Adductor focal laryngeal Dystonia: correlation between clinicians’ ratings and subjects’ perception of Dysphonia

Background Although considerable research has focused on the etiology and symptomology of adductor focal laryngeal dystonia (AD-FLD), little is known about the correlation between clinicians’ ratings and patients’ perception of this voice disturbance. This study has five objectives: first, to determine if there is a relationship between subjects’ symptom-severity and its impact on their quality of life; to compare clinicians’ ratings with subjects’ perception of the individual characteristics and severity of AD-FLD; to document the subjects’ perception of changes in dysphonia since diagnosis; to record the frequency of voice arrest during connected speech; and, finally, to calculate inter-clinician reliability based on results from the Unified Spasmodic Dysphonia Rating Scale (USDRS) (Stewart et al, J Voice 1195-10, 1997). Methods Sixty subjects with AD-FLD who were receiving ongoing injections of BoNT participated in this study. Subjects’ mean age was 60.78 years and their mean duration of symptoms was 16.1 years. Subjects completed the Disease Symptom Questionnaire (DSQ) (specifically designed for this study) and the Voice Handicap Index-10 (VHI-10) (Jacobson et al, Am J Speech Lang Pathol 6:66–70, 1997) to measure the symptoms of their dysphonia and the impact of the disease on their quality of life. Two speech-language pathologists and two laryngologists used the Voice Arrest Measure (VAM) (specifically designed for this study) and the USDRS to independently rate voice recordings of 56/60 subjects. Results The mean VHI-10 score was 21.3 which is clinically significant. The results of the DSQ and the USDRS were highly correlated. The most severe symptoms identified by both subjects and clinicians were roughness, strain-strangled voice quality, and increased expiratory effort. Voice arrest, aphonia, and tremor were uncommon. Subjects rated their current voice quality at the time of reinjection (i.e., at the time of the study) as significantly better than at the time of their initial AD-FLD diagnosis (p < 0.0001). Inter-clinician reliability on the USDRS was significant at the 0.001 level. Conclusions The findings from the VHI-10 suggest that AD-FLD has a profound impact on quality of life. The results of the DSQ and the USDRS suggest that there is a strong correlation between subjects’ perception and clinicians’ assessment of the individual symptoms and the severity of the dysphonia. The findings from the VAM suggest that voice arrests are infrequent in subjects with AD-FLD who are receiving ongoing BoNT injections. The strong inter-clinician reliability on the USDRS suggests that it is an appropriate measure for identifying symptoms and severity of AD-FLD

Neural correlates of abnormal sensory discrimination in laryngeal dystonia

AbstractAberrant sensory processing plays a fundamental role in the pathophysiology of dystonia; however, its underpinning neural mechanisms in relation to dystonia phenotype and genotype remain unclear. We examined temporal and spatial discrimination thresholds in patients with isolated laryngeal form of dystonia (LD), who exhibited different clinical phenotypes (adductor vs. abductor forms) and potentially different genotypes (sporadic vs. familial forms). We correlated our behavioral findings with the brain gray matter volume and functional activity during resting and symptomatic speech production. We found that temporal but not spatial discrimination was significantly altered across all forms of LD, with higher frequency of abnormalities seen in familial than sporadic patients. Common neural correlates of abnormal temporal discrimination across all forms were found with structural and functional changes in the middle frontal and primary somatosensory cortices. In addition, patients with familial LD had greater cerebellar involvement in processing of altered temporal discrimination, whereas sporadic LD patients had greater recruitment of the putamen and sensorimotor cortex. Based on the clinical phenotype, adductor form-specific correlations between abnormal discrimination and brain changes were found in the frontal cortex, whereas abductor form-specific correlations were observed in the cerebellum and putamen. Our behavioral and neuroimaging findings outline the relationship of abnormal sensory discrimination with the phenotype and genotype of isolated LD, suggesting the presence of potentially divergent pathophysiological pathways underlying different manifestations of this disorder

A rare sequence variant in intron 1 of THAP1 is associated with primary dystonia

Although coding variants in THAP1 have been causally associated with primary dystonia, the contribution of noncoding variants remains uncertain. Herein, we examine a previously identified Intron 1 variant (c.71+9C>A, rs200209986). Among 1672 subjects with mainly adult-onset primary dystonia, 12 harbored the variant in contrast to 1/1574 controls (P < 0.01). Dystonia classification included cervical dystonia (N = 3), laryngeal dystonia (adductor subtype, N = 3), jaw-opening oromandibular dystonia (N = 1), blepharospasm (N = 2), and unclassified (N = 3). Age of dystonia onset ranged from 25 to 69 years (mean = 54 years). In comparison to controls with no identified THAP1 sequence variants, the c.71+9C>A variant was associated with an elevated ratio of Isoform 1 (NM_018105) to Isoform 2 (NM_199003) in leukocytes. In silico and minigene analyses indicated that c.71+9C>A alters THAP1 splicing. Lymphoblastoid cells harboring the c.71+9C>A variant showed extensive apoptosis with relatively fewer cells in the G2 phase of the cell cycle. Differentially expressed genes from lymphoblastoid cells revealed that the c.71+9C>A variant exerts effects on DNA synthesis, cell growth and proliferation, cell survival, and cytotoxicity. In aggregate, these data indicate that THAP1 c.71+9C>A is a risk factor for adult-onset primary dystonia

High-throughput mutational analysis of TOR1A in primary dystonia

<p>Abstract</p> <p>Background</p> <p>Although the c.904_906delGAG mutation in Exon 5 of <it>TOR1A </it>typically manifests as early-onset generalized dystonia, DYT1 dystonia is genetically and clinically heterogeneous. Recently, another Exon 5 mutation (c.863G>A) has been associated with early-onset generalized dystonia and some ΔGAG mutation carriers present with late-onset focal dystonia. The aim of this study was to identify <it>TOR1A </it>Exon 5 mutations in a large cohort of subjects with mainly non-generalized primary dystonia.</p> <p>Methods</p> <p>High resolution melting (HRM) was used to examine the entire <it>TOR1A </it>Exon 5 coding sequence in 1014 subjects with primary dystonia (422 spasmodic dysphonia, 285 cervical dystonia, 67 blepharospasm, 41 writer's cramp, 16 oromandibular dystonia, 38 other primary focal dystonia, 112 segmental dystonia, 16 multifocal dystonia, and 17 generalized dystonia) and 250 controls (150 neurologically normal and 100 with other movement disorders). Diagnostic sensitivity and specificity were evaluated in an additional 8 subjects with known ΔGAG DYT1 dystonia and 88 subjects with ΔGAG-negative dystonia.</p> <p>Results</p> <p>HRM of <it>TOR1A </it>Exon 5 showed high (100%) diagnostic sensitivity and specificity. HRM was rapid and economical. HRM reliably differentiated the <it>TOR1A </it>ΔGAG and c.863G>A mutations. Melting curves were normal in 250/250 controls and 1012/1014 subjects with primary dystonia. The two subjects with shifted melting curves were found to harbor the classic ΔGAG deletion: 1) a non-Jewish Caucasian female with childhood-onset multifocal dystonia and 2) an Ashkenazi Jewish female with adolescent-onset spasmodic dysphonia.</p> <p>Conclusion</p> <p>First, HRM is an inexpensive, diagnostically sensitive and specific, high-throughput method for mutation discovery. Second, Exon 5 mutations in <it>TOR1A </it>are rarely associated with non-generalized primary dystonia.</p

Colocalization of Protein Kinase A with Adenylyl Cyclase Enhances Protein Kinase A Activity during Induction of Long-Lasting Long-Term-Potentiation

The ability of neurons to differentially respond to specific temporal and spatial input patterns underlies information storage in neural circuits. One means of achieving spatial specificity is to restrict signaling molecules to particular subcellular compartments using anchoring molecules such as A-Kinase Anchoring Proteins (AKAPs). Disruption of protein kinase A (PKA) anchoring to AKAPs impairs a PKA-dependent form of long term potentiation (LTP) in the hippocampus. To investigate the role of localized PKA signaling in LTP, we developed a stochastic reaction-diffusion model of the signaling pathways leading to PKA activation in CA1 pyramidal neurons. Simulations investigated whether the role of anchoring is to locate kinases near molecules that activate them, or near their target molecules. The results show that anchoring PKA with adenylyl cyclase (which produces cAMP that activates PKA) produces significantly greater PKA activity, and phosphorylation of both inhibitor-1 and AMPA receptor GluR1 subunit on S845, than when PKA is anchored apart from adenylyl cyclase. The spatial microdomain of cAMP was smaller than that of PKA suggesting that anchoring PKA near its source of cAMP is critical because inactivation by phosphodiesterase limits diffusion of cAMP. The prediction that the role of anchoring is to colocalize PKA near adenylyl cyclase was confirmed by experimentally rescuing the deficit in LTP produced by disruption of PKA anchoring using phosphodiesterase inhibitors. Additional experiments confirm the model prediction that disruption of anchoring impairs S845 phosphorylation produced by forskolin-induced synaptic potentiation. Collectively, these results show that locating PKA near adenylyl cyclase is a critical function of anchoring

Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome

With an incidence of ~1 in 800 births, Down syndrome (DS) is the most com- mon chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA 21 that directly contribute to cognitive de fi cits remain incompletely understood. Here, we found that the HSA21- encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued de fi cits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes

Diagnosis and Treatment of Laryngeal Dystonia: Past, Present and Future Directions

Background: Laryngeal dystonia is a task-specific focal dystonia of the internal laryngeal muscles. Methods: Peer-reviewed articles on laryngeal dystonia from PUBMED were identified. Manuscripts that supported selected points of discussion were chosen. Illustrative figures and videos from the authors&rsquo; personal files support selected ideas. Results: This manuscript presents a comprehensive overview of the diagnoses and treatment of laryngeal dystonia and includes a brief history of the terminology, genetic mutations, and common misdiagnosis. In addition, the manuscript provides an in-depth description of the use of botulinum toxin (BoNT), including the mechanism of action, techniques for injections, and outcomes. Discussion: Laryngeal dystonia is a complex clinically heterogeneous disorder. BoNT injection provides targeted therapy to the laryngeal muscles and has shown great efficacy in improving voice fluidity. Nevertheless, BoNT provides only symptomatic relief without altering the underlying disorder. Future therapeutic options that target the central nervous system may help clinicians better understand the pathophysiology of this condition.</p