[How the implementation of a school for people with Parkinson's disease can succeed-Results of a consensus study and a formative evaluation]. / Wie die Umsetzung einer Schule für Menschen mit Parkinson-Krankheit gelingen kann ­ Ergebnisse eines Konsensusverfahrens und einer formativen Evaluation.

BACKGROUND: As the most rapidly increasing neurodegenerative disease worldwide, Parkinson's disease is highly relevant to society. Successful treatment requires active patient participation. Patient education has been successfully implemented for many chronic diseases, such as diabetes and could also provide people with Parkinson's disease with skills to manage the disease better and to participate in shared decision making. MATERIAL AND METHODS: To prepare the implementation of a concept for patient education for people with Parkinson's disease, a structured consensus study was conducted and a pilot project formatively evaluated. The structured consensus study included experts from all over Germany. It consisted of two online surveys and an online consensus conference. The formative evaluation was conducted as three focus groups. Transcripts were evaluated using content-structuring qualitative content analysis. RESULTS: From the consensus procedure 59 consented statements emerged, mainly regarding the contents of a patient school and a group size of 6-8 persons. Only two statements could not be consented. The formative evaluation detected a tendency towards a positive attitude for a digital training format and a very positive evaluation of the contents. DISCUSSION: Overall, important recommendations for a patient school can be drawn from this study. The following subjects require further investigation: format, inclusion criteria, group composition and inclusion of caregivers.

Recessive mutations in the α3 (VI) collagen gene COL6A3 cause early-onset isolated dystonia.

Isolated dystonia is a disorder characterized by involuntary twisting postures arising from sustained muscle contractions. Although autosomal-dominant mutations in TOR1A, THAP1, and GNAL have been found in some cases, the molecular mechanisms underlying isolated dystonia are largely unknown. In addition, although emphasis has been placed on dominant isolated dystonia, the disorder is also transmitted as a recessive trait, for which no mutations have been defined. Using whole-exome sequencing in a recessive isolated dystonia-affected kindred, we identified disease-segregating compound heterozygous mutations in COL6A3, a collagen VI gene associated previously with muscular dystrophy. Genetic screening of a further 367 isolated dystonia subjects revealed two additional recessive pedigrees harboring compound heterozygous mutations in COL6A3. Strikingly, all affected individuals had at least one pathogenic allele in exon 41, including an exon-skipping mutation that induced an in-frame deletion. We tested the hypothesis that disruption of this exon is pathognomonic for isolated dystonia by inducing a series of in-frame deletions in zebrafish embryos. Consistent with our human genetics data, suppression of the exon 41 ortholog caused deficits in axonal outgrowth, whereas suppression of other exons phenocopied collagen deposition mutants. All recessive mutation carriers demonstrated early-onset segmental isolated dystonia without muscular disease. Finally, we show that Col6a3 is expressed in neurons, with relevant mRNA levels detectable throughout the adult mouse brain. Taken together, our data indicate that loss-of-function mutations affecting a specific region of COL6A3 cause recessive isolated dystonia with underlying neurodevelopmental deficits and highlight the brain extracellular matrix as a contributor to dystonia pathogenesis.

Molecular diversity of combined and complex dystonia: insights from diagnostic exome sequencing.

Combined and complex dystonias are heterogeneous movement disorders combining dystonia with other motor and/or systemic signs. Although we are beginning to understand the diverse molecular causes of these disease entities, clinical pattern recognition and conventional genetic workup achieve an etiological diagnosis only in a minority of cases. Our goal was to provide a window into the variable genetic origins and distinct clinical patterns of combined/complex dystonia more broadly. Between August 2016 and January 2017, we applied whole-exome sequencing to a cohort of nine patients with varied combined and/or complex dystonic presentations, being on a diagnostic odyssey. Bioinformatics analyses, co-segregation studies, and sequence-interpretation algorithms were employed to detect causative mutations. Comprehensive clinical review was undertaken to define the phenotypic spectra and optimal management strategies. On average, we observed a delay in diagnosis of 23 years before whole-exome analysis enabled determination of each patient's genetic defect. Whereas mutations in ACTB, ATP1A3, ADCY5, and SGCE were associated with particular phenotypic clues, trait manifestations arising from mutations in PINK1, MRE11A, KMT2B, ATM, and SLC6A1 were different from those previously reported in association with these genes. Apart from improving counseling for our entire cohort, genetic findings had actionable consequences on preventative measures and therapeutic interventions for five patients. Our investigation confirms unique genetic diagnoses, highlights key clinical features and phenotypic expansions, and suggests whole-exome sequencing as a first-tier diagnostic for combined/complex dystonia. These results might stimulate independent teams to extend the scope of agnostic genetic screening to this particular phenotypic group that remains poorly characterized through existing studies.

Clinical exome sequencing in early-onset generalized dystonia and large-scale resequencing follow-up.

BACKGROUND: Dystonia is clinically and genetically heterogeneous. Despite being a first-line testing tool for heterogeneous inherited disorders, whole-exome sequencing has not yet been evaluated in dystonia diagnostics. We set up a pilot study to address the yield of whole-exome sequencing for early-onset generalized dystonia, a disease subtype enriched for monogenic causation. METHODS: Clinical whole-exome sequencing coupled with bioinformatics analysis and detailed phenotyping of mutation carriers was performed on 16 consecutive cases with genetically undefined early-onset generalized dystonia. Candidate pathogenic variants were validated and tested for cosegregation. The whole-exome approach was complemented by analyzing 2 mutated yet unestablished causative genes in another 590 dystonia cases. RESULTS: Whole-exome sequencing detected clinically relevant mutations of known dystonia-related genes in 6 generalized dystonia cases (37.5%), among whom 3 had novel variants. Reflecting locus heterogeneity, identified unique variants were distributed over 5 genes (GCH1, THAP1, TOR1A, ANO3, ADCY5), of which only 1 (ANO3) was mutated recurrently. Three genes (GCH1, THAP1, TOR1A) were associated with isolated generalized dystonia, whereas 2 (ANO3, ADCY5) gave rise to combined dystonia-myoclonus phenotypes. Follow-up screening of ANO3 and ADCY5 revealed a set of distinct variants of interest, the pathogenicity of which was supported by bioinformatics testing and cosegregation work. CONCLUSIONS: Our study identified whole-exome sequencing as an effective strategy for molecular diagnosis of early-onset generalized dystonia and offers insights into the heterogeneous genetic architecture of this condition. Furthermore, it provides confirmatory evidence for a dystonia-relevant role of ANO3 and ADCY5, both of which likely associate with a broader spectrum of dystonic expressions than previously thought. © 2016 International Parkinson and Movement Disorder Society.

The clinical phenotype of early-onset isolated dystonia caused by recessive COL6A3 mutations (DYT27).

BACKGROUND AND PURPOSE: We recently identified mutations in the a3 (VI) collagen gene COL6A3 that cause autosomal-recessive isolated dystonia (DYT27). This article gives a detailed description of the clinical phenotype associated with this new type of dystonia. METHODS: A total of 5 recessive COL6A3 mutation carriers underwent clinical examinations, and case histories were recorded on videotape. RESULTS: Biallelic COL6A3 mutations cause isolated dystonia with interindividual heterogeneity of distribution and severity. Dystonia was generalized in 3 patients, pronounced in the cranio-cervical region, upper limbs, and trunk; segmental in 1 patient, with the neck and upper limbs affected; and focal with cervical involvement in another patient. Symptoms began in childhood, adolescence, or early adulthood, initially affecting the neck as cervical dystonia or the hand as writer's cramp. CONCLUSION: COL6A3-associated dystonia represents a newly identified autosomal-recessive entity characterized clinically by an early symptom onset with variable distribution. © 2015 Movement Disorder Society.

Genetic variants in the immunoglobulin heavy chain locus are associated with the IgG index in multiple sclerosis.

OBJECTIVE: Intrathecal synthesis of immunoglobulin gamma (IgG) synthesis is frequently observed in patients with multiple sclerosis (MS). Whereas the extent of intrathecal IgG synthesis varies largely between patients, it remains rather constant in the individual patient over time. The aim of this study was to identify common genetic variants associated with the IgG index as a marker of intrathecal IgG synthesis in MS. METHODS: We performed a genome-wide association study of the IgG index in a discovery series of 229 patients. For confirmation we performed a replication in 2 independent series comprising 256 and 153 patients, respectively. The impact of associated single nucleotide polymorphisms (SNPs) on MS susceptibility was analyzed in an additional 1,854 cases and 5,175 controls. RESULTS: Significant association between the IgG index and 5 SNPs was detected in the discovery and confirmed in both replication series reaching combined p values of p = 6.5 × 10(-11) to p = 7.5 × 10(-16) . All identified SNPs are clustered around the immunoglobulin heavy chain (IGHC) locus on chromosome 14q32.33 and are in linkage disequilibrium (r(2) range, 0.71-0.95). The best associated SNP is located in an intronic region of the immunoglobulin gamma3 heavy chain gene. Additional sequencing identified the GM21* haplotype to be associated with a high IgG index. Further evaluation of the IGHC SNPs revealed no association with susceptibility to MS in our data set. INTERPRETATION: The extent of intrathecal IgG in MS is influenced by the IGHC locus. No association with susceptibility to MS was found. Therefore GM haplotypes might affect intrathecal IgG synthesis independently of the underlying disease.

Rare sequence variants in ANO3 and GNAL in a primary torsion dystonia series and controls.

BACKGROUND: Rare autosomal-dominant mutations in ANO3 and GNAL have been recently shown to represent novel genetic factors underlying primary torsion dystonia (PTD) with predominantly craniocervical involvement. METHODS: We used high-resolution melting to screen all exons of ANO3 and GNAL for rare sequence variants in a population of 342 German individuals with mainly sporadic PTD and 376 general population controls. RESULTS: We identified 2 novel missense variants in ANO3 (p.Ile833Val and p.Gly973Arg) and 1 novel missense variant in GNAL (p.Val146Met) in three different nonfamilial cases. Variant carriers presented with adult-onset dystonia involving the neck and/or face. In controls, 3 rare ANO3 missense variants (p.Tyr235Cys, p.Asn256Ser, and p.Pro893Leu) but no rare nonsynonymous GNAL variants were present. CONCLUSIONS: GNAL variants seem to be a rare cause of PTD in our mainly sporadic German sample. Low frequency missense variants in ANO3 occur in both cases and controls, warranting further assessment of this gene in PTD pathogenesis.

DYT16 revisited: exome sequencing identifies PRKRA mutations in a European dystonia family.

Recessive DYT16 dystonia associated with mutations in PRKRA has until now been reported only in seven Brazilian patients. The aim of this study was to elucidate the genetic cause underlying disease in a Polish family with autosomal-recessive, early-onset generalized dystonia and slight parkinsonism, and to explore further the role of PRKRA in a dystonia series of European ancestry. We employed whole-exome sequencing in two affected siblings of the Polish family and filtered for rare homozygous and compound heterozygous variants shared by both exomes. Validation of the identified variants as well as homozygosity screening and copy number variation analysis was carried out in the two affected individuals and their healthy siblings. PRKRA was analyzed in 339 German patients with various forms of dystonia and 376 population-based controls by direct sequencing or high-resolution melting. The previously described homozygous p.Pro222Leu mutation in PRKRA was found to segregate with the disease in the studied family, contained in a 1.2 Mb homozygous region identical by state with all Brazilian patients in chromosome 2q31.2. The clinical presentation with young-onset, progressive generalized dystonia and mild parkinsonism resembled the phenotype of the original DYT16 cases. PRKRA mutational screening in additional dystonia samples revealed three novel heterozygous changes (p.Thr34Ser, p.Asn102Ser, c.-14A>G), each in a single subject with focal/segmental dystonia. Our study provides the first independent replication of the DYT16 locus at 2q31.2 and strongly confirms the causal contribution of the PRKRA gene to DYT16. Our data suggest worldwide involvement of PRKRA in dystonia.

Mitochondrial membrane protein associated neurodegenration: a novel variant of neurodegeneration with brain iron accumulation.

BACKGROUND: Recently, mutations in an open-reading frame on chromosome 19 (C19orf12) were identified as a novel genetic factor in neurodegeneration with brain iron accumulation (NBIA). Because of the mitochondrial localization of the derived protein, this variant is referred to as mitochondrial membrane protein-associated neurodegeneration with brain iron accumulation (MPAN). METHODS/RESULTS: We describe the clinical phenotype and MRI of 3 newly identified individuals with MPAN due to either previously reported or novel homozygous or compound heterozygous genetic alterations in C19orf12. CONCLUSIONS: MPAN is characterized by a juvenile-onset, slowly progressive phenotype with predominant lower limb spasticity, generalized dystonia, and cognitive impairment. Typical additional features include axonal motor neuropathy and atrophy of the optic nerve. MRI showed iron deposition in the globus pallidus and substantia nigra without the eye-of-the-tiger sign, which is typical for PKAN, the most frequent form of NBIA.

White-matter lesions drive deep gray-matter atrophy in early multiple sclerosis: support from structural MRI.

BACKGROUND: In MS, the relationship between lesions within cerebral white matter (WM) and atrophy within deep gray matter (GM) is unclear. OBJECTIVE: To investigate the spatial relationship between WM lesions and deep GM atrophy. METHODS: We performed a cross-sectional structural magnetic resonance imaging (MRI) study (3 Tesla) in 249 patients with clinically-isolated syndrome or relapsing-remitting MS (Expanded Disability Status Scale score: median, 1.0; range, 0-4) and in 49 healthy controls. Preprocessing of T1-weighted and fluid-attenuated T2-weighted images resulted in normalized GM images and WM lesion probability maps. We performed two voxel-wise analyses: 1. We localized GM atrophy and confirmed that it is most pronounced within deep GM; 2. We searched for a spatial relationship between WM lesions and deep GM atrophy; to this end we analyzed WM lesion probability maps by voxel-wise multiple regression, including four variables derived from maxima of regional deep GM atrophy (caudate and pulvinar, each left and right). RESULTS: Atrophy of each deep GM region was explained by ipsilateral WM lesion probability, in the area most densely connected to the respective deep GM region. CONCLUSION: We demonstrated that WM lesions and deep GM atrophy are spatially related. Our results are best compatible with the hypothesis that WM lesions contribute to deep GM atrophy through axonal pathology.

Nationwide Retrospective Analysis of Combinations of Advanced Therapies in Patients With Parkinson Disease.

BACKGROUND AND OBJECTIVES: Advanced therapies (ATs; deep brain stimulation [DBS] or pump therapies: continuous subcutaneous apomorphine infusion [CSAI], levodopa/carbidopa intestinal gel [LCIG]) are used in later stages of Parkinson disease (PD). However, decreasing efficacy over time and/or side effects may require an AT change or combination in individual patients. Current knowledge about changing or combining ATs is limited to mostly retrospective and small-scale studies. The nationwide case collection Combinations of Advanced Therapies in PD assessed simultaneous or sequential AT combinations in Germany since 2005 to analyze their clinical outcome, their side effects, and the reasons for AT modifications. METHODS: Data were acquired retrospectively by modular questionnaires in 22 PD centers throughout Germany based on clinical records and comprised general information about the centers/patients, clinical (Mini-Mental Status Test/Montréal Cognitive Assessment, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS], side effects, reasons for AT modification), and therapeutical (ATs with specifications, oral medication) data. Data assessment started with initiation of the second AT. RESULTS: A total of 148 AT modifications in 116 patients were associated with significantly improved objective (median decrease of MDS-UPDRS Part III 4.0 points [p < 0.001], of MDS-UPDRS Part IV 6.0 points [p < 0.001], of MDS-UPDRS Part IV-off-time item 1.0 points [p < 0.001]) and subjective clinical outcome and decreasing side effect rates. Main reasons for an AT modification were insufficient symptom control and side effects of the previous therapy. Subgroup analyses suggest addition of DBS in AT patients with leading dyskinesia, addition of LCIG for leading other cardinal motor symptoms, and addition of LCIG or CSAI for dominant off-time. The most long-lasting therapy-until requiring a modification-was DBS. DISCUSSION: Changing or combining ATs may be beneficial when 1 AT is insufficient in efficacy or side effects. The outcome of an AT combination is comparable with the clinical benefit by introducing the first AT. The added AT should be chosen dependent on dominant clinical symptoms and adverse effects. Furthermore, prospective trials are needed to confirm the results of this exploratory case collection. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, in patients with PD, changing or combining ATs is associated with an improvement in the MDS-UPDRS or subjective symptom reporting.

Thalamic structural connectivity profiles in blepharospam/Meige's syndrome.

BACKGROUND: Blepharospasm is a debilitating focal dystonia characterized by involuntary eyelid spasms that can be accompanied by oromandibular muscle involvement (Meige's syndrome). Frequently observed abnormality in functional neuroimaging hints at an important position of the thalamus, that relays involved cortico-basal ganglia-cortical and cortico-cerebello-cortical circuits, within the abnormal network in blepharospasm. OBJECTIVE: To characterize abnormal cortico-thalamic structural/streamline connectivity (SC) patterns in the disease, as well as their potential co-occurrence with abnormal subcortico-thalamo-cortical projections using diffusion tractography. METHODS: Diffusion imaging was obtained in 17 patients with blepharospasm (5 with mild lower facial involvement) and 17 healthy controls. Probabilistic tractography was used for quantification of SC between six cortical regions and thalamus, and voxel-level thalamic SC mapping as well as evaluation of the thalamic SC distributions' topography by center-of-gravity analysis was performed. Post-hoc, correlations of SC with clinical parameters were evaluated. Further, white matter integrity was investigated within representative segments of the dentato-thalamo-cortical and pallido-thalamo-cortical tract. RESULTS: Connectivity mapping showed significant reduction of right (pre)motor- and left occipital-thalamic SC, as well as a topographic shift of the left occipital-thalamic SC distribution in patients. Significant positive correlation of occipital-thalamic SC with disease severity was found. Post-hoc analysis revealed significantly reduced mean fractional anisotropy in patients within the dentato-thalamo-cortical trajectory connecting to right (pre)motor and left occipital cortex. CONCLUSION: Abnormal occipital/motor SC provides evidence for dysfunction of the thalamus-relayed visual and motor network as a key aspect in the disease. Concurrent impairment of microstructural integrity within the dentato-thalamic trajectories targeting those cortices hints at cerebellar contribution.

Altered sensory system activity and connectivity patterns in adductor spasmodic dysphonia.

Adductor-type spasmodic dysphonia (ADSD) manifests in effortful speech temporarily relievable by botulinum neurotoxin type A (BoNT-A). Previously, abnormal structure, phonation-related and resting-state sensorimotor abnormalities as well as peripheral tactile thresholds in ADSD were described. This study aimed at assessing abnormal central tactile processing patterns, their spatial relation with dysfunctional resting-state connectivity, and their BoNT-A responsiveness. Functional MRI in 14/12 ADSD patients before/under BoNT-A effect and 15 controls was performed (i) during automatized tactile stimulus application to face/hand, and (ii) at rest. Between-group differential stimulation-induced activation and resting-state connectivity (regional homogeneity, connectivity strength within selected sensory(motor) networks), as well as within-patient BoNT-A effects on these differences were investigated. Contralateral-to-stimulation overactivity in ADSD before BoNT-A involved primary and secondary somatosensory representations, along with abnormalities in higher-order parietal, insular, temporal or premotor cortices. Dysphonic impairment in ADSD positively associated with left-hemispheric temporal activity. Connectivity was increased within right premotor (sensorimotor network), left primary auditory cortex (auditory network), and regionally reduced at the temporoparietal junction. Activation/connectivity before/after BoNT-A within-patients did not significantly differ. Abnormal ADSD central somatosensory processing supports its significance as common pathophysiologic focal dystonia trait. Abnormal temporal cortex tactile processing and resting-state connectivity might hint at abnormal cross-modal sensory interactions.

Treatment of blepharospasm and Meige's syndrome with abo- and onabotulinumtoxinA: long-term safety and efficacy in daily clinical practice.

INTRODUCTION: Thirty years after their approval, botulinum toxin injections still are the first-line therapy for blepharospasm. The aim of our study was to analyze long-term data concerning safety and efficacy in a large cohort over decades. METHODS: Treatment data of all patients with blepharospasm and Meige´s syndrome in our outpatient clinic having undergone at least three subsequent treatment sessions with current onabotulinumtoxinA or abobotulinumtoxin A were analyzed with respect to the course of dose, effect duration, side effects, patients´ satisfaction and occurrence/reasons for treatment discontinuation. RESULTS: The observation period was up to 18 years for onabotulinumtoxinA and 29 years for abobotulinumtoxinA with a total of 1778 and 9319 treatment sessions in 69 patients with onabotulinumtoxinA, 281 with abobotulinumtoxin A and 2 of these having used both products. The dose increased in the first years followed by a stable dose in the following years. The mean dose was 39.1/198.7 mouse units (onabotulinumtoxinA/abobotulinumtoxinA). In over 25% of all sessions, inhibition of the eyelid opening was effectively treated with pretarsal injections. The most common adverse events included ptosis (4%/5%), epiphora/sicca (4%/5%), double vision (1%/1%) and facial asymmetry (1%/1%). Reasons for therapy discontinuation were change to a nearby doctor, age, other diseases, spontaneous improvement, side effects or possible treatment failure. Only one patient was tested positive for neutralizing antibodies against botulinum toxin A. CONCLUSION: The treatment of blepharospasm and Meige's syndrome with onabotulinumtoxinA and abobotulinumtoxinA is safe and effective, also over a long observation period of up to 29 years.

Structure-function abnormalities in cortical sensory projections in embouchure dystonia.

BACKGROUND: Embouchure dystonia (ED) is a task-specific focal dystonia in professional brass players leading to abnormal orofacial muscle posturing/spasms during performance. Previous studies have outlined abnormal cortical sensorimotor function during sensory/motor tasks and in the resting state as well as abnormal cortical sensorimotor structure. Yet, potentially underlying white-matter tract abnormalities in this network disease are unknown. OBJECTIVE: To delineate structure-function abnormalities within cerebral sensorimotor trajectories in ED. METHOD: Probabilistic tractography and seed-based functional connectivity analysis were performed in 16/16 ED patients/healthy brass players within a simple literature-informed network model of cortical sensorimotor processing encompassing supplementary motor, superior parietal, primary somatosensory and motor cortex as well as the putamen. Post-hoc grey matter volumetry was performed within cortices of abnormal trajectories. RESULTS: ED patients showed average axial diffusivity reduction within projections between the primary somatosensory cortex and putamen, with converse increases within projections between supplementary motor and superior parietal cortex in both hemispheres. Increase in the mode of anisotropy in patients was accompanying the latter left-hemispheric projection, as well as in the supplementary motor area's projection to the left primary motor cortex. Patient's left primary somatosensory functional connectivity with the putamen was abnormally reduced and significantly associated with the axial diffusivity reduction. Left primary somatosensory grey matter volume was increased in patients. CONCLUSION: Correlates of abnormal tract integrity within primary somatosensory cortico-subcortical projections and higher-order sensorimotor projections support the key role of dysfunctional sensory information propagation in ED pathophysiology. Differential directionality of cortico-cortical and cortico-subcortical abnormalities hints at non-uniform sensory system changes.

Monogenic variants in dystonia: an exome-wide sequencing study.

BACKGROUND: Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. METHODS: For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. FINDINGS: We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. INTERPRETATION: In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations. FUNDING: Else Kröner-Fresenius-Stiftung, Technische Universität München, Helmholtz Zentrum München, Medizinische Universität Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.

Treatment of cervical dystonia with abo- and onabotulinumtoxinA: long-term safety and efficacy in daily clinical practice.

INTRODUCTION: Treatment with botulinum toxin A is the evidence-based first-line therapy of cervical dystonia. The aim of this study was to analyze long-term data of the most commonly used products concerning safety and efficacy in a big cohort over decades. METHODS: We retrospectively analyzed the treatment data of all cervical dystonia patients in our outpatient clinic having at least three treatment sessions with current onabotulinumtoxinA or abobotulinumtoxinA. The observation period was up to 17 years for onabotulinumtoxinA and 27 years for abobotulinumtoxinA. We report on safety and efficacy, comparing parameters such as dose, treatment intervals, side effects, occurrence and reasons of primary or secondary non-response. RESULTS: We analyzed a total of 2592 and 6660 treatment sessions in 135 patients with onabotulinumtoxinA, 209 with abobotulinumtoxinA and 10 having received both preparations. We found a moderate increase of dosage in the first years which was succeeded by a stable mean dose (138 and 663 mouse units, respectively) and stable injection intervals from the beginning. The most frequent side effects were mild dysphagia (2/6%), muscle weakness (2/6%) and pain (2/2%). Reasons for therapy discontinuation were change to a nearby doctor, age, other diseases, spontaneous improvement, side effects or possible treatment failure. Of all patients, only two tested positive for neutralizing antibodies against botulinum toxin A. CONCLUSION: We show that treatment of cervical dystonia with the two most frequently used botulinum toxin A preparations is a safe and effective therapy even over a long treatment duration of up to 27 years.

Abnormalities in grey matter structure in embouchure dystonia.

INTRODUCTION: Embouchure dystonia (ED) is a debilitating movement disorder in professional brass players leading to involuntary muscle contractions/spasms during play. To date, activity changes in sensorimotor cortices during motor tasks and tactile processing, as well as connectivity changes at rest in sensorimotor and auditory brain networks have been described in the disease. OBJECTIVE: To characterize differences in grey matter volume and asymmetry between brass musicians suffering from ED, healthy brass musicians and healthy nonmusicians. METHODS: High-resolution structural magnetic resonance imaging was obtained from 24 brass musicians with ED, 23 healthy brass musicians and 24 healthy nonmusicians. Whole-brain voxel-wise morphometry and asymmetry analyses, as well as region-of-interest-based volumetry analysis were performed on the subjects' images and compared between groups. Further, correlations with clinical parameters were investigated. RESULTS: ED patients showed increased grey matter volume in the primary sensorimotor cortex in relation to both healthy brass players and nonmusicians. Both healthy and diseased musicians showed increased thalamic symmetry in relation to nonmusicians; diseased brass musicians additionally showed increased basal ganglia symmetry compared to nonmusicians. There was an inverse correlation of disease duration with both mean putaminal volume and the extent of basal ganglia asymmetry. CONCLUSION: This work provides first evidence for structural abnormalities in task-specific orofacial (musician's) dystonia. Somatotopy-related structural primary sensorimotor cortex changes underlying previously observed functional abnormalities underscore the role of maladaptive plasticity in the disease. The study further shows subcortical brain (a)symmetry changes in healthy brass players and hints at a possible role of such changes in focal dystonia.

Impaired white matter integrity between premotor cortex and basal ganglia in writer's cramp.

INTRODUCTION: Writer's cramp (WC) as a focal hand dystonia is characterized by abnormal postures of the hand during writing. Impaired inhibition and maladaptive plasticity in circuits linking the basal ganglia and sensorimotor cortices have been described. In particular, a dysfunction of lateral premotor cortices has been associated with impaired motor control in WC. We applied diffusion tensor imaging to identify changes in white matter connectivity between premotor regions and important cortical and subcortical structures. METHODS: Whole brain white matter tracts were reconstructed in 18 right-handed WC patients and 18 matched controls, using probabilistic fiber tracking. We restricted our analyses to left-hemispheric fibers between the middle frontal gyrus (MFG) and basal ganglia, thalamus, primary motor, and sensory cortex. Diffusion parameters (fractional anisotropy and linear anisotropy) were compared between both groups. RESULTS: A significant reduction in fractional anisotropy values was shown for patients (mean ± SD: 0.37 ± 0.02) vs. controls (0.39 ± 0.03) regarding fibers between the left-sided MFG and the putamen (p < 0.05). The same applied for linear anisotropy values in this connection (p < 0.05). CONCLUSIONS: Our results suggest an impaired structural connectivity between the left-hemispheric MFG and putamen with a loss of equally aligned fibers in WC patients. This could reflect a structural basis for functional findings interpreted as altered inhibition and plasticity, both within the premotor cortex and the basal ganglia, that at last lead to the clinical symptoms of WC.