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Kailash P Bhatia - One of the best experts on this subject based on the ideXlab platform.
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KCNN2 mutation in autosomal-dominant tremulous Myoclonus-dystonia.
European Journal of Neurology, 2020Co-Authors: Bettina Balint, Anna Latorre, Kailash P Bhatia, Rita Guerreiro, Susana Carmona, Nadia Dehghani, Carla Cordivari, Jose BrasAbstract:BACKGROUND: Despite recent advances in neurogenetics which have facilitated the identification of a number of dystonia genes, many familial dystonia syndromes remain without known cause. OBJECTIVE: To identify the cause of autosomal dominant tremulous Myoclonus-dystonia in a UK kindred with affected individuals in three generations. RESULTS: The core phenotype consisted of childhood-onset dystonia predominantly affecting hands and neck, with a fast tremor with superimposed Myoclonus and, in some individuals, subtle cerebellar signs. We identified a novel missense variant in potassium calcium-activated channel subfamily N member 2 (KCNN2) [NM_021614:c.1112G>A:p.(Gly371Glu)], which was the only variant that we were able to identify as segregating with the phenotype over three generations. This variant, which is absent from the most recent version of gnomAD, was predicted to be deleterious by SIFT and PolyPhen-2 and had an overall CADD score of 29.7. CONCLUSIONS: KCNN2, a member of the KCNN family of potassium channel genes, is highly conserved across species and in humans is highly expressed in the brain, particularly the cerebellum. KCNN2 mutations have never been described as pathological in human disease, but are recognized abnormalities in two rodent models of fast, jerky tremor. Segregation, absence of the variant in the normal population and in-silico prediction of a deleterious effect together with animal models compatible with the clinical phenotype are all in line with KCNN2 mutations being a plausible cause underlying Myoclonus-dystonia. CONCLUSION: KCNN2 (potassium calcium-activated channel subfamily N member 2), a member of the KCNN family of potassium channel genes, is highly conserved across species and in humans is highly expressed in the brain, particularly the cerebellum. KCNN2 mutations have never been described as pathological in human disease, but are recognised abnormalities in two rodent models of fast, jerky tremor. Segregation, absence of the variant in the normal population and in silico prediction of a deleterious effect together with animal models compatible with the clinical phenotype are all in line with KCNN2 mutations being a plausible cause underlying Myoclonus-dystonia.
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kcnn2 mutation in autosomal dominant tremulous Myoclonus dystonia
European Journal of Neurology, 2020Co-Authors: Bettina Balint, Anna Latorre, Rita Guerreiro, Susana Carmona, Nadia Dehghani, Carla Cordivari, Kailash P BhatiaAbstract:BACKGROUND AND PURPOSE Despite recent advances in neurogenetics that have facilitated the identification of a number of dystonia genes, many familial dystonia syndromes remain without known cause. The aim of the study was to identify the cause of autosomal dominant tremulous Myoclonus-dystonia in a UK kindred with affected individuals in three generations. METHODS Known genetic causes of Myoclonus-dystonia were excluded. We combined clinical and electrophysiological phenotyping with whole-exome sequencing and Sanger sequencing to identify candidate causal variants in a family with tremulous Myoclonus-dystonia. RESULTS The core phenotype consisted of childhood-onset dystonia predominantly affecting hands and neck, with a fast tremor with superimposed Myoclonus and, in some individuals, subtle cerebellar signs. We identified a novel missense variant in potassium calcium-activated channel subfamily N member 2 (KCNN2) [NM_021614:c.1112G>A:p.(Gly371Glu)], which was the only variant that we were able to identify as segregating with the phenotype over three generations. This variant, which is absent from the most recent version of gnomAD, was predicted to be deleterious by SIFT and PolyPhen-2 and had an overall CADD score of 29.7. CONCLUSIONS KCNN2, a member of the KCNN family of potassium channel genes, is highly conserved across species and in humans is highly expressed in the brain, particularly the cerebellum. KCNN2 mutations have never been described as pathological in human disease, but are recognized abnormalities in two rodent models of fast, jerky tremor. Segregation, absence of the variant in the normal population and in-silico prediction of a deleterious effect together with animal models compatible with the clinical phenotype are all in line with KCNN2 mutations being a plausible cause underlying Myoclonus-dystonia.
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twenty years on Myoclonus dystonia and e sarcoglycan neurodevelopment channel and signaling dysfunction
Movement Disorders, 2019Co-Authors: Elisa Menozzi, Bettina Balint, Anna Latorre, Enza Maria Valente, John C Rothwell, Kailash P BhatiaAbstract:Myoclonus-dystonia is a clinical syndrome characterized by a typical childhood onset of myoclonic jerks and dystonia involving the neck, trunk, and upper limbs. Psychiatric symptomatology, namely, alcohol dependence and phobic and obsessive-compulsive disorder, is also part of the clinical picture. Zonisamide has demonstrated effectiveness at reducing both Myoclonus and dystonia, and deep brain stimulation seems to be an effective and long-lasting therapeutic option for medication-refractory cases. In a subset of patients, Myoclonus-dystonia is associated with pathogenic variants in the epsilon-sarcoglycan gene, located on chromosome 7q21, and up to now, more than 100 different pathogenic variants of the epsilon-sarcoglycan gene have been described. In a few families with a clinical phenotype resembling Myoclonus-dystonia associated with distinct clinical features, variants have been identified in genes involved in novel pathways such as calcium channel regulation and neurodevelopment. Because of phenotypic similarities with epsilon-sarcoglycan gene-related Myoclonus-dystonia, these conditions can be collectively classified as "Myoclonus-dystonia syndromes." In the present article, we present Myoclonus-dystonia caused by epsilon-sarcoglycan gene mutations, with a focus on genetics and underlying disease mechanisms. Second, we review those conditions falling within the spectrum of Myoclonus-dystonia syndromes, highlighting their genetic background and involved pathways. Finally, we critically discuss the normal and pathological function of the epsilon-sarcoglycan gene and its product, suggesting a role in the stabilization of the dopaminergic membrane via regulation of calcium homeostasis and in the neurodevelopmental process involving the cerebello-thalamo-pallido-cortical network. © 2019 International Parkinson and Movement Disorder Society.
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Twenty years on: Myoclonus‐dystonia and ε‐sarcoglycan — neurodevelopment, channel, and signaling dysfunction
Movement Disorders, 2019Co-Authors: Elisa Menozzi, Bettina Balint, Anna Latorre, Enza Maria Valente, John C Rothwell, Kailash P BhatiaAbstract:: Myoclonus-dystonia is a clinical syndrome characterized by a typical childhood onset of myoclonic jerks and dystonia involving the neck, trunk, and upper limbs. Psychiatric symptomatology, namely, alcohol dependence and phobic and obsessive-compulsive disorder, is also part of the clinical picture. Zonisamide has demonstrated effectiveness at reducing both Myoclonus and dystonia, and deep brain stimulation seems to be an effective and long-lasting therapeutic option for medication-refractory cases. In a subset of patients, Myoclonus-dystonia is associated with pathogenic variants in the epsilon-sarcoglycan gene, located on chromosome 7q21, and up to now, more than 100 different pathogenic variants of the epsilon-sarcoglycan gene have been described. In a few families with a clinical phenotype resembling Myoclonus-dystonia associated with distinct clinical features, variants have been identified in genes involved in novel pathways such as calcium channel regulation and neurodevelopment. Because of phenotypic similarities with epsilon-sarcoglycan gene-related Myoclonus-dystonia, these conditions can be collectively classified as "Myoclonus-dystonia syndromes." In the present article, we present Myoclonus-dystonia caused by epsilon-sarcoglycan gene mutations, with a focus on genetics and underlying disease mechanisms. Second, we review those conditions falling within the spectrum of Myoclonus-dystonia syndromes, highlighting their genetic background and involved pathways. Finally, we critically discuss the normal and pathological function of the epsilon-sarcoglycan gene and its product, suggesting a role in the stabilization of the dopaminergic membrane via regulation of calcium homeostasis and in the neurodevelopmental process involving the cerebello-thalamo-pallido-cortical network. © 2019 International Parkinson and Movement Disorder Society.
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delineating cerebellar mechanisms in dyt11 Myoclonus dystonia
Movement Disorders, 2018Co-Authors: Anna Sadnicka, John C Rothwell, Kailash P Bhatia, Thomas T Warner, Joseph M Galea, Juicheng Chen, Mark J EdwardsAbstract:BACKGROUND: Recent research has highlighted the role of the cerebellum in the pathophysiology of Myoclonus-dystonia syndrome as a result of mutations in the ɛ-sarcoglycan gene (DYT11). Specifically, a cerebellar-dependent saccadic adaptation task is dramatically impaired in this patient group. OBJECTIVES: The objective of this study was to investigate whether saccadic deficits coexist with impairments of limb adaptation to provide a potential mechanism linking cerebellar dysfunction to the movement disorder within symptomatic body regions. METHODS: Limb adaptation to visuomotor (visual feedback rotated by 30°) and forcefield (force applied by robot to deviate arm) perturbations were examined in 5 patients with DYT11 and 10 aged-matched controls. RESULTS: Patients with DYT11 successfully adapted to both types of perturbation. Modelled and averaged summary metrics that captured adaptation behaviors were equivalent to the control group across conditions. CONCLUSIONS: DYT11 is not characterized by a uniform deficit in adaptation. The previously observed large deficit in saccadic adaption is not reflected in an equivalent deficit in limb adaptation in symptomatic body regions. We suggest potential mechanisms at the root of this discordance and identify key research questions that need future study. © 2018 International Parkinson and Movement Disorder Society.
Marina A J Tijssen - One of the best experts on this subject based on the ideXlab platform.
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natural course of Myoclonus dystonia in adulthood stable motor signs but increased psychiatry
Movement Disorders, 2020Co-Authors: Elze R Timmers, Kathryn J. Peall, E.m.j. Foncke, Cees C Tijssen, Joke M Dijk, Rodi Zutt, Bruno Bergmans, Marina A J TijssenAbstract:Myoclonus‐dystonia (M‐D) is a rare hyperkinetic movement disorder characterized by upper body–predominant Myoclonus and dystonia.1 A large proportion of cases are caused by autosomal‐dominant inherited mutations in the SGCE gene. In addition to the motor manifestations, psychiatric disorders are frequently reported.2 Several studies have suggested that they may form a primary component of the M‐D phenotype.3, 4 This study represents the first long‐term follow‐up study of both motor and psychiatric symptomatology in adults with M‐D (SGCE mutation), providing further insights into the natural history of M‐D and enabling more prognostic information.
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deep brain stimulation of the pallidum is effective and might stabilize striatal d 2 receptor binding in Myoclonus dystonia
Frontiers in Neurology, 2012Co-Authors: Richard J Beukers, Jan Booij, J D Speelman, Maria Fiorella Contarino, P R Schuurman, Marina A J TijssenAbstract:Purpose: To assess clinical efficacy of deep brain stimulation of the pallidum in Myoclonus-dystonia patients, and to compare pre- and postoperative striatal dopamine D2 receptor availability. Methods: Clinical parameters were scored using validated rating scales for Myoclonus and dystonia. Dopamine D2 receptor binding of three patients was studied before surgery and approximately two years post-operatively using 123I-iodobenzamide Single Photon Emission Computed Tomography. Two patients who did not undergo surgery served as controls. Results: Clinically, the 3 Myoclonus-dystonia patients improved 83%, 17% and 100%, respectively on the Myoclonus rating scale and 78%, 23% and 65% on the dystonia rating scale after deep brain stimulation. Dopamine D2 receptor binding did not change after surgery. In the two control subjects, binding has lowered further. Conclusions: These findings confirm that deep brain stimulation of the pallidum has beneficial effects on motor symptoms in Myoclonus-dystonia and suggest this procedure might stabilize dopamine D2 receptor binding.
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Functional Magnetic Resonance Imaging Evidence of Incomplete Maternal Imprinting in Myoclonus-dystonia
JAMA Neurology, 2011Co-Authors: Richard J Beukers, E.m.j. Foncke, Dick J. Veltman, Johan N. Van Der Meer, Marina A J TijssenAbstract:Background: Myoclonus-dystonia is an autosomal dominantly inherited movement disorder, clinically characterized by myoclonic jerks and dystonic postures or movements. A previous functional magnetic resonance imaging study showed altered cortical activation patterns in clinically affected SGCE mutation carriers when compared with controls consistent with defective sensorimotor integration. Genetically, the disorder is characterized by the maternal imprinting mechanism; ie, patients who inherit the mutation from their fathers will develop symptoms. However, several clinically manifest patients with Myoclonus-dystonia who inherited the mutation from their mother have been described. Objective: To compare cerebral activation patterns of paternally inherited SGCE mutation carriers are with maternally inherited mutation carriers and a control group. Design: Case-control study using functional magnetic resonance imaging. Participants: Eight paternally inherited SGCE mutation carriers, 8 asymptomatic or slightly affected (4 of 8) symptomatic maternally inherited mutation carriers, and 11 control subjects. Interventions: Participants were studied using a 3-T functional magnetic resonance imaging scanner with a finger tapping task. Results: When paternal and maternal gene mutation carriers were compared, hyperresponsiveness was seen in the contralateral secondary somatosensory cortex. When maternal mutation carriers and control subjects were compared, hyperresponsiveness of the ipsilateral cerebellum and supplementary motor area were found. Using a nonparametric analysis to study only the 4 clinically asymptomatic patients, no significant differences were found between groups. Contrast estimates were plotted for the known affected sensorimotor brain areas, showing intermediate activation in maternally inherited mutation carriers, even when this was performed for only the 4 clinically unaffected mutation carriers. Conclusions: The results suggest biased gene expression based on parent of origin rather than a strictly dichotomous maternal imprinting mechanism, consistent with clinical observations.
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Severity of dystonia is correlated with putaminal gray matter changes in Myoclonus-dystonia
European Journal of Neurology, 2011Co-Authors: Richard J Beukers, E.m.j. Foncke, J.n. Van Der Meer, S. 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.
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Myoclonus dystonia and spinocerebellar ataxia type 14 presenting with similar phenotypes trunk tremor Myoclonus and dystonia
Parkinsonism & Related Disorders, 2010Co-Authors: E.m.j. Foncke, Richard J Beukers, Cees C Tijssen, Johannes H T M Koelman, Marina A J TijssenAbstract:We describe three genetically confirmed Myoclonus dystonia (M-D) patients and one spinocerebellar ataxia type 14 (SCA14) patient, presenting with a combination of trunk tremor, multifocal Myoclonus and axial dystonia as predominant clinical features. We suggest that in patients with this M-D phenotype, without a mutation in the DYT11 gene, SCA14 should be considered.
David A Grimes - One of the best experts on this subject based on the ideXlab platform.
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refinement of the dyt15 locus in Myoclonus dystonia
Movement Disorders, 2007Co-Authors: Lemuel Racacho, Anthony E Lang, David A Grimes, Dennis E BulmanAbstract:Inherited Myoclonus dystonia (MD) is an autosomal dominant disorder in which we previously mapped a novel locus to chromosome18p11 (OMIM number: 607488). Since no further informative STS markers were found within the flanking shared regions, we utilized single nucleotide polymorphisms (SNP) for fine-mapping. All known or predicted genes within this region were directly sequenced. We identified three recombinant SNPs in the distal region but none from the proximal region. Our previous linked region has now been reduced to 3.18 Mb but direct sequencing of all seven known and four predicted genes with EST support did not identify any mutations. © 2007 Movement Disorder Society
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mutations in the sarcoglycan gene found to be uncommon in seven Myoclonus dystonia families
Neurology, 2003Co-Authors: Anthony E Lang, Dennis E Bulman, Lemuel Racacho, David A GrimesAbstract:Myoclonus–dystonia syndrome (MDS) is a disorder for which the major cause appears to be mutations in the e-sarcoglycan gene ( SGCE ). The authors have now performed mutation screening in 22 affected individuals from seven families with findings of typical MDS. A novel 5-bp deletion in exon 7 of the gene in one family and the previously reported R102X nonsense mutation in exon 3 in two other families were identified. Mutations in the SGCE gene were found in the minority of families screened in this series.
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Mutations in the ∈-sarcoglycan gene found to be uncommon in seven Myoclonus-dystonia families
Neurology, 2003Co-Authors: Anthony E Lang, Dennis E Bulman, Lemuel Racacho, David A GrimesAbstract:Myoclonus–dystonia syndrome (MDS) is a disorder for which the major cause appears to be mutations in the e-sarcoglycan gene ( SGCE ). The authors have now performed mutation screening in 22 affected individuals from seven families with findings of typical MDS. A novel 5-bp deletion in exon 7 of the gene in one family and the previously reported R102X nonsense mutation in exon 3 in two other families were identified. Mutations in the SGCE gene were found in the minority of families screened in this series.
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inherited Myoclonus dystonia evidence supporting genetic heterogeneity
Movement Disorders, 2001Co-Authors: Dennis E Bulman, David A Grimes, P St Georgehyslop, Anthony E LangAbstract:Inherited Myoclonus-dystonia (IMD) is a new term used to describe an autosomal dominant form of Myoclonus. Recently a family with IMD was linked to a region on chromosome 11q23 and a possible mutation identified in the D2 dopamine receptor. We have identified a large family with 12 affected individuals. Using linkage analysis and direct sequencing, the D2 receptor gene was excluded as a cause of Myoclonus in this family. These results indicate that the Val154Ile D2 receptor substitution is not the universal cause of IMD. This suggests either that it is a rare, family specific polymorphism not causative of IMD, or that IMD is genetically heterogeneous. Mov. Disord. 16:106–110, 2001. © 2001 Movement Disorder Society.
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Inherited Myoclonus‐dystonia: Evidence supporting genetic heterogeneity
Movement Disorders, 2001Co-Authors: David A Grimes, Dennis E Bulman, P. St George-hyslop, Anthony E LangAbstract:Inherited Myoclonus-dystonia (IMD) is a new term used to describe an autosomal dominant form of Myoclonus. Recently a family with IMD was linked to a region on chromosome 11q23 and a possible mutation identified in the D2 dopamine receptor. We have identified a large family with 12 affected individuals. Using linkage analysis and direct sequencing, the D2 receptor gene was excluded as a cause of Myoclonus in this family. These results indicate that the Val154Ile D2 receptor substitution is not the universal cause of IMD. This suggests either that it is a rare, family specific polymorphism not causative of IMD, or that IMD is genetically heterogeneous. Mov. Disord. 16:106–110, 2001. © 2001 Movement Disorder Society.
Enza Maria Valente - One of the best experts on this subject based on the ideXlab platform.
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kctd17 related Myoclonus dystonia syndrome clinical and electrophysiological findings of a patient with atypical late onset
Parkinsonism & Related Disorders, 2020Co-Authors: Massimiliano Todisco, Enza Maria Valente, Simone Gana, Giuseppe Cosentino, Edoardo Errichiello, Sebastiano Arceri, Micol Avenali, E AlfonsiAbstract:Abstract Introduction Myoclonus-dystonia is a rare syndrome typically occurring during childhood or adolescence, mainly due to SGCE pathogenic variants. Early-onset, atypical presentations of Myoclonus-dystonia have recently been associated with KCTD17 variants. In these cases, laryngeal involvement was reported in the advanced stages. Methods We evaluated a 52-year-old man with Myoclonus-dystonia and positive family history. He underwent an electromyographic investigation of vocal cord and forearm muscles. Whole-exome sequencing was also performed. Results Onset of symptoms was at 51 years with dysphonia and vocal tremor. Electromyography disclosed abductor spasmodic dysphonia and laryngeal Myoclonus. The patient later developed writer's cramp, upper limb Myoclonus, and blepharospasm. Botulinum toxin injection led to improvement of the writer's cramp and to a lesser extent of the spasmodic dysphonia. Genetic analysis identified a heterozygous missense variant in exon 2 of KCTD17: c.229 C > A (p.Leu77Ile), consistently predicted as damaging. Conclusions We suggest that the KCTD17-associated phenotypic spectrum may include late onset (even in late adulthood) as well as early and prominent laryngeal involvement.
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twenty years on Myoclonus dystonia and e sarcoglycan neurodevelopment channel and signaling dysfunction
Movement Disorders, 2019Co-Authors: Elisa Menozzi, Bettina Balint, Anna Latorre, Enza Maria Valente, John C Rothwell, Kailash P BhatiaAbstract:Myoclonus-dystonia is a clinical syndrome characterized by a typical childhood onset of myoclonic jerks and dystonia involving the neck, trunk, and upper limbs. Psychiatric symptomatology, namely, alcohol dependence and phobic and obsessive-compulsive disorder, is also part of the clinical picture. Zonisamide has demonstrated effectiveness at reducing both Myoclonus and dystonia, and deep brain stimulation seems to be an effective and long-lasting therapeutic option for medication-refractory cases. In a subset of patients, Myoclonus-dystonia is associated with pathogenic variants in the epsilon-sarcoglycan gene, located on chromosome 7q21, and up to now, more than 100 different pathogenic variants of the epsilon-sarcoglycan gene have been described. In a few families with a clinical phenotype resembling Myoclonus-dystonia associated with distinct clinical features, variants have been identified in genes involved in novel pathways such as calcium channel regulation and neurodevelopment. Because of phenotypic similarities with epsilon-sarcoglycan gene-related Myoclonus-dystonia, these conditions can be collectively classified as "Myoclonus-dystonia syndromes." In the present article, we present Myoclonus-dystonia caused by epsilon-sarcoglycan gene mutations, with a focus on genetics and underlying disease mechanisms. Second, we review those conditions falling within the spectrum of Myoclonus-dystonia syndromes, highlighting their genetic background and involved pathways. Finally, we critically discuss the normal and pathological function of the epsilon-sarcoglycan gene and its product, suggesting a role in the stabilization of the dopaminergic membrane via regulation of calcium homeostasis and in the neurodevelopmental process involving the cerebello-thalamo-pallido-cortical network. © 2019 International Parkinson and Movement Disorder Society.
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Twenty years on: Myoclonus‐dystonia and ε‐sarcoglycan — neurodevelopment, channel, and signaling dysfunction
Movement Disorders, 2019Co-Authors: Elisa Menozzi, Bettina Balint, Anna Latorre, Enza Maria Valente, John C Rothwell, Kailash P BhatiaAbstract:: Myoclonus-dystonia is a clinical syndrome characterized by a typical childhood onset of myoclonic jerks and dystonia involving the neck, trunk, and upper limbs. Psychiatric symptomatology, namely, alcohol dependence and phobic and obsessive-compulsive disorder, is also part of the clinical picture. Zonisamide has demonstrated effectiveness at reducing both Myoclonus and dystonia, and deep brain stimulation seems to be an effective and long-lasting therapeutic option for medication-refractory cases. In a subset of patients, Myoclonus-dystonia is associated with pathogenic variants in the epsilon-sarcoglycan gene, located on chromosome 7q21, and up to now, more than 100 different pathogenic variants of the epsilon-sarcoglycan gene have been described. In a few families with a clinical phenotype resembling Myoclonus-dystonia associated with distinct clinical features, variants have been identified in genes involved in novel pathways such as calcium channel regulation and neurodevelopment. Because of phenotypic similarities with epsilon-sarcoglycan gene-related Myoclonus-dystonia, these conditions can be collectively classified as "Myoclonus-dystonia syndromes." In the present article, we present Myoclonus-dystonia caused by epsilon-sarcoglycan gene mutations, with a focus on genetics and underlying disease mechanisms. Second, we review those conditions falling within the spectrum of Myoclonus-dystonia syndromes, highlighting their genetic background and involved pathways. Finally, we critically discuss the normal and pathological function of the epsilon-sarcoglycan gene and its product, suggesting a role in the stabilization of the dopaminergic membrane via regulation of calcium homeostasis and in the neurodevelopmental process involving the cerebello-thalamo-pallido-cortical network. © 2019 International Parkinson and Movement Disorder Society.
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deep brain stimulation in Myoclonus dystonia syndrome
Movement Disorders, 2004Co-Authors: Enza Maria Valente, Simone Hemm, Christine Coubes, Nathalie Vayssiere, Stephanie Serrat, Annalisa Di Giorgio, Philippe CoubesAbstract:Abstract: Myoclonus–dystonia syndrome (MDS) is an auto-somal dominant disorder characterized by bilateral myoclonicjerks. An 8-year-old boy presenting with early onset, medicallyintractable, MDS due to a mutation in the -sarcoglycan gene(SGCE) underwent chronic bilateral stimulation of the globuspallidus internus, which eliminates both Myoclonus and dysto-nia. We conclude that deep brain stimulation can be an effec-tive and safe treatment for MDS. © 2004 Movement DisorderSociety Key words: Myoclonus; dystonia; neurosurgeryMyoclonus–dystonia syndrome (MDS; DYT11; MIM[159900]) is an autosomal dominant disorder characterized bybilateral, alcohol-responsive myoclonic jerks with onset inchildhood or early adolescence. 1,2 Although MDS is geneti-cally heterogeneous, 3 heterozygous mutations in the -sarco-glycan gene on chromosome 7q21 (SGCE) have been identifiedin several MDS families. 4–8 Myoclonus is the most prominentclinical feature of MDS, with jerks usually involving neck,head, and upper limbs, but occasionally extending to lowerlimbs. dystonia (mainly torticollis and writer’s cramp) oftencoexists with Myoclonus and may occasionally be the onlymanifestation of the disease.
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analysis of the epsilon sarcoglycan gene in familial and sporadic Myoclonus dystonia evidence for genetic heterogeneity
Movement Disorders, 2003Co-Authors: Enza Maria Valente, Nardo Nardocci, Anjum Misbahuddin, Francesco Brancati, Mark R Placzek, Barbara Garavaglia, S Salvi, Andrea H Nemeth, Charles Shawsmith, Anna Rita BentivoglioAbstract:The ϵ-sarcoglycan gene (SGCE) on human chromosome 7q21 has been reported to be a major locus for inherited Myoclonus–dystonia. Linkage to the SGCE locus has been detected in the majority of families tested, and mutations in the coding region have been found recently in families with autosomal dominant Myoclonus–dystonia. To evaluate the relevance of SGCE in Myoclonus–dystonia, we sequenced the entire coding region of the ϵ-sarcoglycan gene in 16 patients with either sporadic or familial Myoclonus–dystonia. No mutations were found. This study suggests that ϵ-sarcoglycan does not play an important role in sporadic Myoclonus–dystonia and supports genetic heterogeneity in familial cases. © 2003 Movement Disorder Society
Anthony E Lang - One of the best experts on this subject based on the ideXlab platform.
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Myoclonus dystonia classification phenomenology pathogenesis and treatment
Current Opinion in Neurology, 2018Co-Authors: Emmanuel Roze, Anthony E Lang, Marie VidailhetAbstract:Purpose of reviewThe present study will highlight recent advances in the field of Myoclonus-dystonia with a focus on clinical aspects, pathogenesis, and treatment. We will also discuss genetics, classification issues, and diagnostic criteria.Recent findingsMyoclonus-dystonia is a clinical syndrome c
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alcohol improves cerebellar learning deficit in Myoclonus dystonia a clinical and electrophysiological investigation
Annals of Neurology, 2017Co-Authors: Anne Weissbach, Dagmar Timmann, Norbert Brüggemann, Vera Tadic, Elisa Werner, Julien F Bally, Sinem Tunc, Sebastian Lons, Kirsten E Zeuner, Anthony E LangAbstract:Objectives: To characterize neurophysiological subcortical abnormalities in Myoclonus-dystonia and their modulation by alcohol administration. Methods: Cerebellar associative learning and basal ganglia-brainstem interaction were investigated in 17 Myoclonus-dystonia patients with epsilon-sarcoglycan (SGCE) gene mutation and 21 age- and sex-matched healthy controls by means of classical eyeblink conditioning and blink reflex recovery cycle before and after alcohol intake resulting in a breath alcohol concentration of 0.08% (0.8 g/l). The alcohol responsiveness of clinical symptoms was evaluated by three blinded raters with a standardized video protocol and clinical rating scales including the Unified Myoclonus Rating Scale (UMRS) and the Burke Fahn Marsden dystonia Rating Scale (BFMDRS). Results: Patients showed a significantly reduced number of conditioned eyeblink responses before alcohol administration compared to controls. While the conditioning response rate decreased under alcohol intake in controls, it increased in patients (ANOVA: alcohol state x Group p = 0.004). Blink reflex recovery cycle before and after alcohol intake did not differ between groups. Myoclonus improved significantly after alcohol intake (p = 0.016). The severity of action Myoclonus at baseline correlated negatively with the conditioning response in classical eyeblink conditioning in patients. Interpretation: The combination of findings with reduced baseline acquisition of conditioned eyeblink responses and normal blink reflex recovery cycle in patients that improved significantly by alcohol intake suggests a crucial role of cerebellar networks in the generation of symptoms in these patients. This article is protected by copyright. All rights reserved.
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electrophysiological features of Myoclonus dystonia
Movement Disorders, 2008Co-Authors: Anthony E Lang, Jieyuan Li, Danny I Cunic, Guillermo Paradiso, Carolyn Gunraj, Robert ChenAbstract:Inherited Myoclonus-dystonia (M-D) is an autosomal dominant disorder characterized by Myoclonus and dystonia that often improves with alcohol. To examine the electrophysiologic characteristics of M-D, we studied 6 patients from 4 different families and 9 age-matched healthy subjects. Neurophysiological studies performed include electromyography (EMG)-electroencephalography (EEG) polygraphy, jerk-locked back-averaged EEG, somatosensory evoked potentials (SEP), long-latency reflex (LLR) to median and digital nerve stimulation, and transcranial magnetic stimulation studies with short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), and long-interval intracortical inhibition (LICI). All 6 patients showed Myoclonus and dystonia on clinical examination and EMG testing. The EMG burst durations ranged from 30.4 to 750.6 milliseconds (mean, 101.5 milliseconds). Jerk-locked back-averaged EEG failed to reveal any preceding cortical correlates. Median nerve SEP revealed no giant potential. No patients had exaggerated LLR to median or digital nerve stimulation. There was no significant difference in SICI, ICF, and LICI between M-D patients and normal subjects. Myoclonus in inherited M-D is likely of subcortical origin. Normal intracortical inhibition and facilitation suggest that the GABAergic circuits in the motor cortex are largely intact and that the mechanisms of Myoclonus and dystonia are different from those for cortical Myoclonus and other dystonic disorders.
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refinement of the dyt15 locus in Myoclonus dystonia
Movement Disorders, 2007Co-Authors: Lemuel Racacho, Anthony E Lang, David A Grimes, Dennis E BulmanAbstract:Inherited Myoclonus dystonia (MD) is an autosomal dominant disorder in which we previously mapped a novel locus to chromosome18p11 (OMIM number: 607488). Since no further informative STS markers were found within the flanking shared regions, we utilized single nucleotide polymorphisms (SNP) for fine-mapping. All known or predicted genes within this region were directly sequenced. We identified three recombinant SNPs in the distal region but none from the proximal region. Our previous linked region has now been reduced to 3.18 Mb but direct sequencing of all seven known and four predicted genes with EST support did not identify any mutations. © 2007 Movement Disorder Society
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mutations in the sarcoglycan gene found to be uncommon in seven Myoclonus dystonia families
Neurology, 2003Co-Authors: Anthony E Lang, Dennis E Bulman, Lemuel Racacho, David A GrimesAbstract:Myoclonus–dystonia syndrome (MDS) is a disorder for which the major cause appears to be mutations in the e-sarcoglycan gene ( SGCE ). The authors have now performed mutation screening in 22 affected individuals from seven families with findings of typical MDS. A novel 5-bp deletion in exon 7 of the gene in one family and the previously reported R102X nonsense mutation in exon 3 in two other families were identified. Mutations in the SGCE gene were found in the minority of families screened in this series.
