Large-Scale Screening: Phenotypic and Mutational Spectrum in Isolated and Combined Dystonia Genes.

BACKGROUND: Pathogenic variants in several genes have been linked to genetic forms of isolated or combined dystonia. The phenotypic and genetic spectrum and the frequency of pathogenic variants in these genes have not yet been fully elucidated, neither in patients with dystonia nor with other, sometimes co-occurring movement disorders such as Parkinson's disease (PD). OBJECTIVES: To screen >2000 patients with dystonia or PD for rare variants in known dystonia-causing genes. METHODS: We screened 1207 dystonia patients from Germany (DysTract consortium), Spain, and South Korea, and 1036 PD patients from Germany for pathogenic variants using a next-generation sequencing gene panel. The impact on DNA methylation of KMT2B variants was evaluated by analyzing the gene's characteristic episignature. RESULTS: We identified 171 carriers (109 with dystonia [9.0%]; 62 with PD [6.0%]) of 131 rare variants (minor allele frequency <0.005). A total of 52 patients (48 dystonia [4.0%]; four PD [0.4%, all with GCH1 variants]) carried 33 different (likely) pathogenic variants, of which 17 were not previously reported. Pathogenic biallelic variants in PRKRA were not found. Episignature analysis of 48 KMT2B variants revealed that only two of these should be considered (likely) pathogenic. CONCLUSION: This study confirms pathogenic variants in GCH1, GNAL, KMT2B, SGCE, THAP1, and TOR1A as relevant causes in dystonia and expands the mutational spectrum. Of note, likely pathogenic variants only in GCH1 were also found among PD patients. For DYT-KMT2B, the recently described episignature served as a reliable readout to determine the functional effect of newly identified variants. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Disordered network structure and function in dystonia: pathological connectivity vs. adaptive responses.

Primary dystonia is thought to emerge through abnormal functional relationships between basal ganglia and cerebellar motor circuits. These interactions may differ across disease subtypes and provide a novel biomarker for diagnosis and treatment. Using a network mapping algorithm based on resting-state functional MRI (rs-fMRI), a method that is readily implemented on conventional MRI scanners, we identified similar disease topographies in hereditary dystonia associated with the DYT1 or DYT6 mutations and in sporadic patients lacking these mutations. Both networks were characterized by contributions from the basal ganglia, cerebellum, thalamus, sensorimotor areas, as well as cortical association regions. Expression levels for the two networks were elevated in hereditary and sporadic dystonia, and in non-manifesting carriers of dystonia mutations. Nonetheless, the distribution of abnormal functional connections differed across groups, as did metrics of network organization and efficiency in key modules. Despite these differences, network expression correlated with dystonia motor ratings, significantly improving the accuracy of predictions based on thalamocortical tract integrity obtained with diffusion tensor MRI (DTI). Thus, in addition to providing unique information regarding the anatomy of abnormal brain circuits, rs-fMRI functional networks may provide a widely accessible method to help in the objective evaluation of new treatments for this disorder.

DYT6 mutated THAP1 is a cell type dependent regulator of the SP1 family.

DYT6 dystonia is caused by mutations in the transcription factor THAP1. THAP1 knock-out or knock-in mouse models revealed complex gene expression changes, which are potentially responsible for the pathogenesis of DYT6 dystonia. However, how THAP1 mutations lead to these gene expression alterations and whether the gene expression changes are also reflected in the brain of THAP1 patients are still unclear. In this study we used epigenetic and transcriptomic approaches combined with multiple model systems [THAP1 patients' frontal cortex, THAP1 patients' induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic neurons, THAP1 heterozygous knock-out rat model, and THAP1 heterozygous knock-out SH-SY5Y cell lines] to uncover a novel function of THAP1 and the potential pathogenesis of DYT6 dystonia. We observed that THAP1 targeted only a minority of differentially expressed genes caused by its mutation. THAP1 mutations lead to dysregulation of genes mainly through regulation of SP1 family members, SP1 and SP4, in a cell type dependent manner. Comparing global differentially expressed genes detected in THAP1 patients' iPSC-derived midbrain dopaminergic neurons and THAP1 heterozygous knock-out rat striatum, we observed many common dysregulated genes and 61 of them were involved in dystonic syndrome-related pathways, like synaptic transmission, nervous system development, and locomotor behaviour. Further behavioural and electrophysiological studies confirmed the involvement of these pathways in THAP1 knock-out rats. Taken together, our study characterized the function of THAP1 and contributes to the understanding of the pathogenesis of primary dystonia in humans and rats. As SP1 family members were dysregulated in some neurodegenerative diseases, our data may link THAP1 dystonia to multiple neurological diseases and may thus provide common treatment targets.

Neuropsychological Functioning in Primary Dystonia: Updated and Expanded Multidomain Meta-Analysis.

BACKGROUND: Primary dystonia is conventionally considered as a motor disorder, though an emerging literature reports associated cognitive dysfunction. OBJECTIVES: Here, we conducted meta-analyses on studies comparing clinical measures of cognition in persons with primary dystonia and healthy controls (HCs). METHODS: We searched PubMed, Embase, Cochrane Library, Scopus, and PsycINFO (January 2000-October 2020). Analyses were modeled under random effects. We used Hedge's g as a bias-corrected estimate of effect size, where negative values indicate lower performance in dystonia versus controls. Between-study heterogeneity and bias were primarily assessed with Cochran's Q, I2 , and Egger's regression. RESULTS: From 866 initial results, 20 studies met criteria for analysis (dystonia n = 739, controls n = 643; 254 effect sizes extracted). Meta-analysis showed a significant combined effect size of primary dystonia across all studies (g = -0.56, P < 0.001), with low heterogeneity (Q = 25.26, P = 0.15, I2  = 24.78). Within-domain effects of primary dystonia were motor speed = -0.84, nonmotor speed = -0.83, global cognition = -0.65, language = -0.54, executive functioning = -0.53, learning/memory = -0.46, visuospatial/construction = -0.44, and simple/complex attention = -0.37 (P-values <0.01). High heterogeneity was observed in the motor/nonmotor speed and learning/memory domains. There was no evidence of publication bias. Moderator analyses were mostly negative but possibly underpowered. Blepharospasm samples showed worse performance than other focal/cervical dystonias. Those with inherited (ie, genetic) disease etiology demonstrated worse performance than acquired. CONCLUSIONS: Dystonia patients consistently demonstrated lower performances on neuropsychological tests versus HCs. Effect sizes were generally moderate in strength, clustering around -0.50 SD units. Within the speed domain, results suggested cognitive slowing beyond effects from motor symptoms. Overall, findings indicate dystonia patients experience multidomain cognitive difficulties, as detected by neuropsychological tests. © 2022 International Parkinson and Movement Disorder Society.

Perturbed Ca2+-dependent signaling of DYT2 hippocalcin mutant as mechanism of autosomal recessive dystonia.

A recent report of autosomal-recessive primary isolated dystonia (DYT2 dystonia) identified mutations in HPCA, a gene encoding a neuronal calcium sensor protein, hippocalcin (HPCA), as the cause of this disease. However, how mutant HPCA leads to neuronal dysfunction remains unknown. Using a multidisciplinary approach, we demonstrated the failure of dystonic N75K HPCA mutant to decode short bursts of action potentials and theta rhythms in hippocampal neurons by its Ca2+-dependent translocation to the plasma membrane. This translocation suppresses neuronal activity via slow afterhyperpolarization (sAHP) and we found that the N75K mutant could not control sAHP during physiologically relevant neuronal activation. Simulations based on the obtained experimental results directly demonstrated an increased excitability in neurons expressing N75K mutant instead of wild type (WT) HPCA. In conclusion, our study identifies sAHP as a downstream cellular target perturbed by N75K mutation in DYT2 dystonia, demonstrates its impact on neuronal excitability, and suggests a potential therapeutic strategy to efficiently treat DYT2.

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

BACKGROUND: Adult onset idiopathic isolated focal dystonia presents with a number of phenotypes. Reported prevalence rates vary considerably; well-characterized cohorts are important to our understanding of this disorder. AIM: To perform a nationwide epidemiological study of adult onset idiopathic isolated focal dystonia in the Republic of Ireland. METHODS: Patients with adult onset idiopathic isolated focal dystonia were recruited from multiple sources. Diagnosis was based on assessment by a neurologist with an expertise in movement disorders. When consent was obtained, a number of clinical features including family history were assessed. RESULTS: On the prevalence date there were 592 individuals in Ireland with adult onset idiopathic isolated focal dystonia, a point prevalence of 17.8 per 100 000 (95% confidence interval 16.4-19.2). Phenotype numbers were cervical dystonia 410 (69.2%), blepharospasm 102 (17.2%), focal hand dystonia 39 (6.6%), spasmodic dysphonia 18 (3.0%), musician's dystonia 17 (2.9%) and oromandibular dystonia six (1.0%). Sixty-two (16.5%) of 375 consenting index cases had a relative with clinically confirmed adult onset idiopathic isolated focal dystonia (18 multiplex and 24 duplex families). Marked variations in the proportions of patients with tremor, segmental spread, sensory tricks, pain and psychiatric symptoms by phenotype were documented. CONCLUSIONS: 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.

Altered sensorimotor activation patterns in idiopathic dystonia-an activation likelihood estimation meta-analysis of functional brain imaging studies.

Dystonia is characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements or postures. Functional neuroimaging studies have yielded abnormal task-related sensorimotor activation in dystonia, but the results appear to be rather variable across studies. Further, study size was usually small including different types of dystonia. Here we performed an activation likelihood estimation (ALE) meta-analysis of functional neuroimaging studies in patients with primary dystonia to test for convergence of dystonia-related alterations in task-related activity across studies. Activation likelihood estimates were based on previously reported regional maxima of task-related increases or decreases in dystonia patients compared to healthy controls. The meta-analyses encompassed data from 179 patients with dystonia reported in 18 functional neuroimaging studies using a range of sensorimotor tasks. Patients with dystonia showed bilateral increases in task-related activation in the parietal operculum and ventral postcentral gyrus as well as right middle temporal gyrus. Decreases in task-related activation converged in left supplementary motor area and left postcentral gyrus, right superior temporal gyrus and dorsal midbrain. Apart from the midbrain cluster, all between-group differences in task-related activity were retrieved in a sub-analysis including only the 14 studies on patients with focal dystonia. For focal dystonia, an additional cluster of increased sensorimotor activation emerged in the caudal cingulate motor zone. The results show that dystonia is consistently associated with abnormal somatosensory processing in the primary and secondary somatosensory cortex along with abnormal sensorimotor activation of mesial premotor and right lateral temporal cortex. Hum Brain Mapp 37:547-557, 2016. © 2015 Wiley Periodicals, Inc.

Cognitive Flexibility in Primary Dystonia.

Objectives Although primary dystonia is typically characterized as a movement disorder, it is also associated with cognitive alterations in the domain of executive functioning which may arise from changes in cortico-basal ganglia circuits. Specifically, in comparison to healthy controls, patients with dystonia show deficits in neuropsychological tests of cognitive flexibility. However, it is unclear whether cognitive inflexibility is caused by the pathomechanisms underlying primary dystonia or by confounding factors such as depression or symptom-related distraction.Methods The present study aimed to eliminate these confounds by examining cognitive flexibility in dystonia patients and in patients with similar motor symptoms but without a comparable central pathophysiology. Eighteen patients with primary blepharospasm, a common form of dystonia affecting the muscles around the eyes, and 19 patients with hemifacial spasm, a facial nerve disorder causing similar eyelid spasms, completed a computerized version of the Wisconsin Card Sorting Test (cWCST). The two groups were further compared on tests of global cognitive functioning, psychiatric symptoms, health status, and impulsiveness. Results Blepharospasm patients committed significantly more errors on the cWCST than patients with hemifacial spasm. Group differences were most pronounced with regard to integration errors, a measure of rule-inference processes on the cWCST. Integration errors were also associated with impulsiveness in patients with blepharospasm. Conclusions Primary blepharospasm is related to deficits in cognitive flexibility, even when blepharospasm patients are compared with patients who suffer from motor symptoms of non-dystonic origin. Our results support the possibility that cognitive inflexibility results from the specific pathophysiological processes underlying primary dystonia. (JINS, 2016, 22, 662-670).

Late-onset primary dystonia in Zhejiang province of China: a service-based epidemiological study.

Dystonia is characterized by sustained muscle contractions, causing repetitive movements and abnormal postures. The epidemiological study of dystonia of Chinese population was limited reported. In this study, we investigated the epidemiology of primary dystonia, and its clinical characteristics in an adult population in China. We identified all dystonia patients from the movement disorders database and botulinum toxin clinic between 2009 and 2013. The medical records were reviewed to verify the diagnosis of dystonia, and demographic and clinical data were collected. A total of 1481 patients with primary dystonia were studied. The most common focal dystonia were blepharospasm (56.4 %), cervical dystonia (36.7 %), limb dystonia (3.4 %), oromandibular dystonia (2.9 %) and laryngeal dystonia (0.6 %). Males with primary dystonia were found to have an earlier age of onset. A female predominance was noted for most of the primary dystonia, with a men to women ratio (M:F) of 1:2.01. The minimum estimate of prevalence of primary dystonia was 27.0 (95 % confidence interval: 25.6-28.3) per million persons in this study. Despite the difference in genetic background and geographic area, the epidemiological features of dystonia in China from our study share most features around the world, such as women dystonia dominance, early-onset age of dystonia with women, etc. But East Asia countries (China and Japan) may share more common features of dystonia.

Lack of validation of variants associated with cervical dystonia risk: a GWAS replication study.

BACKGROUND: A recent genome-wide association study (GWAS) has identified a putative association, not statistically confirmed, of cervical dystonia within several regions in a British population. Hence, the authors proposed dysfunction of the ion channel NALCN (for sodium leak channel, nonselective) as a plausible cause of cervical dystonia. The objective of our study was to investigate the association of five single nucleotide polymorphisms (SNPs) previously reported with high signals as putative genetic risk factors for cervical dystonia in a British GWAS, including two located in the NALCN gene region. METHODS: We performed a case-control association study in a Spanish population. The SNPs selected for genotyping were two SNPS in the NALCN gene (rs61973742 and rs1338041), one SNP in the OR4X2 gene (rs67863238), one SNP in the COL4A1 region (rs619152), and one intergenic SNP (rs1249277). Genomic DNA was collected from 252 patients with cervical dystonia, with a mean age of 55.3 ± 14.1 years (mean age at onset, 43.5 ± 15.7 years), and 342 unrelated control subjects with a mean age of 56.3 ± 14.3 years. Genotyping of SNPs was performed using TaqMan assays and SimpleProbe assays. RESULTS: The SNP rs619152 had to be excluded because of assay failure. No significant differences were found in allele distribution between cases and controls for all analyzed SNPs. Therefore, we found no association with cervical dystonia for the analyzed SNPs in our Spanish population. CONCLUSIONS: We did not find any evidence supporting the association of NALCN with cervical dystonia, indicating that this gene is not implicated in the pathogenesis of this disorder in our cervical dystonia population.

BDNF Val66Met polymorphism in primary adult-onset dystonia: a case-control study and meta-analysis.

BACKGROUND: A polymorphism in brain-derived neurotrophic factor (BDNF) (Val66Met) has been reported as a risk factor in primary dystonia. However, overall the results have been inconclusive. Our aim was to clarify the association of Val66Met with primary dystonia, and with the most prevalent clinical subtypes, cervical dystonia and blepharospasm. METHODS: We conducted a Spanish multicenter case-control study (including 680 primary dystonia patients and 788 healthy controls) and performed a meta-analysis integrating our study and six previously published studies (including a total of 1,936 primary dystonia patients and 2,519 healthy controls). RESULTS: We found no allelic or genotypic association with primary dystonia, cervical dystonia, or blepharospasm risks, for the allele A (Met) from a BDNF Val66Met polymorphism in our case-control study. This was confirmed by results from our meta-analysis in white and mixed ethnic populations in any genetic model. CONCLUSION: We did not find any evidence supporting the association of the BDNF Val66Met polymorphism with primary dystonia.

Combined occurrence of a novel TOR1A and a THAP1 mutation in primary dystonia.

BACKGROUND: The ΔGAG deletion of the TOR1A gene (DYT1) is responsible for DYT1 dystonia. However, no other TOR1A mutation has been reported in the Chinese population. METHODS: Two hundred one dystonia patients without the ΔGAG deletion were screened for other mutations in TOR1A. Gene function changes were analyzed by subcellular distribution and luciferase reporter assay. RESULTS: A novel TOR1A mutation (c.581A>T, p.Asp194Val) was found in a patient with early-onset segmental dystonia harboring a THAP1 mutation (c.539T>C, p.Leu180Ser). Overexpression of mutant TOR1A Asp194Val protein induces inclusion formation in SK-N-AS cell lines, and the repressive activity of the mutant THAP1 Leu180Ser protein on TOR1A gene expression is decreased compared with wild-type THAP1. CONCLUSIONS: This is the first report about a dystonia patient harboring two distinct dystonia gene mutations. Functional analysis indicated a potential additive effect of these two mutations, which might provoke the occurrence of dystonic symptoms in this patient.

Subthalamus deep brain stimulation for primary dystonia patients: a long-term follow-up study.

BACKGROUND: Deep brain stimulation has generated sustained improvement in motor function for patients with dystonia, but the long-term impact of subthalamic nucleus stimulation on dystonia has not been elucidated. METHODS: Patients with primary dystonia underwent bilateral subthalamic nucleus stimulation and were evaluated with the Burke-Fahn-Marsden dystonia rating scale and the Medical Outcomes Study 36-item Short-Form General Health Survey at baseline and 1 month, 1 year, and 3 to 10 years postoperatively. RESULTS: Improvements in motor function according to the Burke-Fahn-Marsden dystonia rating scale at 1 month, 1 year, and 3 to 10 years of stimulation were 55%, 77%, and 79%, respectively. The quality of life improved after 1 month of stimulation (P < 0.001), progressed within 1 year (P < 0.001), and then remained stable. Disease duration was negatively correlated with an improvement in motor function. CONCLUSIONS: Our results demonstrate that the subthalamus is an alternative to the globus pallidus internus as a target for deep brain stimulation to treat primary dystonia.

Scoliosis Causing Cervical Dystonia in a Chiropractic Office.

Cervical dystonia is a movement disorder characterized by continuous and involuntary muscular contractions that result in aberrant head and neck motions or postures. A recent study indicates that persons with a history of scoliosis may be at a higher risk of acquiring cervical dystonia later in life. Although muscular tension and contraction abnormalities are linked in both illnesses, the pathophysiological pathways linking these two ailments are not entirely understood. A 13-year-old boy previously diagnosed with adolescent idiopathic scoliosis developed symptoms of cervical dystonia, including moderate neck pain, left-sided migraines, and tingling in the neck and shoulders. During the course of three months, the patient attended 16 chiropractic therapy sessions. He reported slow but considerable improvements in his symptoms, such as the recovery of normal cervical range of motion, decreases in neck discomfort and accompanying headaches as well as paresthesia, and enhancements in sleep quality, daily functioning, and learning capacities. The patient's clinical and radiographic improvements show that chiropractic spinal manipulation may assist in reducing pain and improving spine alignment and mobility in these circumstances. To further investigate the efficacy and safety of chiropractic therapy for the treatment of cervical dystonia, particularly in the setting of associated scoliosis, more study with bigger patient populations is required.

Correlates of deep brain stimulation consensus conference decision to treat primary dystonia.

BACKGROUND: Deep brain stimulation (DBS) is an effective treatment for motor disturbance in people with primary dystonia (PWD). Numerous factors are considered by an interdisciplinary consensus conference before deciding candidacy for DBS surgery (e.g., demographic, medical, cognitive, and behavioral factors). However, little is known about which of these factors are associated with PWD DBS surgery consensus conference decisions. OBJECTIVE: Our goal was to examine whether pre-operative demographic, medical, and cognitive/behavioral variables are associated DBS consensus conference decisions in patients with dystonia. METHODS: Thirty-two PWD completed comprehensive presurgery workup included neurological and neuropsychological exams, and neuroimaging in consideration for DBS surgery. An interdisciplinary conference committee either recommended or did not recommend DBS surgery based upon these data. Demographic and medical data (e.g., dystonia disease characteristics, medical comorbidities, medications) were also collected. We also examined impact from cardiovascular disease factors, using a Revised Cardiac Risk Index. PWD were grouped based on DBS conference decision (eligible: n = 21, ineligible: n = 11) and compared across demographic, medical, and cognitive/behavioral variables. RESULTS: Across clinical variables, PWD who were deemed ineligible for DBS surgery had a higher Revised Cardiac Risk Index. PWD who were classified as ineligible displayed lower global cognitive functioning, working memory, phonemic fluency, memory retrieval, and cognitive flexibility. CONCLUSIONS: Consensus decision making regarding DBS surgery eligibility involves a multifactorial process. We found that deficits in executive functioning were associated with the DBS consensus committee decision. We also observed elevated cardiac risk among these individuals, likely reflecting the relation between vascular health and cognition. Implications, and clinical and scientific applications of these findings are discussed.

An examination of the neurocognitive profile and base rate of performance impairment in primary dystonia.

BACKGROUND: Primary dystonia has been traditionally viewed as a motor disorder. However, non-motor symptoms are frequently present and significantly quality of life. Neuropsychiatric and cognitive symptoms have been identified, but prior studies have been limited in sample size and lack of control groups. This study examined the neurocognitive profile of a sample of persons with primary dystonia (PWD) as compared to demographically matched healthy control group. METHODS: A cognitive test battery was administered to 25 PWD who presented for pre-surgical candidacy evaluation for deep brain stimulation surgery. The test battery domains included global cognitive function, attention, expressive language, visuospatial skills, memory, and executive functioning. Twenty-five age, gender, education-matched healthy control participants were compared to the PWD. RESULTS: Compared to demographically matched healthy controls, PWD performed worse on measures of global cognitive function, attention, memory, and conceptualization. Based on normative comparison, a large portion of PWD were impaired on tasks of executive functioning and expressive language. Over 80% of the PWD showed impairment on at least one neurocognitive measure and over 60% showed impairment on 3 or more tests. CONCLUSIONS: Neurocognitive deficits were prevalent among our PWD sample. These impairments were present across a broad range of cognitive domains. Given the degree of cognitive impairment found in this study, our results have implications for health care providers with providing interventions to PWD.

COL6A3 mutation associated early-onset isolated dystonia (DYT)-27: Report of a new case and review of published literature.

BACKGROUND: Still, the genetic basis of a large number of cases of early-onset isolated dystonia continues to be a mystery. In recent years, many new candidate genes are being identified as putative pathogenic factors in children with isolated dystonia due to the easy availability of whole-exome sequencing. Recently biallelic mutations in the COL6A3 gene were identified as a cause of rare dystonia (DYT)-27 syndrome. Till date, only six cases of DYT27 have been reported in the literature. METHODS: We report a new case of COL6A3 mutation associated early-onset isolated dystonia-DYT27. We did a review of the previously published cases of DYT27. Citations were identified through PubMed, Embase, Web of Science and Google scholar searches using the search terms (including variations), "Dystonia-27 or DYT27" or/and "COL6A3 mutation associated early-onset isolated dystonia", combined with study filters for original research, case reports and case series. RESULTS: Next-generation sequencing in the index patient revealed two pathogenic compound heterozygous loss of function mutations in exon 10 and exon 12 of the COL6A3 gene coding for the alpha(α)3(VI) chain of type VI collagen. Together with the presented case, seven cases (five males) were available for analysis. The median age at onset was 22 years (range: 6-61). Dystonic symptoms were started from hands in five and from the neck in the remaining two patients. Five patients had favorable outcomes with trihexyphenidyl and botulinum toxin while tetrabenazine and levodopa were ineffective. CONCLUSIONS: Although it is a new entity that is only recently discovered, in future years many more new cases suffering from this particular entity are likely to be reported and the already heterogeneous clinical spectrum is likely to be further widespread in years to come.

The matter of significance - Has the p.(Glu121Lys) variant of TOR1A gene a pathogenic role in dystonia or Parkinson disease?

Next Generation Sequencing (NGS), has now become a very powerful tool for decoding variants of genes involved in pathogenesis of number of human disorders. One of the challenges of this method is to decipher the real pathogenic variants from a number of identified, not related to the disorder in analyzed case. Another issue is recognition of new phenotypes previously unrecognized but related to new variants combinations' in known genes. The other aspect is the HGMD or ClinVar mutation databases usage in data interpretation. The aim of this paper is to discuss pathogenicity of p.(Glu121Lys) missense mutation in the TOR1A gene previously described as dystonia causing variant. The patient diagnosed with typical Parkinson disease and positive family history was included into analysis. Also the internal whole exome sequencing (WES) database containing 600 subjects who has performed WES due to different causes was searched. All subjects had WES performed on SureSelect Human All Exon v.6 enrichment, Illumina NovaSeq 6000 platform, (annotations according to internal Institute Mother and Child's pipeline). The TOR1A p.(Glu121Lys) heterozygous mutation was revealed in 1 patient diagnosed with PD and 2 healthy subjects who has no dystonia symptoms. To conclude the TOR1A p.Glu121Lys variant should not be recognized as clearly pathogenic now.

Auditory-Perceptual Evaluation of Deep Brain Stimulation on Voice and Speech in Patients With Dystonia.

OBJECTIVE: To determine the effects of globus pallidus interna (GPi) deep brain stimulation (DBS) on speech and voice quality of patients with primary, medically refractory dystonia. METHODS: Voices of 14 patients aged ≥18 years (males = 7 and females = 7) with primary dystonia (DYT1 gene mutation dystonia = 4, cervical dystonia = 6, and generalized dystonia = 4) with bilateral GPi DBS were assessed. Five blinded raters (two fellowship-trained laryngologists and three speech/language pathologists) evaluated audio recordings of each patient pre- and post-DBS. Perceptual voice quality was rated using the Grade, Roughness, Breathiness, Asthenia, and Strain scale and changes in speech intelligibility were assessed with the Clinical Global Impression scale of Severity instrument. Inter-rater and intrarater reliability rates for perceptual voice ratings were assessed using the kappa coefficient. RESULTS: Voice quality parameters showed mean improvements in Grade (P < 0.0001), Roughness (P = 0.0043), and Strain (P < 0.0001) 12 months post-DBS. Asthenia increased from baseline to 6 months (P = 0.0022) and declined significantly from 6 to 12 months (P = 0.0170). Breathiness did not change significantly over time. Speech intelligibility also improved from 6 to 12 months (P = 0.0202) and from pre-DBS to 12 months post-DBS (P = 0.0022). Grade and Strain ratings had nearly perfect and substantial inter-rater agreement (0.84 and 0.71, respectively). CONCLUSIONS: Voice and speech intelligibility improved after bilateral GPi DBS for dystonia. GPi DBS may emerge as a potential treatment option for patients with medically refractory laryngeal dystonia.

Deep brain stimulation in dystonia: State of art and future directions.

When considering Deep Brain Stimulation (DBS) surgical treatment of dystonia syndromes, it is important to consider multiple aspects of the disease and its presentation. It is crucial to know if the dystonia is idiopathic, inherited or acquired as well as focal, segmental or generalised. Careful phenotyping of idiopathic as well as inherited dystonias and accurate diagnosis of acquired dystonias informs the decision-making process for patients and clinicians by providing them with useful predictors of outcomes of the proposed surgery. Here, we provided a review of the current literature, highlighted the areas where evidence is scarce and suggested future directions for research.