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Kailash P Bhatia - One of the best experts on this subject based on the ideXlab platform.
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paroxysmal asymmetric dystonic arm posturing a less recognized but characteristic manifestation of atp1a3 related disease
Movement Disorders Clinical Practice, 2019Co-Authors: Bettina Balint, Christopher D. Stephen, Vrajesh Udani, Charulata Savant Sankhla, Narendrakumar H. Barad, Anthony E. Lang, Kailash P BhatiaAbstract:Background ATP1A3 mutations cause a wide clinical spectrum, and are one of the "commoner rare diseases". Methods Case series of four patients with ATP1A3 mutations. Results The patients displayed characteristic episodes of dystonic arm posturing, involving a dystonic, flexed arm held in front of the body or close to the body, but with the hand raised upwards. Other attacks manifested with arm extension, either beside the body or reaching upwards. Dystonic posturing occurred paroxysmally, with no neurological signs between attacks, or combined with other signs like chorea, ataxia, and hypotonia. Conclusions While previous diagnostic criteria have not included paroxysmal or episodic Dystonia, recent expert consensus has proposed to include alternating or paroxysmal Dystonia as major feature calling for ATP1A3 genetic testing. Attacks of marked arm flexion posturing, either paroxysmal or as episodic exacerbation of mild pre-existent Dystonia, are a characteristic clue to ATP1A3-related disease.
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isolated and combined Dystonia syndromes an update on new genes and their phenotypes
European Journal of Neurology, 2015Co-Authors: Bettina Balint, Kailash P BhatiaAbstract:Recent consensus on the definition, phenomenology and classification of Dystonia centres around phenomenology and guides our diagnostic approach for the heterogeneous group of Dystonias. Current terminology classifies conditions where Dystonia is the sole motor feature (apart from tremor) as 'isolated Dystonia', while 'combined Dystonia' refers to Dystonias with other accompanying movement disorders. This review highlights recent advances in the genetics of some isolated and combined dystonic syndromes. Some genes, such as ANO3, GNAL and CIZ1, have been discovered for isolated Dystonia, but they are probably not a common cause of classic cervical Dystonia. Conversely, the phenotype associated with TUBB4A mutations expanded from that of isolated Dystonia to a syndrome of hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC syndrome). Similarly, ATP1A3 mutations cause a wide phenotypic spectrum ranging from rapid-onset Dystonia-parkinsonism to alternating hemiplegia of childhood. Other entities entailing Dystonia-parkinsonism include dopamine transporter deficiency syndrome (SLC63 mutations); dopa-responsive Dystonias; young-onset parkinsonism (PARKIN, PINK1 and DJ-1 mutations); PRKRA mutations; and X-linked TAF1 mutations, which rarely can also manifest in women. Clinical and genetic heterogeneity also characterizes myoclonus-Dystonia, which includes not only the classical phenotype associated with epsilon-sarcoglycan mutations but rarely also presentation of ANO3 gene mutations, TITF1 gene mutations typically underlying benign hereditary chorea, and some dopamine synthesis pathway conditions due to GCH1 and TH mutations. Thus, new genes are being recognized for isolated Dystonia, and the phenotype of known genes is broadening and now involves different combined Dystonia syndromes.
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characteristic forcible geste antagoniste in oromandibular Dystonia resulting from pantothenate kinase associated neurodegeneration
Movement Disorders Clinical Practice, 2014Co-Authors: Igor Petrovic, Kailash P Bhatia, Christos Ganos, Nikola Kresojevic, Marina Svetel, Natasa Dragasevic, Vladimir S KosticAbstract:Geste antagonistes are usually considered typical of primary Dystonia, although rarely they have been described in secondary/heredodegenerative Dystonias. We have recently come across a particular geste antagoniste in 5 of 10 patients with pantothenate kinase-associated neurodegeneration (PKAN) who had prominent oromandibular involvement with severe jaw-opening Dystonia. It consists of touching the chin with both hands characteristically clenched into a fist with flexion at the elbows. Because of the resemblance of this geste antagoniste with the praying-like posture of Mantis religiosa, we coined the term "mantis sign." Reviewing videos of PKAN cases in literature, including what is considered the first cinematic depiction of a case of this disorder, 3 additional cases with akin maneuvers were identified. In contrast, examining 205 videos of non-PKAN dystonic patients from our database for the presence of a similar maneuver was unrevealing. Thus, we consider the mantis sign to be quite typical of PKAN and propose it to be added as a clinical hint toward diagnosis.
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Rest and other types of tremor in adult-onset primary Dystonia
Journal of Neurology Neurosurgery & Psychiatry, 2013Co-Authors: Roberto Erro, Ignacio Rubio-agusti, Tabish A. Saifee, Carla Cordivari, Christos Ganos, Amit Batla, Kailash P BhatiaAbstract:Introduction Knowledge regarding tremor prevalence and phenomenology in patients with adult-onset primary Dystonia is limited. Dystonic tremor is presumably underreported, and we aimed to assess the prevalence and the clinical correlates of tremor in patients with adultonset primary Dystonia. Methods We enrolled 473 consecutive patients with different types of adult-onset primary Dystonia. They were assessed for presence of head tremor and arm tremor (rest, postural and kinetic). Results A total of 262 patients (55.4%) were tremulous: 196 patients presented head tremor, 140 patients presented arm tremor and 98 of them had a combination of head and arm tremor. Of the 140 patients with arm tremor, all presented postural tremor, 103 patients (73.6%) presented also a kinetic component, whereas 57 patients (40.7%) had rest tremor. Rest tremor was unilateral/asymmetric in up to 92.9% of them. Patients with segmental and multifocal Dystonia were more likely tremulous than patients with focal Dystonia. Dystonic symptoms involving the neck were more frequently observed in patients with head tremor, whereas dystonic symptoms involving the arms were more frequently observed in patients with arm tremor. Discussion Here we show that tremor is a common feature of patients with adult-onset primary Dystonia. It may involve different body segments, with the head being the most commonly affected site. Arm tremor is also frequent (postural>kinetic>rest), occurring in up to one-third of cases. There is a suggestion of a stronger tendency for spread of dystonic features in patients with associated tremor. Dystonic tremor is under-reported and this underscores the importance of careful clinical examination when assessing tremulous patients without overt Dystonia.
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Primary and secondary dystonic syndromes: an update.
Current Opinion in Neurology, 2013Co-Authors: Gavin Charlesworth, Kailash P BhatiaAbstract:PURPOSE OF REVIEW: The Dystonias are a common but complex group of disorders that show considerable variation in cause and clinical presentation. The purpose of this review is to highlight the most important discoveries and insights from across the field over the period of the past 18 months. RECENT FINDINGS: Five new genes for primary Dystonia (PRRT2, CIZ1, ANO3, TUBB4A and GNAL) have made their appearance in the literature. New subtypes of neuronal brain iron accumulation have been delineated and linked to mutations in C19orf12 and WDR45, while a new treatable form of Dystonia with brain manganese deposition related to mutations in SLC30A10 has been described. At the same time, the phenotypes of other forms of dystonic syndromes have been expanded or linked together. Finally, there has been increasing recognition of both the extramotor phenotype in Dystonia and the part played by the cerebellum in its pathophysiology. SUMMARY: Recently, there has been unprecedented change in the scientific landscape with respect to the cause of various dystonic syndromes that is likely to make a direct impact on clinical practice in the near future. Understanding the genetic cause of these syndromes and the often wide phenotypic variation in their presentations will improve diagnosis and treatment. With time, these discoveries may also lead to much-needed progress in elucidating the underlying pathophysiology of Dystonia.
Marina A J Tijssen - One of the best experts on this subject based on the ideXlab platform.
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physiological movement disorder like features during typical motor development
European Journal of Paediatric Neurology, 2018Co-Authors: M J Kuiper, Marina A J Tijssen, R Brandsma, L Vrijenhoek, Huibert Burger, Bernard Dan, D A SivalAbstract:Abstract Aim To compare physiological age-relatedness between dyskinesia (Dystonia/choreoathetosis), Dystonia and ataxia rating scale scores in healthy children. Method Three movement disorders specialists quantified dyskinetic-like features in healthy children (n = 52; 4–16 years) using the Dyskinesia Impairment Scale (DIS = DIS-choreoathetosis (DIS-C) + DIS-Dystonia (DIS-D)). We compared the age-related regression coefficients of the DIS with data processed from previous studies on Dystonia and ataxia rating scales (Burke-Fahn-Marsden Movement and Disability Scales (BFMMS and BFMDS) and Scale for Assessment and Rating of Ataxia (SARA), International Cooperative Ataxia Rating Scale (ICARS) and Brief Ataxia Rating Scale (BARS)). Results Dyskinetic scores were obtained in 79% (DIS); 65% (DIS-D) and 17% (DIS-C) versus dystonic and ataxic scores in 98% (BFMMS) and 89% (SARA/ICARS/BARS) of the children. Age-related DIS and DIS-D scores (B = −0.90 and 0.77; p Interpretation In healthy children, comparison between physiological dyskinesia, Dystonia and ataxia rating scale scores revealed: 1. inverse age-relatedness for dystonic and ataxic scores, but not for choreoathetotic scores, 2. interrelated dystonic DIS-D and BFMMS scores, 3. the strongest age-related expression by ataxic scores. In healthy children, these physiological movement disorder-like features are interpreted as an expression of the developing underlying motor centres.
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Severity of Dystonia is correlated with putaminal gray matter changes in Myoclonus-Dystonia
European Journal of Neurology, 2011Co-Authors: Richard Johan Beukers, E.m.j. Foncke, J.n. Van Der Meer, Sandra M A Van Der Salm, Dick J. Veltman, Marina A J TijssenAbstract:Background: Myoclonus-Dystonia (M-D) is an autosomal dominantly inherited movement disorder characterized by myoclonic jerks and dystonic postures or movements. Morphometric studies have been performed in other, mainly heterogenous, types of Dystonia producing conflicting results. However, all these studies agree on abnormalities in sensorimotor structures, mainly in the basal ganglia. We aimed to study gray matter (GM) volumes in sensorimotor brain structures with magnetic resonance imaging (MRI) in a genetically homogeneous form of Dystonia, M-D. Methods: Twenty-five clinically affected DYT11 mutation carriers (MC) and 25 matched control subjects were studied using T1-weighted 3D anatomical images of the entire brain, obtained with a 3.0 Tesla MRI. MC were clinically scored using the Burke Fahn Marsden dsytonia rating scale (BFMDRS) and the unified myoclonus rating scale (UMRS). GM volumes in sensorimotor cortices and basal ganglia of patients and controls were compared, and multiple regression analyses were used to correlate the GM volumes of patients with the clinical rating scales BFMDRS and UMRS. Results: No significant differences were found between groups, but Dystonia severity in MC was strongly correlated with increased GM volume in bilateral putamina. Conclusions: This study provides further evidence for the involvement of putamina as important motor structures in the pathophysiology of (myoclonus-) Dystonia. Changes in these structures are associated with the severity of Dystonia.
Adolfo M Bronstein - One of the best experts on this subject based on the ideXlab platform.
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role of the vestibular system in the pathophysiology of spasmodic torticollis
Journal of Neurology Neurosurgery and Psychiatry, 2001Co-Authors: Alexander Munchau, Adolfo M BronsteinAbstract:Idiopathic spasmodic torticollis is a form of focal Dystonia affecting the neck. It is characterised by involuntary repetitive or sustained neck muscle contractions leading to abnormal head postures and impaired control of head movement.1-3 With an estimated prevalence of 9/100 0004 spasmodic torticollis is the most common focal Dystonia. Onset peaks around the age of 40 and there is a female preponderance with a sex ratio of about 1.5:1.5 Symptoms typically start gradually over a period of days or weeks and remain largely confined to the neck although spread of Dystonia to the face (blepharospasm, oromandibular Dystonia), larynx (laryngeal Dystonia), and arms (dystonic arm postures and writer's cramp), but not the legs, can occur.1 Abnormal head and neck postures in spasmodic torticollis cause considerable disability, often interfering with the patient's ability to work, and cause pain, social stigmatisation, and depression.6 Most cases are sporadic. However, a family history is reported in about 15% of patients1 and several families with more than four affected members have been described,7-12 all of whom showed autosomal dominant inheritance. Thus genetic factors seem to have some aetiological importance. The pathophysiology of spasmodic torticollis is still unclear. In idiopathic spasmodic torticollis no structural lesions are found in the CNS. However, there are two lines of evidence that dysfunction of the basal ganglia plays a part. Firstly, spasmodic torticollis can be seen either in isolation or as part of a more widespread hemiDystonia after lesions of the basal ganglia or its connections.13-16Secondly, it is sometimes part of the clinical presentation in generalised primary torsion Dystonia,17 in which functional imaging data and neurophysiological studies have shown abnormalities in the basal ganglia and its projections.18-21 If focal Dystonias, including spasmodic torticollis, were solely caused by dysfunction of the basal …
Angelika Richter - One of the best experts on this subject based on the ideXlab platform.
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chapter h2 the genetically dystonic hamster an animal model of paroxysmal Dystonia
Animal Models of Movement Disorders, 2005Co-Authors: Angelika RichterAbstract:The genetically dystonic hamster (gene symbol: dt sz ) shows the phenotypic characteristics of paroxysmal non kinesigenic dyskinesia in which episodes of Dystonia and choreoathetosis occur spontaneously or can be provoked by stress, excitement, and intake of methylxanthines. The dt sz mutant hamster is one of the most extensively examined genetic animal models of movement disorders. The genetically dystonic hamsters represent an excellent model that can be helpful to give new insights into the pathogenesis of this movement disorder and to identify new strategies for the treatment of paroxysmal Dystonia. The finding of a reduced discharge rate and an irregular firing pattern of entopeduncular neurons in mutant hamsters substantiates the hypothesis of the pathophysiology of dyskinesias in humans. Although most changes are found in the basal ganglia–thalamocortical circuit, it is emphasized that abnormalities are also detected in the cerebellum, rednucleus, vestibular nuclei, and limbic structures of dystonic hamsters. The genetically dystonic hamster represents a unique animal model of inherited paroxysmal Dystonia. This animal model shows high face, predictive, and constructive validity. The primary defect probably differs dependent of the type of Dystonia or paroxysmal dyskinesia in humans, but these defects may finally result in common alterations of the neuronal activity with the consequence to provoke similar symptoms. Animal models that allow invasive examinations can be useful to enhance the knowledge about the underlying mechanisms.
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altered discharge pattern of basal ganglia output neurons in an animal model of idiopathic Dystonia
The Journal of Neuroscience, 2002Co-Authors: Manuela Gernert, Mustapha Bennay, Maren Fedrowitz, Jan H Rehders, Angelika RichterAbstract:A decreased activity of basal ganglia output neurons is thought to underlie idiopathic Dystonias and other hyperkinetic movement disorders. We found recently a reduced spontaneous discharge rate of entopeduncular neurons (internal globus pallidus in primates) in dt(sz) hamsters, an unique model for idiopathic paroxysmal Dystonia in which stress-inducible attacks show an age-dependent severity. Otherwise, it has been suggested that an altered discharge pattern may be more important for the occurrence of Dystonia than a reduced discharge rate. Based on qualitative and computerized quantitative evaluations of interspike interval histograms and spike trains of extracellularly recorded single neurons, we investigated the spontaneous discharge pattern of GABAergic entopeduncular and nigral neurons in dt(sz) hamsters at different ages. The discharge pattern of entopeduncular neurons was highly irregular and showed an altered burst-like firing in dt(sz) hamsters at the age of the most marked expression of Dystonia when compared with age-matched nondystonic controls. In line with a recently reported normalization of discharge rates after age-dependent disappearance of Dystonia, we found an almost complete normalization of the discharge pattern of entopeduncular neurons after remission of Dystonia in dt(sz) hamsters. Investigations of GABAergic nigral neurons, reported recently to have the same spontaneous discharge rates in dystonic and nondystonic hamsters, did not show an altered firing pattern in dt(sz) hamsters. The present data clearly indicate the fundamental importance of an altered discharge pattern of entopeduncular neurons for the expression of paroxysmal Dystonia, and probably also for other dyskinesias, and may explain the improvements obtained by pallidotomy in dystonic patients despite an obviously reduced pallidal output.
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effects of striatal injections of gabaa receptor agonists and antagonists in a genetic animal model of paroxysmal Dystonia
European Journal of Pharmacology, 2002Co-Authors: Melanie Hamann, Angelika RichterAbstract:The underlying mechanisms of idiopathic Dystonias are poorly understood. The dystonic phenotype in the dt(sz) mutant hamster, a model of paroxysmal Dystonia, has been suggested to be based on a deficit of gamma-aminobutyric acid (GABA)ergic interneurons and changes of the GABA(A)-benzodiazepine receptor complex in the striatum. In order to confirm and extend previous observations, the effects of compounds which bind to different sites of the GABA(A) receptor on the severity of Dystonia were determined after striatal microinjections in comparison to systemic treatments in dt(sz) mutants. The GABA(A) receptor agonist (muscimol) and the benzodiazepine (flurazepam) reduced the severity of Dystonia after striatal and systemic injections. The antidystonic effects of the barbiturate phenobarbital were less marked both after striatal and intraperitoneal administration of drugs. Intrastriatal injections of GABA delayed the onset of dystonic attacks. Striatal and systemic treatments with the GABA(A) receptor antagonist, bicuculline, and with pentylenetetrazole, which reduces GABAergic function, accelerated the onset of Dystonia at subconvulsant doses. The benzodiazepine receptor antagonists flumazenil aggravated Dystonia after systemic and intrastriatal injections. In all, the present data substantiate the relevance of striatal GABAergic disinhibition in the pathogenesis of paroxysmal Dystonia in dt(sz) mutants.
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quantitative eeg analysis of depth electrode recordings from several brain regions of mutant hamsters with paroxysmal Dystonia discloses frequency changes in the basal ganglia
Movement Disorders, 1998Co-Authors: Manuela Gernert, Angelika Richter, Chris Rundfeldt, Wolfgang LoscherAbstract:: Computerized EEG spectral analyses of depth electrode recordings from striatum (caudate/putamen; CPu), globus pallidus (GP), and parietal cortex (pCtx) were performed before and after dystonic attacks in freely moving mutant dt(sz) hamsters with paroxysmal Dystonia. In these hamsters, sustained attacks of abnormal movements and postures can be reproducibly induced by stress, such as placing the animals in a new environment. Data recorded from mutant hamsters were compared with recordings from age-matched nondystonic control hamsters. The predominant EEG changes in CPu and GP of dystonic hamsters were significant decreases in the high-frequency beta2 range and there was a tendency to increase in delta and theta activities. These changes were seen both before and after onset of dystonic attacks, indicating a permanent disturbance of neural activities in the basal ganglia of dystonic animals. No such changes were seen in the pCtx. Furthermore, no epileptic or epileptiform activity was seen in any of the recordings, substantiating a previous notion from cortical and hippocampal recordings that paroxysmal Dystonia in these mutant hamsters has no epileptogenic basis. The present finding of abnormal synchronization of neural activity in the CPu and GP of dystonic hamsters adds to the belief that the striatopallidal-thalamocortical circuit is the most likely site in which to search for the unknown defect in primary (idiopathic) Dystonia. As suggested by this study, quantitative EEG analysis can increase the likelihood of detecting subtle EEG abnormalities in different types of idiopathic Dystonia and thereby improves our understanding of the pathogenetic mechanisms of this movement disorder.
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alterations in the brain gabaa benzodiazepine receptor chloride ionophore complex in a genetic model of paroxysmal Dystonia a quantitative autoradiographic analysis
Neuroscience, 1995Co-Authors: José N. Nobrega, Angelika Richter, W.m. Burnham, Wolfgang LoscherAbstract:Dystonia is a relatively common syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. The most frequent type of Dystonia is idiopathic generalized Dystonia, whose pathophysiology is largely unknown. In this respect, mutant animal strains with inborn Dystonia may be helpful to elucidate the pathophysiological defects involved in idiopathic Dystonia. The genetically dystonic (dtsz) hamster is an animal model of paroxysmal Dystonia that displays attacks of generalized Dystonia either spontaneously or in response to mild environmental stimuli. In the present study, a quantitative autoradiographic analysis of ligand binding to different sites of the GABAA/benzodiazepine receptor-chloride ionophore complex was carried out in 123 brain areas from genetically dystonic mutant hamsters and age-matched control hamsters. Animals were killed 2 weeks after their last dystonic attack. Analysis of the GABA-binding site of the receptor complex, using the ligand [3H]muscimol, and the benzodiazepine site labelled with [3H]flunitrazepam revealed no significant alterations in the binding of either ligand in any of the brain regions examined. In contrast, widespread changes were observed in binding densities of [35S]t-butylbicyclophosphorothionate ([35S]t-butylbicyclophosphorothionate), which labels the picrotoxinin site of the GABAA receptor-chloride ionophore complex. Significantly increased [35S]t-butylbicyclophosphorothionate binding was found in several parts of the thalamus, cortex, and hippocampus as well as in the red nucleus, the subthalamic nucleus, and the granular layer of the cerebellum. Since high-affinity [35S]TBPS binding is thought to represent the closed conformation of the GABA-gated chloride ionophore, increased TBPS binding would indicate an impaired GABAergic function. The study is consistent with the concept that Dystonia is caused by impaired connections between the basal ganglia, the thalamus, and frontal association areas. The data on increased [35S]TBPS binding are the first evidence implicating alterations in the GABA-gated chloride ion channel function in a movement disorder, i.e. idiopathic generalized Dystonia.
Bertram Mullermyhsok - One of the best experts on this subject based on the ideXlab platform.
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mutations in the gene encoding e sarcoglycan cause myoclonus Dystonia syndrome
Nature Genetics, 2001Co-Authors: Alexander Zimprich, Monika Grabowski, Friedrich Asmus, Markus Naumann, Daniela Berg, M Bertram, Karl Scheidtmann, Peter Kern, Juliane Winkelmann, Bertram MullermyhsokAbstract:The Dystonias are a common clinically and genetically heterogeneous group of movement disorders. More than ten loci for inherited forms of Dystonia have been mapped, but only three mutated genes have been identified so far. These are DYT1, encoding torsin A1 and mutant in the early-onset generalized form, GCH1 (formerly known as DYT5), encoding GTP–cyclohydrolase I and mutant in dominant dopa-responsive Dystonia2, and TH, encoding tyrosine hydroxylase and mutant in the recessive form of the disease3. Myoclonus–Dystonia syndrome (MDS; DYT11) is an autosomal dominant disorder characterized by bilateral, alcohol-sensitive myoclonic jerks involving mainly the arms and axial muscles4,5. Dystonia, usually torticollis and/or writer's cramp, occurs in most but not all affected patients and may occasionally be the only symptom of the disease6,7. In addition, patients often show prominent psychiatric abnormalities, including panic attacks and obsessive–compulsive behavior8,9,10. In most MDS families, the disease is linked to a locus on chromosome 7q21 (refs. 11–13). Using a positional cloning approach, we have identified five different heterozygous loss-of-function mutations in the gene for ɛ-sarcoglycan (SGCE), which we mapped to a refined critical region of about 3.2 Mb. SGCE is expressed in all brain regions examined. Pedigree analysis shows a marked difference in penetrance depending on the parental origin of the disease allele. This is indicative of a maternal imprinting mechanism, which has been demonstrated in the mouse ɛ-sarcoglycan gene14.
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mutations in the gene encoding epsilon sarcoglycan cause myoclonus Dystonia syndrome
Nature Genetics, 2001Co-Authors: Alexander Zimprich, Monika Grabowski, Friedrich Asmus, Markus Naumann, Daniela Berg, M Bertram, Karl Scheidtmann, Peter Kern, Juliane Winkelmann, Bertram MullermyhsokAbstract:The Dystonias are a common clinically and genetically heterogeneous group of movement disorders. More than ten loci for inherited forms of Dystonia have been mapped, but only three mutated genes have been identified so far. These are DYT1, encoding torsin A1 and mutant in the early-onset generalized form, GCH1 (formerly known as DYT5), encoding GTP–cyclohydrolase I and mutant in dominant dopa-responsive Dystonia2, and TH, encoding tyrosine hydroxylase and mutant in the recessive form of the disease3. Myoclonus–Dystonia syndrome (MDS; DYT11) is an autosomal dominant disorder characterized by bilateral, alcohol-sensitive myoclonic jerks involving mainly the arms and axial muscles4,5. Dystonia, usually torticollis and/or writer's cramp, occurs in most but not all affected patients and may occasionally be the only symptom of the disease6,7. In addition, patients often show prominent psychiatric abnormalities, including panic attacks and obsessive–compulsive behavior8,9,10. In most MDS families, the disease is linked to a locus on chromosome 7q21 (refs. 11–13). Using a positional cloning approach, we have identified five different heterozygous loss-of-function mutations in the gene for ɛ-sarcoglycan (SGCE), which we mapped to a refined critical region of about 3.2 Mb. SGCE is expressed in all brain regions examined. Pedigree analysis shows a marked difference in penetrance depending on the parental origin of the disease allele. This is indicative of a maternal imprinting mechanism, which has been demonstrated in the mouse ɛ-sarcoglycan gene14.
