCI), for example, complicating thoracoabdominal aortic aneurysm repair is associated with ischemic trauma. The rate of this devastating complication has been decreased significantly by instituting physiological methods of protection. Traumatic SCI causes complex changes in spinal cord blood flow, which are closely related to the severity of injury. Manipulating physiological parameters such as mean arterial blood pressure and intrathecal pressure may be beneficial for patients with an SCI. Studying the physiopathological processes of the spinal cord under vascular compromise remains challenging because of its central role in almost all of the body's hemodynamic and neurofunctional processes.