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The Lancet. Neurology Nov 2020Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined...
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.
Topics: Adolescent; Child; Child, Preschool; Dystonia; Exome; Female; Genetic Variation; Humans; Infant; Infant, Newborn; Male; Pedigree; Exome Sequencing; Young Adult
PubMed: 33098801
DOI: 10.1016/S1474-4422(20)30312-4 -
Brain : a Journal of Neurology Aug 2023In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later...
In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with foetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71%, with higher mortality in males. Death occurred at a median age of 1.2 months (1 week-9 years), due to respiratory failure, cardiac arrest or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival.
Topics: Male; Humans; Cross-Sectional Studies; Mutation; Phenotype; Dystonia; Dystonic Disorders; Nervous System Malformations; Molecular Chaperones
PubMed: 36757831
DOI: 10.1093/brain/awad039 -
Journal of Neural Transmission (Vienna,... Mar 2021Botulinum toxin (BT) therapy is a complex and highly individualised therapy defined by treatment algorithms and injection schemes describing its target muscles and their...
Botulinum toxin (BT) therapy is a complex and highly individualised therapy defined by treatment algorithms and injection schemes describing its target muscles and their dosing. Various consensus guidelines have tried to standardise and to improve BT therapy. We wanted to update and improve consensus guidelines by: (1) Acknowledging recent advances of treatment algorithms. (2) Basing dosing tables on statistical analyses of real-life treatment data of 1831 BT injections in 36 different target muscles in 420 dystonia patients and 1593 BT injections in 31 different target muscles in 240 spasticity patients. (3) Providing more detailed dosing data including typical doses, dose variabilities, and dosing limits. (4) Including total doses and target muscle selections for typical clinical entities thus adapting dosing to different aetiologies and pathophysiologies. (5) In addition, providing a brief and concise review of the clinical entity treated together with general principles of its BT therapy. For this, we collaborated with IAB-Interdisciplinary Working Group for Movement Disorders which invited an international panel of experts for the support.
Topics: Algorithms; Botulinum Toxins; Botulinum Toxins, Type A; Dystonia; Dystonic Disorders; Humans; Muscle Spasticity
PubMed: 33635442
DOI: 10.1007/s00702-021-02312-4 -
Movement Disorders : Official Journal... Nov 2022The objective of this study was to better delineate the genetic landscape and key clinical characteristics of complex, early-onset, monogenic hyperkinetic movement...
BACKGROUND AND OBJECTIVE
The objective of this study was to better delineate the genetic landscape and key clinical characteristics of complex, early-onset, monogenic hyperkinetic movement disorders.
METHODS
Patients were recruited from 14 international centers. Participating clinicians completed standardized proformas capturing demographic, clinical, and genetic data. Two pediatric movement disorder experts reviewed available video footage, classifying hyperkinetic movements according to published criteria.
RESULTS
One hundred forty patients with pathogenic variants in 17 different genes (ADCY5, ATP1A3, DDC, DHPR, FOXG1, GCH1, GNAO1, KMT2B, MICU1, NKX2.1, PDE10A, PTPS, SGCE, SLC2A1, SLC6A3, SPR, and TH) were identified. In the majority, hyperkinetic movements were generalized (77%), with most patients (69%) manifesting combined motor semiologies. Parkinsonism-dystonia was characteristic of primary neurotransmitter disorders (DDC, DHPR, PTPS, SLC6A3, SPR, TH); chorea predominated in ADCY5-, ATP1A3-, FOXG1-, NKX2.1-, SLC2A1-, GNAO1-, and PDE10A-related disorders; and stereotypies were a prominent feature in FOXG1- and GNAO1-related disease. Those with generalized hyperkinetic movements had an earlier disease onset than those with focal/segmental distribution (2.5 ± 0.3 vs. 4.7 ± 0.7 years; P = 0.007). Patients with developmental delay also presented with hyperkinetic movements earlier than those with normal neurodevelopment (1.5 ± 2.9 vs. 4.7 ± 3.8 years; P < 0.001). Effective disease-specific therapies included dopaminergic agents for neurotransmitters disorders, ketogenic diet for glucose transporter deficiency, and deep brain stimulation for SGCE-, KMT2B-, and GNAO1-related hyperkinesia.
CONCLUSIONS
This study highlights the complex phenotypes observed in children with genetic hyperkinetic movement disorders that can lead to diagnostic difficulty. We provide a comprehensive analysis of motor semiology to guide physicians in the genetic investigation of these patients, to facilitate early diagnosis, precision medicine treatments, and genetic counseling. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Child; Humans; Hyperkinesis; Movement Disorders; Dystonic Disorders; Chorea; Dystonia; Nerve Tissue Proteins; Forkhead Transcription Factors; Phosphoric Diester Hydrolases; Sodium-Potassium-Exchanging ATPase; GTP-Binding Protein alpha Subunits, Gi-Go
PubMed: 36054588
DOI: 10.1002/mds.29182 -
Brain : a Journal of Neurology Dec 2020Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal...
Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.
Topics: Adolescent; Adult; Child; Child, Preschool; Chromosome Deletion; Cohort Studies; Computer Simulation; Deep Brain Stimulation; Disease Progression; Dystonic Disorders; Endocrine System Diseases; Female; Fetal Growth Retardation; Gait Disorders, Neurologic; Histone-Lysine N-Methyltransferase; Humans; Laryngeal Diseases; Male; Mutation; Mutation, Missense; Phenotype; Quality of Life; Treatment Outcome; Young Adult
PubMed: 33150406
DOI: 10.1093/brain/awaa304 -
Journal of Veterinary Internal Medicine Nov 2022Dystonia is a clinical sign and main feature of many movement disorders in humans as well as veterinary species. It is characterized by sustained or intermittent... (Review)
Review
Dystonia is a clinical sign and main feature of many movement disorders in humans as well as veterinary species. It is characterized by sustained or intermittent involuntary muscle contractions causing abnormal (often repetitive) movements, postures, or both. This review discusses the terminology and definition of dystonia, its phenomenology, and its pathophysiology, and provides considerations regarding the diagnosis and treatment of dystonia in dogs and cats. In addition, currently recognized or reported disorders in dogs and cats in which dystonia is a particular or main feature are discussed and comparisons are made between disorders featuring dystonia in humans and animals. We suggest that when describing the phenomenology of dogs and cats with dystonia, if possible the following should be included: activity being performed at onset (e.g., resting or running or exercise-induced), body distribution, duration, responsiveness (subjective), severity, temporal pattern (i.e., paroxysmal or persistent, severity at onset and at later stages), presence or absence of autonomic signs (e.g., salivation), presence or absence of preceding signs (e.g., restlessness), presence or absence of signs after dystonia subsides (e.g., sleepiness), coexistence of other movement disorders, any other neurological manifestations, and possible links to administered medications, intoxications or other associated factors. We also suggest that dystonia be classified based on its etiology as either structural genetic, suspected genetic, reactive, or unknown.
Topics: Humans; Cats; Dogs; Animals; Dystonia; Cat Diseases; Dog Diseases; Movement Disorders; Neurology
PubMed: 36086931
DOI: 10.1111/jvim.16532 -
Toxins Aug 2021The differences in analgesic effects of botulinum toxin type A were compared in 28 patients with trigeminal neuralgia, 53 patients with myofascial temporomandibular... (Comparative Study)
Comparative Study
The differences in analgesic effects of botulinum toxin type A were compared in 28 patients with trigeminal neuralgia, 53 patients with myofascial temporomandibular disorders, and 89 patients with the jaw closing oromandibular dystonia. The patients were treated by injection of botulinum toxin type A into the masseter, temporalis, medial pterygoid, and other muscles based on the symptoms of each patient. The pain severity was evaluated using the visual analog scale, pain frequency, and pain scale of the oromandibular dystonia rating scale. Botulinum toxin injection was performed 1068 times in all patients without significant adverse effects. The visual analog, pain frequency, and pain scales at baseline were reduced ( < 0.001) after two, four, eight, and 12 weeks after the first botulinum toxin therapy and at the endpoint. The effects differed significantly ( < 0.001) among the groups (repeated-measures analysis of variance). The mean improvement (0%, no effect; 100%, complete recovery) at the endpoint was 86.8% for trigeminal neuralgia, 80.8% for myofascial pain, and 75.4% for oromandibular dystonia. Injection of the botulinum toxin can be a highly effective and safe method to treat trigeminal neuralgia, myofascial pain, and oromandibular dystonia.
Topics: Adult; Aged; Aged, 80 and over; Botulinum Toxins, Type A; Dystonic Disorders; Female; Humans; Injections, Intramuscular; Male; Middle Aged; Myofascial Pain Syndromes; Neuromuscular Agents; Neurotoxins; Pain Management; Temporomandibular Joint Disorders; Treatment Outcome; Trigeminal Neuralgia
PubMed: 34564609
DOI: 10.3390/toxins13090605 -
BMJ (Clinical Research Ed.) Apr 2022
Topics: Dystonia; Humans
PubMed: 35410890
DOI: 10.1136/bmj-2020-062659 -
Ugeskrift For Laeger May 2023Laryngeal dystonia (LD) is a rare neurological disorder emerging in middle-aged persons as a chronic and disabling voice disorder. It is a focal dystonia affecting... (Review)
Review
Laryngeal dystonia (LD) is a rare neurological disorder emerging in middle-aged persons as a chronic and disabling voice disorder. It is a focal dystonia affecting intrinsic laryngeal muscle control only during speech, resulting in voice breaks, effortful phonation, and strangled voice. Due to lack of awareness and lack of well-defined diagnostic criteria, it can be difficult for patients to be diagnosed and treated. This review, the first Danish publication on the subject of LD, presents the latest terminology, a brief history, treatment options and the psychosocial consequences of LD.
Topics: Middle Aged; Humans; Dystonia; Dysphonia; Laryngeal Muscles; Electromyography
PubMed: 37264860
DOI: No ID Found -
Neurology India 2020Deep brain stimulation (DBS) is currently the preferred surgical treatment for various movement disorders. Pallidotomy is an effective procedure for patients with...
BACKGROUND
Deep brain stimulation (DBS) is currently the preferred surgical treatment for various movement disorders. Pallidotomy is an effective procedure for patients with dystonia and Parkinson's disease and was the surgical treatment of choice before the advent of DBS. However, it can be the preferred modality in immunocompromised patients and those patients who cannot afford DBS due to financial constraints. Hypophonia, dysarthria and dysphagia are the most significant complications of bilateral pallidotomy.
OBJECTIVE
The aim of this study was to present the surgical technique and nuances involved in bilateral simultaneous pallidotomy in a patient with generalized dystonia.
PROCEDURE
A 30-year male with primary generalized dystonia presented to us with preoperative Burke-Fahn-Marsden (BFM) Dystonia Rating Scale of 24. After acquiring preoperative volumetric 3T MRI and stereotactic CT, bilateral pallidotomy was done under general anesthesia. There were no procedure related complications.
RESULTS
At two months of follow-up, his BFM dystonia score improved from 24 to 4.5.
CONCLUSION
Appropriately acquired volumetric MRI, meticulous planning and meticulously performed surgical procedure can help in achieving good outcome and minimize the complications.
Topics: Deep Brain Stimulation; Dystonia; Dystonic Disorders; Globus Pallidus; Humans; Male; Movement Disorders; Pallidotomy; Treatment Outcome
PubMed: 33318369
DOI: 10.4103/0028-3886.302460