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Yuqing Li - One of the best experts on this subject based on the ideXlab platform.
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alteration of striatal dopaminergic neurotransmission in a mouse model of dyt11 myoclonus dystonia
PLOS ONE, 2012Co-Authors: Lin Zhang, Fumiaki Yokoi, Dee S. Parsons, David G. Standaert, Yuqing LiAbstract:Background DYT11 myoclonus-dystonia (M-D) syndrome is a neurological movement disorder characterized by myoclonic jerks and dystonic postures or movement that can be alleviated by alcohol. It is caused by mutations in SGCE encoding e-sarcoglycan (e-SG); the mouse homolog of this gene is SGCE. Paternally-inherited SGCE heterozygous knockout (SGCE KO) mice exhibit myoclonus, motor impairment and anxiety- and depression-like behaviors, modeling several clinical symptoms observed in DYT11 M-D patients. The behavioral deficits are accompanied by abnormally high levels of dopamine and its metabolites in the striatum of SGCE KO mice. Neuroimaging studies of DYT11 M-D patients show reduced dopamine D2 receptor (D2R) availability, although the possibility of increased endogenous dopamine, and consequently, competitive D2R occupancy cannot be ruled out.
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abnormal nuclear envelopes in the striatum and motor deficits in dyt11 myoclonus dystonia mouse models
Human Molecular Genetics, 2012Co-Authors: Fumiaki Yokoi, Mai T Dang, Tong Zhou, Yuqing LiAbstract:DYT11 myoclonus-dystonia (M-D) is a movement disorder characterized by myoclonic jerks with dystonic symptoms and caused by mutations in paternally expressed SGCE, which codes for 1-sarcoglycan. Paternally inherited SGCE heterozygous knock-out (KO) mice exhibit motor deficits and spontaneous myoclonus. Abnormal nuclear envelopes have been reported in cellular and mouse models of early-onset DYT1 generalized torsion dystonia; however, the relationship between the abnormal nuclear envelopes and motor symptoms are not clear. Furthermore, it is not known whether abnormal nuclear envelope exists in nonDYT1 dystonia. In the present study, abnormal nuclear envelopes in the striatal medium spiny neurons (MSNs) were found in SGCE KO mice. To analyze whether the loss of 1-sarcoglycan in the striatum alone causes abnormal nuclear envelopes, motor deficits or myoclonus, we produced paternally inherited striatum-specific SGCE conditional KO (SGCE sKO) mice and analyzed their phenotypes. SGCE sKO mice exhibited motor deficits in both beam-walking and accelerated rotarod tests, while they did not exhibit abnormal nuclear envelopes, alteration in locomotion, or myoclonus. The results suggest that the loss of 1-sarcoglycan in the striatum contributes to motor deficits, while it alone does not produce abnormal nuclear envelopes or myoclonus. Development of therapies targeting the striatum to compensate for the loss of 1-sarcoglycan function may rescue the motor deficits in DYT11 M-D patients.
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abnormal nuclear envelope in the cerebellar purkinje cells and impaired motor learning in dyt11 myoclonus dystonia mouse models
Behavioural Brain Research, 2012Co-Authors: Fumiaki Yokoi, Mai T Dang, Jindong Li, Atbin Doroodchi, Tong Zhou, Guang Yang, Yuqing LiAbstract:Myoclonus-dystonia (M-D) is a movement disorder characterized by myoclonic jerks with dystonia. DYT11 M-D is caused by mutations in SGCE which codes for e-sarcoglycan. SGCE is maternally imprinted and paternally expressed. Abnormal nuclear envelope has been reported in mouse models of DYT1 generalized torsion dystonia. However, it is not known whether similar alterations occur in DYT11 M-D. We developed a mouse model of DYT11 M-D using paternally-inherited SGCE heterozygous knockout (SGCE KO) mice and reported that they had myoclonus and motor coordination and learning deficits in the beam-walking test. However, the specific brain regions that contribute to these phenotypes have not been identified. Since e-sarcoglycan is highly expressed in the cerebellar Purkinje cells, here we examined the nuclear envelope in these cells using a transmission electron microscope and found that they are abnormal in SGCE KO mice. Our results put DYT11 M-D in a growing family of nuclear envelopathies. To analyze the effect of loss of e-sarcoglycan function in the cerebellar Purkinje cells, we produced paternally-inherited cerebellar Purkinje cell-specific SGCE conditional knockout (SGCE pKO) mice. SGCE pKO mice showed motor learning deficits, while they did not show abnormal nuclear envelope in the cerebellar Purkinje cells, robust motor deficits, or myoclonus. The results suggest that e-sarcoglycan in the cerebellar Purkinje cells contributes to the motor learning, while loss of e-sarcoglycan in other brain regions may contribute to nuclear envelope abnormality, myoclonus and motor coordination deficits.
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myoclonus motor deficits alterations in emotional responses and monoamine metabolism in e sarcoglycan deficient mice
Journal of Biochemistry, 2006Co-Authors: Fumiaki Yokoi, Mai T Dang, Jianyong Li, Yuqing LiAbstract:: Mutations of epsilon-sarcoglycan gene (SGCE) have been implicated in myoclonus-dystonia (M-D), a movement disorder. To determine the pathophysiology of M-D, we produced SGCE knockout mice and found that the knockout mice exhibited myoclonus, motor impairments, hyperactivity, anxiety, depression, significantly higher levels of striatal dopamine and its metabolites, and an inverse correlation between the dopamine and serotonin metabolites. The results suggest that the diverse symptoms associated with M-D are indeed resulted from a single SGCE gene mutation that leads to alterations of dopaminergic and serotonergic systems. Therefore, antipsychotic agents and serotonin reuptake inhibitors may offer potential benefits for M-D patients.
Anne Grunewald - One of the best experts on this subject based on the ideXlab platform.
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faithful SGCE imprinting in ipsc derived cortical neurons an endogenous cellular model of myoclonus dystonia
Scientific Reports, 2017Co-Authors: Karen Grutz, Francesca A Carlisle, Philip Seibler, Anne Grunewald, Anne Weissbach, Ana Westenberger, Katja Lohmann, Derek J Blake, Christine KleinAbstract:In neuropathology research, induced pluripotent stem cell (iPSC)-derived neurons are considered a tool closely resembling the patient brain. Albeit in respect to epigenetics, this concept has been challenged. We generated iPSC-derived cortical neurons from myoclonus-dystonia patients with mutations (W100G and R102X) in the maternally imprinted e-sarcoglycan (SGCE) gene and analysed properties such as imprinting, mRNA and protein expression. Comparison of the promoter during reprogramming and differentiation showed tissue-independent differential methylation. DNA sequencing with methylation-specific primers and cDNA analysis in patient neurons indicated selective expression of the mutated paternal SGCE allele. While fibroblasts only expressed the ubiquitous mRNA isoform, brain-specific SGCE mRNA and e-sarcoglycan protein were detected in iPSC-derived control neurons. However, neuronal protein levels were reduced in both mutants. Our phenotypic characterization highlights the suitability of iPSC-derived cortical neurons with SGCE mutations for myoclonus-dystonia research and, in more general terms, prompts the use of iPSC-derived cellular models to study epigenetic mechanisms impacting on health and disease.
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prominent psychiatric comorbidity in the dominantly inherited movement disorder myoclonus dystonia
Parkinsonism & Related Disorders, 2013Co-Authors: Anne Weissbach, Anne Grunewald, Meike Kasten, Christine Klein, Norbert Bruggemann, Peter Trillenberg, Johann HagenahAbstract:Abstract Background Neurological and psychiatric disorders show clinical overlap suggesting a shared pathophysiological background. We evaluated myoclonus-dystonia, a monogenic movement disorder as a disease model for inherited psychopathology. Method We investigated 12 SGCE mutation carriers using standardized neurological and psychiatric examinations to assign DSM-IV diagnoses. Furthermore, we analyzed all studies in the Medline database which included psychiatric information on SGCE mutation-positive patients. Results Of our twelve SGCE mutation carriers, 10 were older than 16 years. Two of them (20%) reported psychiatric diagnoses before our examination, which resulted in at least one psychiatric diagnosis in seven (70%) patients, most frequently anxiety (60%), depression (30%) or both. Substance abuse was observed in 20%, whereas obsessive-compulsive disorders were absent. One mutation carrier showed Axis 2 features. In the literature analysis, the ten studies using standardized tools covering DSM-IV criteria reported prevalences similar to those in our sample. This was three times the frequency of psychiatric disorders detected in 13 studies using clinical history or patient report only. Conclusion About two thirds of SGCE mutation carriers develop psychiatric comorbidity and >80% are previously undiagnosed.
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myoclonus dystonia significance of large SGCE deletions
Human Mutation, 2008Co-Authors: Anne Grunewald, Katja Lohmannhedrich, Ana Djarmati, K Farrell, J A Zeller, N Allert, Frank Papengut, Brittsabina Petersen, Victor S C Fung, D J OsullivanAbstract:Myoclonus-dystonia (M-D) is an autosomal-dominant movement disorder caused by mutations in SGCE. We investigated the frequency and type of SGCE mutations with emphasis on gene dosage alterations and explored the associated phenotypes. We tested 35 M-D index patients by multiplex ligation-dependent probe amplification (MLPA) and genomic sequencing. Mutations were found in 26% (9/35) of the cases, all but three with definite M-D. Two heterozygous deletions of the entire SGCE gene and flanking DNA and a heterozygous deletion of exon 2 only were detected, accounting for 33% (3/9) of the mutations found. Both large deletions contained COL1A2 and were additionally associated with joint problems. Further, we discovered one novel small deletion (c.771_772delAT, p.C258X) and four recurrent point mutations (c.289C>T, p.R97X; c.304C>T, p.R102X; c.709C>T, p.R237X; c.1114C>T, p.R372X). A Medline search identified 22 articles on SGCE mutational screening. Sixty-four unrelated M-D patients were described with 41 different mutations. No genotype–phenotype association was found, except in patients with deletions encompassing additional genes. In conclusion, a rigorous clinical preselection of patients and careful accounting for non-motor signs should precede mutational tests. Gene dosage studies should be included in routine SGCE genetic testing. © 2007 Wiley-Liss, Inc.
Fumiaki Yokoi - One of the best experts on this subject based on the ideXlab platform.
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Alteration of Striatal Dopaminergic Neurotransmission in a Mouse Model of DYT11 Myoclonus-Dystonia
2013Co-Authors: Lin Zhang, Fumiaki Yokoi, Dee S. ParsonsAbstract:Background: DYT11 myoclonus-dystonia (M-D) syndrome is a neurological movement disorder characterized by myoclonic jerks and dystonic postures or movement that can be alleviated by alcohol. It is caused by mutations in SGCE encoding e-sarcoglycan (e-SG); the mouse homolog of this gene is SGCE. Paternally-inherited SGCE heterozygous knockout (SGCE KO) mice exhibit myoclonus, motor impairment and anxiety- and depression-like behaviors, modeling several clinical symptoms observed in DYT11 M-D patients. The behavioral deficits are accompanied by abnormally high levels of dopamine and its metabolites in the striatum of SGCE KO mice. Neuroimaging studies of DYT11 M-D patients show reduced dopamine D2 receptor (D2R) availability, although the possibility of increased endogenous dopamine, and consequently, competitive D2R occupancy cannot be ruled out. Methodology/Principal Findings: The protein levels of striatal D2R, dopamine transporter (DAT), and dopamine D1 receptor (D1R) in SGCE KO mice were analyzed by Western blot. The striatal dopamine release after amphetamine injection in SGCE KO mice were analyzed by microdialysis in vivo. The striatal D2R was significantly decreased in SGCE KO mice without altering DAT and D1R. SGCE KO mice also exhibited a significant increase of dopamine release after amphetamine injection in comparison to wild-type (WT) littermates. Conclusion/Significance: The results suggest e-SG may have a role in the regulation of D2R expression. The loss of e-S
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alteration of striatal dopaminergic neurotransmission in a mouse model of dyt11 myoclonus dystonia
PLOS ONE, 2012Co-Authors: Lin Zhang, Fumiaki Yokoi, Dee S. Parsons, David G. Standaert, Yuqing LiAbstract:Background DYT11 myoclonus-dystonia (M-D) syndrome is a neurological movement disorder characterized by myoclonic jerks and dystonic postures or movement that can be alleviated by alcohol. It is caused by mutations in SGCE encoding e-sarcoglycan (e-SG); the mouse homolog of this gene is SGCE. Paternally-inherited SGCE heterozygous knockout (SGCE KO) mice exhibit myoclonus, motor impairment and anxiety- and depression-like behaviors, modeling several clinical symptoms observed in DYT11 M-D patients. The behavioral deficits are accompanied by abnormally high levels of dopamine and its metabolites in the striatum of SGCE KO mice. Neuroimaging studies of DYT11 M-D patients show reduced dopamine D2 receptor (D2R) availability, although the possibility of increased endogenous dopamine, and consequently, competitive D2R occupancy cannot be ruled out.
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abnormal nuclear envelopes in the striatum and motor deficits in dyt11 myoclonus dystonia mouse models
Human Molecular Genetics, 2012Co-Authors: Fumiaki Yokoi, Mai T Dang, Tong Zhou, Yuqing LiAbstract:DYT11 myoclonus-dystonia (M-D) is a movement disorder characterized by myoclonic jerks with dystonic symptoms and caused by mutations in paternally expressed SGCE, which codes for 1-sarcoglycan. Paternally inherited SGCE heterozygous knock-out (KO) mice exhibit motor deficits and spontaneous myoclonus. Abnormal nuclear envelopes have been reported in cellular and mouse models of early-onset DYT1 generalized torsion dystonia; however, the relationship between the abnormal nuclear envelopes and motor symptoms are not clear. Furthermore, it is not known whether abnormal nuclear envelope exists in nonDYT1 dystonia. In the present study, abnormal nuclear envelopes in the striatal medium spiny neurons (MSNs) were found in SGCE KO mice. To analyze whether the loss of 1-sarcoglycan in the striatum alone causes abnormal nuclear envelopes, motor deficits or myoclonus, we produced paternally inherited striatum-specific SGCE conditional KO (SGCE sKO) mice and analyzed their phenotypes. SGCE sKO mice exhibited motor deficits in both beam-walking and accelerated rotarod tests, while they did not exhibit abnormal nuclear envelopes, alteration in locomotion, or myoclonus. The results suggest that the loss of 1-sarcoglycan in the striatum contributes to motor deficits, while it alone does not produce abnormal nuclear envelopes or myoclonus. Development of therapies targeting the striatum to compensate for the loss of 1-sarcoglycan function may rescue the motor deficits in DYT11 M-D patients.
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abnormal nuclear envelope in the cerebellar purkinje cells and impaired motor learning in dyt11 myoclonus dystonia mouse models
Behavioural Brain Research, 2012Co-Authors: Fumiaki Yokoi, Mai T Dang, Jindong Li, Atbin Doroodchi, Tong Zhou, Guang Yang, Yuqing LiAbstract:Myoclonus-dystonia (M-D) is a movement disorder characterized by myoclonic jerks with dystonia. DYT11 M-D is caused by mutations in SGCE which codes for e-sarcoglycan. SGCE is maternally imprinted and paternally expressed. Abnormal nuclear envelope has been reported in mouse models of DYT1 generalized torsion dystonia. However, it is not known whether similar alterations occur in DYT11 M-D. We developed a mouse model of DYT11 M-D using paternally-inherited SGCE heterozygous knockout (SGCE KO) mice and reported that they had myoclonus and motor coordination and learning deficits in the beam-walking test. However, the specific brain regions that contribute to these phenotypes have not been identified. Since e-sarcoglycan is highly expressed in the cerebellar Purkinje cells, here we examined the nuclear envelope in these cells using a transmission electron microscope and found that they are abnormal in SGCE KO mice. Our results put DYT11 M-D in a growing family of nuclear envelopathies. To analyze the effect of loss of e-sarcoglycan function in the cerebellar Purkinje cells, we produced paternally-inherited cerebellar Purkinje cell-specific SGCE conditional knockout (SGCE pKO) mice. SGCE pKO mice showed motor learning deficits, while they did not show abnormal nuclear envelope in the cerebellar Purkinje cells, robust motor deficits, or myoclonus. The results suggest that e-sarcoglycan in the cerebellar Purkinje cells contributes to the motor learning, while loss of e-sarcoglycan in other brain regions may contribute to nuclear envelope abnormality, myoclonus and motor coordination deficits.
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Alteration of Striatal Dopaminergic Neurotransmission in a Mouse Model of DYT11 Myoclonus-Dystonia
2012Co-Authors: Lin Zhang, Fumiaki Yokoi, Dee S. Parsons, David G. StandaertAbstract:BackgroundDYT11 myoclonus-dystonia (M-D) syndrome is a neurological movement disorder characterized by myoclonic jerks and dystonic postures or movement that can be alleviated by alcohol. It is caused by mutations in SGCE encoding ε-sarcoglycan (ε-SG); the mouse homolog of this gene is SGCE. Paternally-inherited SGCE heterozygous knockout (SGCE KO) mice exhibit myoclonus, motor impairment and anxiety- and depression-like behaviors, modeling several clinical symptoms observed in DYT11 M-D patients. The behavioral deficits are accompanied by abnormally high levels of dopamine and its metabolites in the striatum of SGCE KO mice. Neuroimaging studies of DYT11 M-D patients show reduced dopamine D2 receptor (D2R) availability, although the possibility of increased endogenous dopamine, and consequently, competitive D2R occupancy cannot be ruled out. Methodology/Principal FindingsThe protein levels of striatal D2R, dopamine transporter (DAT), and dopamine D1 receptor (D1R) in SGCE KO mice were analyzed by Western blot. The striatal dopamine release after amphetamine injection in SGCE KO mice were analyzed by microdialysis in vivo. The striatal D2R was significantly decreased in SGCE KO mice without altering DAT and D1R. SGCE KO mice also exhibited a significant increase of dopamine release after amphetamine injection in comparison to wild-type (WT) littermates. Conclusion/SignificanceThe results suggest ε-SG may have a role in the regulation of D2R expression. The loss of ε-SG results in decreased striatal D2R, and subsequently leads to increased discharge of dopamine which could contribute to the behavioral impairment observed in DYT11 dystonia patients and in SGCE KO mice. The results suggest that reduction of striatal D2R and enhanced striatal dopamine release may contribute to the pathophysiology of DYT11 M-D patients.
Christine Klein - One of the best experts on this subject based on the ideXlab platform.
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faithful SGCE imprinting in ipsc derived cortical neurons an endogenous cellular model of myoclonus dystonia
Scientific Reports, 2017Co-Authors: Karen Grutz, Francesca A Carlisle, Philip Seibler, Anne Grunewald, Anne Weissbach, Ana Westenberger, Katja Lohmann, Derek J Blake, Christine KleinAbstract:In neuropathology research, induced pluripotent stem cell (iPSC)-derived neurons are considered a tool closely resembling the patient brain. Albeit in respect to epigenetics, this concept has been challenged. We generated iPSC-derived cortical neurons from myoclonus-dystonia patients with mutations (W100G and R102X) in the maternally imprinted e-sarcoglycan (SGCE) gene and analysed properties such as imprinting, mRNA and protein expression. Comparison of the promoter during reprogramming and differentiation showed tissue-independent differential methylation. DNA sequencing with methylation-specific primers and cDNA analysis in patient neurons indicated selective expression of the mutated paternal SGCE allele. While fibroblasts only expressed the ubiquitous mRNA isoform, brain-specific SGCE mRNA and e-sarcoglycan protein were detected in iPSC-derived control neurons. However, neuronal protein levels were reduced in both mutants. Our phenotypic characterization highlights the suitability of iPSC-derived cortical neurons with SGCE mutations for myoclonus-dystonia research and, in more general terms, prompts the use of iPSC-derived cellular models to study epigenetic mechanisms impacting on health and disease.
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prominent psychiatric comorbidity in the dominantly inherited movement disorder myoclonus dystonia
Parkinsonism & Related Disorders, 2013Co-Authors: Anne Weissbach, Anne Grunewald, Meike Kasten, Christine Klein, Norbert Bruggemann, Peter Trillenberg, Johann HagenahAbstract:Abstract Background Neurological and psychiatric disorders show clinical overlap suggesting a shared pathophysiological background. We evaluated myoclonus-dystonia, a monogenic movement disorder as a disease model for inherited psychopathology. Method We investigated 12 SGCE mutation carriers using standardized neurological and psychiatric examinations to assign DSM-IV diagnoses. Furthermore, we analyzed all studies in the Medline database which included psychiatric information on SGCE mutation-positive patients. Results Of our twelve SGCE mutation carriers, 10 were older than 16 years. Two of them (20%) reported psychiatric diagnoses before our examination, which resulted in at least one psychiatric diagnosis in seven (70%) patients, most frequently anxiety (60%), depression (30%) or both. Substance abuse was observed in 20%, whereas obsessive-compulsive disorders were absent. One mutation carrier showed Axis 2 features. In the literature analysis, the ten studies using standardized tools covering DSM-IV criteria reported prevalences similar to those in our sample. This was three times the frequency of psychiatric disorders detected in 13 studies using clinical history or patient report only. Conclusion About two thirds of SGCE mutation carriers develop psychiatric comorbidity and >80% are previously undiagnosed.
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myoclonus dystonia due to maternal uniparental disomy
JAMA Neurology, 2008Co-Authors: Emilie Guettard, Katja Lohmannhedrich, Boris Keren, Susen Winkler, Imen El Kamel, Emmanuelle Apartis, Marie-france Portnoï, Marie Vidailhet, Sylvie Rossignol, Christine KleinAbstract:Background Myoclonus-dystonia is a movement disorder often associated with mutations in the maternally imprinted e-sarcoglycan ( SGCE ) gene located on chromosome 7q21. Silver-Russell syndrome is a heterogeneous disorder characterized by prenatal and postnatal growth restriction and a characteristic facies, caused in some cases by maternal uniparental disomy of chromosome 7. Objectives To describe and investigate the combination of a typical myoclonus-dystonia syndrome and Silver-Russell syndrome. Design Clinical and neurophysiological examination as well as cytogenetic and molecular analyses. Setting Movement disorder clinic. Patient A 36-year-old man with typical myoclonus-dystonia and Silver-Russell syndrome. Main Outcome Measures Clinical description of the disease and its genetic cause. Results Cytogenetic analysis revealed mosaicism for a small chromosome 7 marker chromosome. Microsatellite analysis indicated loss of the paternal allele and maternal uniparental disomy of chromosome 7. In keeping with the maternal imprinting mechanism, no unmethylated allele of SGCE was detected after bisulfite treatment of the patient's DNA, and reverse transcription–polymerase chain reaction demonstrated loss of SGCE expression. Molecular analysis ruled out mutations in the SGCE gene. Conclusions We identified a new genetic alteration—maternal chromosome 7 disomy—that can cause myoclonus-dystonia. This alteration results in repression of both alleles of the maternally imprinted SGCE gene and suggests SGCE loss of function as the disease mechanism.
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phenotype genotype correlation in dutch patients with myoclonus dystonia
Neurology, 2006Co-Authors: M C F Gerrits, E.m.j. Foncke, Katja Hedrich, Y Van De Leemput, Johannes D. Speelman, Laurie J Ozelius, Christine Klein, Frank Baas, R J De Haan, Marina A J TijssenAbstract:The e-sarcoglycan (SGCE) gene is an important cause of myoclonus-dystonia (M-D), although the majority of cases with an M-D phenotype test negative. Seven of 31 patients with the M-D phenotype carried a mutation in the SGCE gene. Positive family history and truncal myoclonus were independent prognostic factors. Early disease onset, onset with both myoclonus and dystonia, and axial dystonia were detected significantly more often in the mutation carriers.
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ε‐sarcoglycan mutations found in combination with other dystonia gene mutations
Annals of neurology, 2002Co-Authors: Christine Klein, Dana Doheny, Deborah De Leon, Susan Bressman, Joanne Leung, Norman Kock, Patricia De Carvalho Aguiar, Liu Liu, Birgitt Müller, Jeremy M. SilvermanAbstract:Myoclonus-dystonia is a movement disorder associated with mutations in the epsilon-sarcoglycan gene (SGCE) in most families and in the DRD2 and DYT1 genes in two single families. In both of the latter families, we also found a mutation of SGCE. The molecular mechanisms through which the detected mutations may contribute to myoclonus-dystonia remain to be determined.
Kathryn J. Peall - One of the best experts on this subject based on the ideXlab platform.
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Psychiatric disorders, myoclonus dystonia and SGCE: an international study
Annals of clinical and translational neurology, 2015Co-Authors: Kathryn J. Peall, E.m.j. Foncke, Manju A Kurian, Joke M. Dijk, Rachel Saunders-pullman, Yasmine E. M. Dreissen, Ilke Van Loon, Danielle C. Cath, Michael John Owen, Huw R. MorrisAbstract:OBJECTIVE: Myoclonus-dystonia (M-D) is a hyperkinetic movement disorder, typically alcohol-responsive upper body myoclonus and dystonia. The majority of autosomal dominant familial cases are caused by epsilon-sarcoglycan gene (SGCE) mutations. Previous publications have observed increased rates of psychiatric disorders amongst SGCE mutation-positive populations. We analyzed the psychiatric data from four international centers, forming the largest cohort to date, to further determine the extent and type of psychiatric disorders in M-D. METHODS: Psychiatric data from SGCE mutation-positive M-D cohorts, collected by movement disorder specialists in the Netherlands, United Kingdom, United States, and Germany, were analyzed. These data were collected using standardized, systematic questionnaires allowing classification of symptoms according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria. Based on motor findings and SGCE mutation analysis, participants were classified into one of three groups: manifesting carriers, nonmanifesting carriers and noncarriers. RESULTS: Data from 307 participants were evaluated (140 males, 167 females, mean age at examination: 42.5 years). Two-thirds of motor affected mutation carriers (n = 132) had ≥1 psychiatric diagnosis, specific, and social phobias being most common followed by alcohol dependence and obsessive-compulsive disorder (OCD). Compared to familial controls, affected mutation carriers had significantly elevated overall rates of psychiatric disorders (P < 0.001). The most significant differences were observed with alcohol dependence (P < 0.001), OCD (P < 0.001), social and specific phobias (P < 0.001). INTERPRETATION: M-D due to SGCE mutations is associated with specific psychiatric disorders, most commonly OCD, anxiety-related disorders, and alcohol dependence. These suggest either a potential pleiotropic function for SGCE within the central nervous system or a secondary effect of the motor disorder.
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SGCE and myoclonus dystonia: motor characteristics, diagnostic criteria and clinical predictors of genotype
Journal of Neurology, 2014Co-Authors: Kathryn J. Peall, Manju A Kurian, Tammy Hedderly, Alan L Whone, Adrian J. Waite, Cathy White, Hardev Pall, Mark Wardle, Martin Smith, Philip E. JardineAbstract:Myoclonus dystonia syndrome (MDS) is a young-onset movement disorder. A proportion of cases are due to mutations in the maternally imprinted SGCE gene. We assembled the largest cohort of MDS patients to date, and determined the frequency and type of SGCE mutations. The aim was to establish the motor phenotype in mutation carriers and utility of current diagnostic criteria. Eighty-nine probands with clinical features compatible with MDS were recruited from the UK and Ireland. Patients were phenotypically classified as “definite”, “probable” or “possible” MDS according to previous guidelines. SGCE was analyzed using direct sequencing and copy number variant analysis. In those where no mutation was found, DYT1 (GAG deletion), GCH1 , THAP1 and NKX2.1 genes were also sequenced. Nineteen (21.3 %) probands had an SGCE mutation. Three patterns of motor symptoms emerged: (1) early childhood onset upper body myoclonus and dystonia, (2) early childhood onset lower limb dystonia, progressing later to more pronounced myoclonus and upper body involvement, and (3) later childhood onset upper body myoclonus and dystonia with evident cervical involvement. Five probands had large contiguous gene deletions ranging from 0.7 to 2.3 Mb in size with distinctive clinical features, including short stature, joint laxity and microcephaly. Our data confirms that SGCE mutations are most commonly identified in MDS patients with (1) age at onset ≤10 years and (2) predominant upper body involvement of a pure myoclonus-dystonia. Cases with whole SGCE gene deletions had additional clinical characteristics, which are not always predicted by deletion size or gene involvement.
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are psychiatric symptoms a core phenotype of myoclonus dystonia syndrome caused by SGCE mutations
Journal of Neurology Neurosurgery and Psychiatry, 2013Co-Authors: Kathryn J. Peall, Adrian James Waite, Manju A Kurian, Tammy Hedderly, Alan L Whone, Martin D. Smith, Hardev Pall, Mark Wardle, Deborah L Smith, Cathy WhiteAbstract:Objective Myoclonus Dystonia Syndrome (MDS) is a childhood onset, alcohol responsive movement disorder caused by mutations in the SGCE gene in a proportion of cases. Single family and case series have suggested co-morbid psychiatric disease but have not compared cases to a control group. Aims To establish a cohort of MDS patients with SGCE mutations and a control group of alcohol-responsive tremor patients, and to systematically assess for psychiatric symptoms using standardised questionnaires. Method We collected 27 patients with SGCE mutations and 45 tremor control cases. The MINI International Neuropsychiatric Interview, PHQ-9, MADRS, YBOCS and AUDIT were used to assess psychiatric disease according to DSM-IV criteria. Results There was a higher rate of psychiatric disease in MDS patients compared to controls (p Conclusion Overall psychiatric disease is elevated amongst the MDS cohort compared to a control group with a chronic, socially stigmatizing disorder. OCD appears to be the greatest contributor to this effect and may reflect a pleiotropic function for the SGCE gene.
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1624 myoclonus dystonia a clinical and genetic description
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: Kathryn J. Peall, Adrian James Waite, Manju A Kurian, Tammy Hedderly, Alan L Whone, Martin D. Smith, Hardev Pall, Patrick F Chinnery, Thomas T Warner, M OwenAbstract:Background Myoclonus Dystonia Syndrome (MDS) is a childhood onset movement disorder involving trunk and upper limb myoclonus and dystonia of the neck and hands. Psychiatric co-morbidity has also been described and most cases are due to mutations in the epsilonsarcoglycan gene (SGCE). Aims We aimed to establish a cohort of MDS cases to identify the rate and type of SGCE mutations and to systematically establish the psychiatric and motor features. Methods We have collected 80 unrelated patients with clinically suspected myoclonus dystonia syndrome. Clinical information was collected by clinical examination using standardised questionnaires or from the referring clinician. SGCE mutations were identified using Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Results Conclusion 14/80 samples have SGCE mutations. Mutation carriers had features consistent with the proposed diagnostic criteria, and four families were identified with additional lower limb dystonia. 8/14 families had concurrent psychiatric disease. Genetic mutations included single exon and whole gene deletions, splice site mutations and most commonly, premature stop codon mutations. There is no clear genotype/phenotype relationship with the exception of dysmorphic features in some of the whole gene deletion cases.
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clinical and genetic investigation of the epsilon sarcoglycan complex in neurologic and psychiatric disease
2012Co-Authors: Kathryn J. PeallAbstract:Myoclonus Dystonia Syndrome is a childhood onset hyperkinetic movement disorder characterised by alcohol responsive upper body myoclonus and dystonia. A proportion of cases are due to mutations in the maternally imprinted SGCE gene, which encodes the transmembrane epsilon-sarcoglycan protein. Previous studies suggest an increased rate of psychiatric disorders in those with SGCE mutations. This study aimed to establish a cohort of myoclonus dystonia syndrome patients, identify the rate and type of SGCE mutations, determine differences in motor characteristics between mutation positive and negative cases and whether psychiatric disorders form part of the disease phenotype. Eighty-nine probands with clinically suspected MDS were recruited. Information regarding onset and distribution of motor symptoms was collected via systematic questionnaires and video taped examination. SGCE was analysed using direct sequencing and for copy number variants. Psychiatric symptoms were assessed using systematic and standardised questionnaires and compared to a disability-matched, alcohol responsive tremor control group. Nineteen (21%) probands had an SGCE mutation. All had evidence of upper body predominant myoclonus and dystonia during their disease course. Five had contiguous gene deletions ranging from 0.7 to 2.3Mb in size with distinctive clinical features. Recruitment of family members increased the affected SGCE mutation positive group to 27 of whom 21 (77%) had psychiatric symptoms. Obsessive-Compulsive Disorder was eight times more likely (p<0.001) in mutation positive cases, compulsivity being the predominant feature (p<0.001). Generalized Anxiety Disorder (p=0.003) and alcohol dependence (p=0.02) were five times more likely in cases than tremor controls. Overall, SGCE mutations are associated with a narrow clinical and specific psychiatric phenotype. The presence of myoclonus, dystonia, age at onset ≤10 years and a positive family history of the disorder are the strongest predictors of an SGCE mutation. SGCE mutations are likely to have a pleiotropic effect in causing both motor and specific psychiatric symptoms.
