Dissecting genetic architecture of rare dystonia: genetic, molecular and clinical insights.

BACKGROUND: Dystonia is one of the most common movement disorders. To date, the genetic causes of dystonia in populations of European descent have been extensively studied. However, other populations, particularly those from the Middle East, have not been adequately studied. The purpose of this study is to discover the genetic basis of dystonia in a clinically and genetically well-characterised dystonia cohort from Turkey, which harbours poorly studied populations. METHODS: Exome sequencing analysis was performed in 42 Turkish dystonia families. Using co-expression network (CEN) analysis, identified candidate genes were interrogated for the networks including known dystonia-associated genes and genes further associated with the protein-protein interaction, animal model-based characteristics and clinical findings. RESULTS: We identified potentially disease-causing variants in the established dystonia genes (PRKRA, SGCE, KMT2B, SLC2A1, GCH1, THAP1, HPCA, TSPOAP1, AOPEP; n=11 families (26%)), in the uncommon forms of dystonia-associated genes (PCCB, CACNA1A, ALDH5A1, PRKN; n=4 families (10%)) and in the candidate genes prioritised based on the pathogenicity of the variants and CEN-based analyses (n=11 families (21%)). The diagnostic yield was found to be 36%. Several pathways and gene ontologies implicated in immune system, transcription, metabolic pathways, endosomal-lysosomal and neurodevelopmental mechanisms were over-represented in our CEN analysis. CONCLUSIONS: Here, using a structured approach, we have characterised a clinically and genetically well-defined dystonia cohort from Turkey, where dystonia has not been widely studied, and provided an uncovered genetic basis, which will facilitate diagnostic dystonia research.

Axial dystonia as a manifestation of stiff-person syndrome in a paediatric patient.

Stiff-person syndrome (SPS) is a rare neurological condition that frequently affects adults, with the neurologist diagnosing only one or two cases during his or her career. Reports of paediatric SPS are exceedingly rare, with less than 20 cases described in the literature.The patient presented was initially diagnosed with a functional movement disorder then a genetic dystonia, with a poor response to treatment trials and negative genetic testing. Consideration of Wilson's disease was refuted with non-supportive investigations and assessments.We aim to present the long road to diagnosing our first paediatric patient with SPS, who presented in middle childhood.

Are Cognitive Symptoms Part of the Phenotypic Spectrum of Idiopathic Adult-Onset Dystonia? Summary of Evidence from Controlled Studies.

BACKGROUND: Cognitive dysfunction has been reported in idiopathic adult-onset dystonia (IAOD), but whether this is a primary or secondary component of the disorder remains uncertain. OBJECTIVE: Here, we aimed to analyze the key domains of abnormal cognitive performance in IAOD and whether this is associated with motor or mood changes. METHODS: Article selection for our critical review was guided by PRISMA guidelines (mesh terms "dystonia" and "cognitive," publication period: 2000-2022). Only peer-reviewed, English-language original case-control studies involving patients with IAOD who were not exposed to dopamine- or acetylcholine-modulating agents and validated cognitive assessments were included. RESULTS: Abstract screening ultimately yielded 22 articles for full-text review and data extraction. A greater proportion of studies (17 of 22, 82%) reported abnormal cognitive performance in IAOD. Most of these studies focused on blepharospasm (BSP) and cervical dystonia (10 and 14, respectively). Most studies reporting cognitive impairment (11 of 17) identified multidomain impairment in cognition. Executive functions were the domain most frequently explored (14 of 22 studies), 79% of which detected worse performance in people with dystonia. Results related to other domains were inconclusive. Cognitive abnormalities were independent of motor symptoms in most studies (7 of 12) that explored this relationship and independent of mood status in all 8 that investigated this. CONCLUSIONS: Within IAOD, cognitive dysfunction (in particular, executive dysfunction) has been documented mainly in BSP and cervical dystonia. More comprehensive testing is warranted to assess abnormalities in other domains and in other forms of IAOD, as well as to evaluate longitudinal progression of cognitive disturbances in this condition.

Caregiver descriptions of dystonia in cerebral palsy.

OBJECTIVE: To determine how caregivers describe dystonia in people with cerebral palsy (CP). METHODS: In this prospective cohort study, paper surveys were administered to caregivers between September 7, 2021 and October 28, 2021 during CP Center visits at a large tertiary care center. Caregivers were asked to describe involuntary movements triggered by voluntary movement or triggered by tactile stimulation in the people with CP they cared for. Their CP Center medical provider separately assessed people with CP for dystonia. Movement features described exclusively by caregivers of people with CP and dystonia were determined using conventional content analysis. RESULTS: 113 caregivers responded on behalf of 56 people with and 57 people without dystonia. If caregivers noted that both voluntary movement and tactile stimulation triggered involuntary movements, that had a 92% positive predictive value for a dystonia diagnosis. Movement features exclusively described in people with CP and dystonia included: (1) stiffening, tensing, or tightening (15% of respondents); (2) involvement of the head (10%), torso (5%), or feet (5%); and (3) triggers of stretching (12.5%), excitement (5%), or transfers (5%). INTERPRETATION: In addition to a thorough exam, asking caregivers of people with CP to describe involuntary movements triggered by voluntary movement or tactile stimulation may inform clinical dystonia diagnosis.

Dominant VPS16 Pathogenic Variants: Not Only Isolated Dystonia.

BACKGROUND: VPS16 pathogenic variants have been recently associated with inherited dystonia. Most patients affected by dominant VPS16-related disease display early-onset isolated dystonia with prominent oromandibular, bulbar, cervical, and upper limb involvement, followed by slowly progressive generalization. CASES: We describe six newly reported dystonic patients carrying VPS16 mutations displaying unusual phenotypic features in addition to dystonia, such as myoclonus, choreoathetosis, pharyngospasm and freezing of gait. Response to bilateral Globus Pallidus Internus Deep Brain Stimulation (GPi-DBS) is reported in three of them, associated with significant improvement of dystonia but only minor effect on other hyperkinetic movements. Moreover, five novel pathogenic/likely pathogenic variants are described. CONCLUSIONS: This case collection expands the genetic and clinical spectrum of VPS16-related disease, prompting movement disorder specialists to suspect mutations of this gene not only in patients with isolated dystonia.

A scoping review on the diagnosis and treatment of X-linked dystonia-parkinsonism.

INTRODUCTION: X-linked dystonia-parkinsonism (XDP) is a progressive neurodegenerative disorder that has been studied well in recent years. OBJECTIVES: This scoping review aimed to describe the current state of knowledge about the diagnosis and treatment of XDP, to provide clinicians with a concise and up-to-date overview. METHODS: We conducted a scoping review of pertinent literature on the diagnosis and treatment of XDP using Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines. RESULTS: There were 24 articles on diagnostic methods and 20 articles on therapeutic interventions for XDP, with 7 review articles describing both. The detection of the SVA retrotransposon insertion within the TAF1 gene is confirmatory for XDP. Oral medications are marginally effective. Chemodenervation with botulinum toxin is an effective treatment. Pallidal deep brain stimulation (DBS) has been shown to provide significant improvement in the dystonia and quality of life of patients with XDP for a longer time. A less invasive surgical option is the transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS), which has shown promising effects with the limited number of case reports available. CONCLUSION: XDP is a geneti disorder characterized by striatal symptoms and pathology on neuroimaging. No effective oral medications are available for the management of XDP. The use of botulinum toxin is limited by its cost and duration of effects. As of now, pallidal DBS is deemed to be the best option. Another promising option is the tcMRgFUS but still has limited studies on its safety and efficacy in XDP.

ATP1A3 related disease manifesting as rapid onset dystonia-parkinsonism with prominent myoclonus and exaggerated startle.

We report ATP1A3-associated rapid-onset dystonia-parkinsonism with an atypical presentation including myoclonus and exaggerated startle in four patients. Their prominence over parkinsonism prompted consideration of a syndromic diagnosis of myoclonus dystonia. ATP1α3 dysfunction in GABAergic neurons could explain these examination findings. The spectrum of ATP1A3-associated movement disorders includes myoclonus-dystonia.

Whole exome sequencing and clinical investigation of young onset dystonia: What can we learn?

BACKGROUND: Dystonia is a heterogeneous movement disorder involving various genetic backgrounds, and the implication of whole exome sequencing (WES) has yet to be clearly elucidated. In this study, we performed WES in Korean patients with young-onset dystonia. METHODS: We recruited patients with young-onset dystonia based on the new MDS dystonia classification at Samsung Medical Centre from 2015 to 2019. We excluded subjects diagnosed by single gene tests (GCH1, TOR1A, PANK2, PRRT2, and SGCE) or levodopa trials and subjects with focal or possible secondary dystonia. We performed WES in all enrolled subjects and confirmed the results with Sanger sequencing. RESULTS: Of the 43 patients, we detected 11 disease-causing variants, classified as either pathogenic or likely pathogenic, in 9 patients (20.9%). Generalized dystonia, infancy-childhood-onset dystonia, and other combined neurologic manifestations were related with PV/LPV. When we retrospectively reviewed the patients with PV/LPV, brain imaging was diagnostic in 3 subjects (HTRA1, SCL20A, and WDR45), clinical characteristics of paroxysmal presentation were observed in 2 (ADCY5 and ATP1A3), and microcephaly was noted in 1 patient (KMT2B). CONCLUSION: Clinical exome sequencing is helpful for the diagnosis of dystonia, especially for that with infancy-childhood onset, and generalized dystonia with other neurologic manifestations. Additionally, careful evaluations and examinations could provide information for selecting candidates for genetic testing.

A Genetics Pearl for Counseling Patients with Epsilon-Sarcoglycan Myoclonus-Dystonia.

Background: Epsilon-sarcoglycan (SGCE) myoclonus-dystonia is autosomal dominant (AD) with reduced penetrance due to maternal imprinting 95% of the time. Patients may lack family history delaying diagnosis and treatment. Additionally, counseling patients on their risk of passing on the variant differs for females versus males. Case Report: A woman in her thirties with typical phenotype of myoclonus-dystonia but lacking an AD pedigree was found to have a pathogenic variant in the SGCE gene. She was counseled that her daughters each have a 2.5% chance of expressing the phenotype. Discussion: Understanding the genetics of SGCE-myoclonus-dystonia enables effective genetic counseling and arrival at a timely diagnosis and treatment. Summary: In an era of advancing genetic analysis and precision medicine-based treatments, neurologists will be faced with increasing responsibility to properly counsel patients on the results of genetic testing. This case highlights a genetics pearl for counseling patients with epsilon-sarcoglycan myoclonus-dystonia, an autosomal dominant condition with penetrance differing by sex.

Clinical features of dystonia and the science of classification.

This chapter describes advances in understanding the clinical features of dystonia since initial clinical recognition and its organization into a coherent and systematic clinical set. The clinical features of dystonia were at first considered an odd neurological movement disorder. Etymology of the word misleadingly underlined muscle tone. The main clinical features of dystonia were recognized gradually. They encompass dystonic movements, dystonic postures, alleviating maneuvers, overflow and mirroring. These features are observed in patients who present a variety of syndromes where dystonia occurs in isolation or combined with other movement disorders, or with other neurologic or systemic features. A large number of syndromic combinations is observed in the clinic and some of the syndomes are highlighted here. Practitioners are required to exert dedicated skills to recognize dystonia and correctly diagnose and classify their patients.

Genetic Screening of a Hungarian Cohort with Focal Dystonia Identified Several Novel Putative Pathogenic Gene Variants.

Dystonia is a rare movement disorder which is characterized by sustained or intermittent muscle contractions causing abnormal and often repetitive movements, postures, or both. The two most common forms of adult-onset focal dystonia are cervical dystonia (CD) and benign essential blepharospasm (BSP). A total of 121 patients (CD, 74; BSP, 47) were included in the study. The average age of the patients was 64 years. For the next-generation sequencing (NGS) approach, 30 genes were selected on the basis of a thorough search of the scientific literature. Assessment of 30 CD- and BSP-associated genes from 121 patients revealed a total of 209 different heterozygous variants in 24 genes. Established clinical and genetic validity was determined for nine heterozygous variations (three likely pathogenic and six variants of uncertain significance). Detailed genetic examination is an important part of the work-up for focal dystonia forms. To our knowledge, our investigation is the first such study to be carried out in the Middle-European region.

[Abnormal movements "Motare" in Kyudo have the characteristics of task-specific focal dystonia].

Among the abnormal kyudo movements ("yips"), "motare" is the inability to release the arrow at the intended timing if aiming the target. We hypothesized that "motare" is a task-specific focal dystonia (TSFD). We interviewed three participants with "motare," three participants with "hayake", and three controls without "motare" nor "hayake". Moreover, we conducted a surface electromyography (sEMG) examination and found that "motare" was characterized by stereotypy, sensory tricks, and morning benefit; however, these findings were not observed in "hayake". Abnormal co-contraction of the upper extremity antagonist muscles was observed in one of the three "motare" participants. Overall, these findings suggest that "motare" have the characteristics of TSFD not previously reported.

New developments in diagnostics and treatment of adult-onset focal dystonia.

PURPOSE OF REVIEW: The aim of this review is to showcase the recent developments in the field of diagnosis and treatment of adult-onset focal dystonia. RECENT FINDINGS: Accurate phenotyping of focal dystonia is essential in the process of finding an underlying cause, including acquired, genetic, and idiopathic causes. Motor symptoms as well as the associated nonmotor symptoms and their detrimental impact on quality of life have received increased interest over the last years. The diagnostic process is complicated by the steadily increasing numbers of newly discovered genes associated with dystonia. Recent efforts have been aimed at further developing recommendations and algorithms to aid in diagnosis and in navigating the use of diagnostic tools. In terms of treatment, research on DBS is advancing towards a better understanding of the most effective stimulation locations within the globus pallidus. Moreover, with the introduction of the LFP-recording devices, the search continues for an accurate electrophysiological biomarker for dystonia. SUMMARY: Accurate phenotyping and (sub)classification of patients with dystonia is important for improving diagnosis, subsequent treatment effect and population-based study outcomes in research. Medical practitioners should be attentive to the presence of nonmotor symptoms in dystonia.

The Collicular-Pulvinar-Amygdala Axis and Adult-Onset Idiopathic Focal Dystonias.

Adult-onset idiopathic focal dystonias (AOIFD) are the most common type of dystonia. It has varied expression including multiple motor (depending on body part affected) and non-motor symptoms (psychiatric, cognitive and sensory). The motor symptoms are usually the main reason for presentation and are most often treated with botulinum toxin. However, non-motor symptoms are the main predictors of quality of life and should be addressed appropriately, as well as treating the motor disorder. Rather than considering AOIFD as a movement disorder, a syndromic approach should be taken, one that accommodates all the symptoms. Dysfunction of the collicular-pulvinar-amygdala axis, with the superior colliculus as a central node, can explain the diverse expression of this syndrome.

Abnormalities in the face primary motor cortex in oromandibular dystonia.

OBJECTIVE: To comprehensively investigate excitability in face and hand M1 and sensorimotor integration in oromandibular dystonia (OMD) patients. METHODS: Short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), short (SAI) and long (LAI) afferent inhibition were investigated in face and hand M1 using transcranial magnetic stimulation protocols in 10 OMD patients. Data were compared with those obtained in 10 patients with focal hand dystonia (FHD), in 10 patients with blepharospasm (BSP), and 10 matched healthy subjects (HS). RESULTS: Results demonstrated that in OMD patients SICI was reduced in face M1 (p < 0.001), but not in hand M1, compared to HS. In FHD, SICI was significantly impaired in hand M1 (p = 0.029), but not in face M1. In BSP, SICI was normal in both face and hand M1 while ICF and LAI were normal in all patient groups and cortical area tested. SAI was significantly reduced (p = 0.003) only in the face M1 of OMD patients. CONCLUSIONS: In OMD, SICI and SAI were significantly reduced. These abnormalities are specific to the motor cortical area innervating the muscular district involved in focal dystonia. SIGNIFICANCE: In OMD, the integration between sensory inflow and motor output seem to be disrupted at cortical level with topographic specificity.

Is Behavioural Therapy a New Treatment Option for Task-Specific Dystonia in Athletes? A Case Series.

Background: Task-specific dystonia is a movement disorder of the central nervous system characterized by focal involuntary spasms and muscle contractions, which can negatively affect performance of a specific task. It can affect a wide range of fine motor skills, also in athletes. Current management of task-specific dystonia includes mainly prescribing drugs, exercise therapy or botulinum injections to the affected muscles. Psychological interventions for athletes suffering from task-specific dystonia have not been described extensively so far. Methods: We present a case-series of 4 different advanced skill-level athletes with suspected task-specific dystonia, which had a major impact on their performance. They all received treatment consisting of a combination of standardized behavioural therapy and relaxation techniques in the form of hypnosis in a total of 8 sessions in a 16-week time period. Results: After treatment, all athletes returned to their original high level of sport performance without further symptoms of their suspected task-specific dystonia. Discussion: Behavioural therapy in combination with a relaxation technique seems to be a safe and promising treatment for athletes with suspected task-specific dystonia. Further studies in a larger, preferably randomized controlled trial, are warranted to evaluate if this treatment strategy is effective in athletes with suspected task-specific dystonia.