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Laurie J Ozelius - One of the best experts on this subject based on the ideXlab platform.
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genetic and clinical features of primary Torsion Dystonia
Neurobiology of Disease, 2011Co-Authors: Laurie J Ozelius, Susan B. BressmanAbstract:Abstract Primary Torsion Dystonia (PTD) is defined as a syndrome in which Dystonia is the only clinical sign (except for tremor), and there is no evidence of neuronal degeneration or an acquired cause by history or routine laboratory assessment. Seven different loci have been recognized for PTD but only two of the genes have been identified. In this review we will describe the phenotypes associated with these loci and discuss the responsible gene. This article is part of a Special Issue entitled “Advances in Dystonia”.
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mutations in the thap1 gene are responsible for dyt6 primary Torsion Dystonia
Nature Genetics, 2009Co-Authors: Tania Fuchs, Susan B. Bressman, Michelle E Ehrlich, Sophie Gavarini, Deborah Raymond, Rachel Saunderspullman, Laurie J OzeliusAbstract:We report the discovery of a mutation in the THAP1 gene in three Amish-Mennonite families with mixed-onset primary Torsion Dystonia (also known as DYT6 Dystonia). Another mutation in a German family with primary Torsion Dystonia suggests that THAP1 mutations also cause Dystonia in other ancestry groups. We demonstrate that the missense mutation impairs DNA binding, suggesting that transcriptional dysregulation may contribute to the phenotype of DYT6 Dystonia.
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mutations in the thap1 gene are responsible for dyt6 primary Torsion Dystonia
Nature Genetics, 2009Co-Authors: Tania Fuchs, Susan B. Bressman, Michelle E Ehrlich, Sophie Gavarini, Deborah Raymond, Rachel Saunderspullman, Laurie J OzeliusAbstract:Laurie Ozelius and colleagues identify mutations in THAP1 in families with a mixed type (DYT6) of primary Torsion Dystonia, a movement disorder characterized by twisting movements and abnormal posture.
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The TOR1A (DYT1) Gene Family and Its Role in Early Onset Torsion Dystonia
Genomics, 1999Co-Authors: Laurie J Ozelius, Deborah De Leon, Susan B. Bressman, Curtis E. Page, Christine Klein, Jeffrey W. Hewett, Mari Mineta, Joanne Leung, Christo Shalish, Mitchell F. BrinAbstract:Most cases of early onset Torsion Dystonia are caused by a 3-bp deletion (GAG) in the coding region of the TOR1A gene (alias DYT1, DQ2), resulting in loss of a glutamic acid in the carboxy terminal of the encoded protein, torsin A. TOR1A and its homologue TOR1B (alias DQ1) are located adjacent to each other on hu- man chromosome 9q34. Both genes comprise five sim- ilar exons; each gene spans a 10-kb region. Mutational analysis of most of the coding region and splice junc- tions of TOR1A and TOR1B did not reveal additional mutations in typical early onset cases lacking the GAG deletion (N 5 17), in dystonic individuals with appar- ent homozygosity in the 9q34 chromosomal region (N 5 5), or in a representative Ashkenazic Jewish in- dividual with late onset Dystonia, who shared a com- mon haplotype in the 9q34 region with other late onset individuals in this ethnic group. A database search revealed a family of nine related genes (50 -70% simi- larity) and their orthologues in species including hu- man, mouse, rat, pig, zebrafish, fruitfly, and nematode. At least four of these genes occur in the human ge- nome. Proteins encoded by this gene family share functional domains with the AAA/HSP/Clp-ATPase su- perfamily of chaperone-like proteins, but appear to represent a distinct evolutionary branch. © 1999 Academic
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expression of the early onset Torsion Dystonia gene dyt1 in human brain
Annals of Neurology, 1998Co-Authors: Sarah J Augood, Laurie J Ozelius, John B Penney, Ingrid K Friberg, Xandra O Breakefield, Anne B Young, David G StandaertAbstract:Early-onset Torsion Dystonia, an autosomal dominant disease associated with the DYT1 locus on 9q34, is the most frequent genetic form of Dystonia. Recent work has revealed that the causative mutation in most cases is deletion of a glutamate residue from the carboxy terminal of torsinA, a 332 amino acid protein encoded by the DYT1 gene. To gain insight into how deletion of a single amino acid can produce such a profound movement disorder, we have mapped the expression of the DYT1 gene in normal human postmortem brain. DYT1 mRNA is highly enriched in the dopamine neurons of the substantia nigra pars compacta. Intense expression was also found in the cerebellum and hippocampal subfields. The prominent expression of the DYT1 gene within the substantia nigra pars compacta, which provides dopaminergic innervation to the basal ganglia, implicates a disturbance of dopaminergic function in the pathophysiology of early-onset Torsion Dystonia.
Alberto Albanese - One of the best experts on this subject based on the ideXlab platform.
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Non-DYT1 Early-Onset Primary Torsion Dystonia: Comparison with DYT1 Phenotype and Review of the Literature
2015Co-Authors: Alfonso Fasano, Anna Rita Bentivoglio, Alberto AlbaneseAbstract:Abstract: To investigate the clinical features of early-onset primary Torsion Dystonia (EO-PTD), 57 consecutive genetically characterized patients with onset before 21 years were studied. Sex, ethnic origin, family history of Dystonia, age at onset, disease duration, site of Dystonia onset and distribution at latest examination, Dystonia progression, time to generalization, and motor disability were noted. The 14 patients (25%) with GAG deletion (904_906/907_909delGAG) in the DYT1 gene were compared with the remaining non-DYT1 patients. Cranial in-volvement was present in 49 % of non-DYT1 cases, but only 14 % of DYT1 cases; non-DYT1 patients were younger at time of generalization. DYT1 cases had features similar to sporadic non-DYT1 cases but differed markedly from familial non-DYT1 cases, the latter having later age at onset, less common limb onset, more frequent cervical involvement, and slower progression than DYT1 PTD. These findings indicate that non-DYT1 forms of EO-PTD differ clinically from those of DYT1 forms. Cranial involvement before 21 years of age is the strongest predictor of non-DYT1 status. Positive family history and cervical involvement are associated with less severe pro-gression in non-DYT1 forms. © 2006 Movement Disorde
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Advances in the genetics of primary Torsion Dystonia
F1000 biology reports, 2010Co-Authors: Enza Maria Valente, Alberto AlbaneseAbstract:Knowledge about the genetics of primary Torsion Dystonia (PTD) has been progressing at a very slow pace compared with other movement disorders. For many years, only one causative gene was known, DYT1/TOR1A, yet the recent identification of a second PTD causative gene (DYT6/THAP1), the detection of subclinical alterations caused by mutations in PTD genes in some healthy non-penetrant individuals, and functional studies on TOR1A and THAP1 protein products have significantly improved mutation detection, genotype-phenotype correlates, and our understanding of the cellular mechanisms underlying the development of Dystonia.
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non dyt1 early onset primary Torsion Dystonia comparison with dyt1 phenotype and review of the literature
Movement Disorders, 2006Co-Authors: Alfonso Fasano, Anna Rita Bentivoglio, Antonio E. Elia, Nardo Nardocci, Giovanna Zorzi, Alberto AlbaneseAbstract:To investigate the clinical features of early-onset primary Torsion Dystonia (EO-PTD), 57 consecutive genetically characterized patients with onset before 21 years were studied. Sex, ethnic origin, family history of Dystonia, age at onset, disease duration, site of Dystonia onset and distribution at latest examination, Dystonia progression, time to generalization, and motor disability were noted. The 14 patients (25%) with GAG deletion (904_906/907_909delGAG) in the DYT1 gene were compared with the remaining non-DYT1 patients. Cranial involvement was present in 49% of non-DYT1 cases, but only 14% of DYT1 cases; non-DYT1 patients were younger at time of generalization. DYT1 cases had features similar to sporadic non-DYT1 cases but differed markedly from familial non-DYT1 cases, the latter having later age at onset, less common limb onset, more frequent cervical involvement, and slower progression than DYT1 PTD. These findings indicate that non-DYT1 forms of EO-PTD differ clinically from those of DYT1 forms. Cranial involvement before 21 years of age is the strongest predictor of non-DYT1 status. Positive family history and cervical involvement are associated with less severe progression in non-DYT1 forms.
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Onset and progression of primary Torsion Dystonia in sporadic and familial cases
European journal of neurology, 2006Co-Authors: Antonio E. Elia, Anna Rita Bentivoglio, Tamara Ialongo, Graziella Filippini, Alfonso Fasano, Alberto AlbaneseAbstract:Four hundred and sixty records of patients with primary Torsion Dystonia (296 women and 164 men) were evaluated. The mean age at disease onset was 48.3 ± 17.7 years; 13 patients carried the DYT1 CAG deletion. The distribution of age at onset was represented by a bi-modal curve, with a nadir at 21 year separating early onset from late onset cases. In 15.9% of cases there was a positive family history of Dystonia. Cranial, cervical or lower limb onset was more common amongst women (M:F ratios were 1:2.7, 1:1.9, and 1:3); by contrast, onset in the upper limb was more common in men (M:F ratio 2.2:1). As expected, disease progression was more pronounced in cases with early onset; it was reckoned that onset at or above 32 years was associated with a negligible likelihood to progress to a generalized form. The mean age at onset of familial cases was 44.8 ± 11.2 years, significantly lower than the mean age at onset of sporadic cases (53.5 ± 13.4 years). Familial cases were characterized by more sites involved throughout disease course. Familial cases had a higher tendency to progress to a segmental or generalized form than sporadic cases.
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phenotypic characterization of dyt13 primary Torsion Dystonia
Movement Disorders, 2004Co-Authors: Anna Rita Bentivoglio, Enza Maria Valente, Tamara Ialongo, Fiorella M Contarino, Alberto AlbaneseAbstract:We describe the phenotype of DYT13 primary Torsion Dystonia (PTD) in a family first examined in 1994. A complete neurological evaluation was performed on all available family members: 8 individuals were definitely affected by Dystonia. The family was re-evaluated in March 2000: at that time, 3 more individuals had developed symptoms of Dystonia. Inheritance of PTD was autosomal dominant, with affected individuals spanning three consecutive generations and male-to-male transmission. Age at onset ranged from 5 to 43 years. Onset occurred either in the craniocervical region or in upper limbs. Progression was mild, and the disease course was benign in most affected individuals; generalization occurred only in 2 cases. We did not find anticipation of age at onset or of disease severity through generations. Most subjects presented with jerky, myoclonic-like dystonic movements of the neck or shoulders. DYT13-PTD is an autosomal dominant disease, with incomplete penetrance (58%). Clinical presentation and age at onset were more variable than in DYT1-PTD, and the neck was involved in most of those affected. Moreover, the individuals with generalised Dystonia were not severely disabled and were able to lead independent lives. To date, this is the only family with DYT13-PTD.
Susan B. Bressman - One of the best experts on this subject based on the ideXlab platform.
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Mutations in GNAL cause primary Torsion Dystonia
2016Co-Authors: Tania Fuchs, Rachel Saunders-pullman, Ikuo Masuho, Anthony E. Lang, Tsao-wei Liang, Richard Trosch, Marta San Luciano, Stewart Factor, Kirill A. Martemyanov, Susan B. BressmanAbstract:Dystonia is a movement disorder characterized by repetitive twisting muscle contractions and postures1,2. Its molecular pathophysiology is poorly understood, in part due to limited knowledge of the genetic basis of the disorder. Only three genes for primary Torsion Dystonia (PTD), TOR1A (DYT1)3, THAP1 (DYT6)4, and CIZ15 have been identified. Using exome sequencing in two PTD families we identified a novel causative gene, GNAL, with a nonsense p.S293X mutatio
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genetic and clinical features of primary Torsion Dystonia
Neurobiology of Disease, 2011Co-Authors: Laurie J Ozelius, Susan B. BressmanAbstract:Abstract Primary Torsion Dystonia (PTD) is defined as a syndrome in which Dystonia is the only clinical sign (except for tremor), and there is no evidence of neuronal degeneration or an acquired cause by history or routine laboratory assessment. Seven different loci have been recognized for PTD but only two of the genes have been identified. In this review we will describe the phenotypes associated with these loci and discuss the responsible gene. This article is part of a Special Issue entitled “Advances in Dystonia”.
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mutations in the thap1 gene are responsible for dyt6 primary Torsion Dystonia
Nature Genetics, 2009Co-Authors: Tania Fuchs, Susan B. Bressman, Michelle E Ehrlich, Sophie Gavarini, Deborah Raymond, Rachel Saunderspullman, Laurie J OzeliusAbstract:We report the discovery of a mutation in the THAP1 gene in three Amish-Mennonite families with mixed-onset primary Torsion Dystonia (also known as DYT6 Dystonia). Another mutation in a German family with primary Torsion Dystonia suggests that THAP1 mutations also cause Dystonia in other ancestry groups. We demonstrate that the missense mutation impairs DNA binding, suggesting that transcriptional dysregulation may contribute to the phenotype of DYT6 Dystonia.
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mutations in the thap1 gene are responsible for dyt6 primary Torsion Dystonia
Nature Genetics, 2009Co-Authors: Tania Fuchs, Susan B. Bressman, Michelle E Ehrlich, Sophie Gavarini, Deborah Raymond, Rachel Saunderspullman, Laurie J OzeliusAbstract:Laurie Ozelius and colleagues identify mutations in THAP1 in families with a mixed type (DYT6) of primary Torsion Dystonia, a movement disorder characterized by twisting movements and abnormal posture.
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The TOR1A (DYT1) Gene Family and Its Role in Early Onset Torsion Dystonia
Genomics, 1999Co-Authors: Laurie J Ozelius, Deborah De Leon, Susan B. Bressman, Curtis E. Page, Christine Klein, Jeffrey W. Hewett, Mari Mineta, Joanne Leung, Christo Shalish, Mitchell F. BrinAbstract:Most cases of early onset Torsion Dystonia are caused by a 3-bp deletion (GAG) in the coding region of the TOR1A gene (alias DYT1, DQ2), resulting in loss of a glutamic acid in the carboxy terminal of the encoded protein, torsin A. TOR1A and its homologue TOR1B (alias DQ1) are located adjacent to each other on hu- man chromosome 9q34. Both genes comprise five sim- ilar exons; each gene spans a 10-kb region. Mutational analysis of most of the coding region and splice junc- tions of TOR1A and TOR1B did not reveal additional mutations in typical early onset cases lacking the GAG deletion (N 5 17), in dystonic individuals with appar- ent homozygosity in the 9q34 chromosomal region (N 5 5), or in a representative Ashkenazic Jewish in- dividual with late onset Dystonia, who shared a com- mon haplotype in the 9q34 region with other late onset individuals in this ethnic group. A database search revealed a family of nine related genes (50 -70% simi- larity) and their orthologues in species including hu- man, mouse, rat, pig, zebrafish, fruitfly, and nematode. At least four of these genes occur in the human ge- nome. Proteins encoded by this gene family share functional domains with the AAA/HSP/Clp-ATPase su- perfamily of chaperone-like proteins, but appear to represent a distinct evolutionary branch. © 1999 Academic
Enza Maria Valente - One of the best experts on this subject based on the ideXlab platform.
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DYT13, a Novel Primary Torsion Dystonia Locus, Maps to Chromosome 1p36.13– 36.32 in an Italian Family with Cranial- Cervical or Upper Limb Onset
2015Co-Authors: Enza Maria ValenteAbstract:Primary Torsion Dystonia (PTD) is a clinically and genetically heterogeneous group of movement disorders, usually inherited in an autosomal dominant fashion with reduced penetrance. The DYT1 gene on chromosome 9q34 is respon-sible for most cases of early limb-onset PTD. Two other PTD loci have been mapped to date. The DYT6 locus on chromosome 8 is associated with a mixed phenotype, whereas the DYT7 locus on chromosome 18p is associated with adult onset focal cervical Dystonia. Several families have been described in which linkage to the known PTD loci have been excluded. We identified a large Italian PTD family with 11 definitely affected members. Phenotype was character-ized by prominent cranial-cervical and upper limb involvement and mild severity. A genome-wide search was performed in the family. Linkage analysis and haplotype construction allowed us to identify a novel PTD locus (DYT13) within a 22 cM interval on the short arm of chromosome 1, with a maximum lod score of 3.44 between the disease and marker D1S2667. Ann Neurol 2001;49:362–366 Dystonia is characterised by sustained involuntary mus-cle contractions causing twisting movements and ab-normal postures, without other neurological signs.1 Primary Torsion Dystonia (PTD) is a movement disor
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Advances in the genetics of primary Torsion Dystonia
F1000 biology reports, 2010Co-Authors: Enza Maria Valente, Alberto AlbaneseAbstract:Knowledge about the genetics of primary Torsion Dystonia (PTD) has been progressing at a very slow pace compared with other movement disorders. For many years, only one causative gene was known, DYT1/TOR1A, yet the recent identification of a second PTD causative gene (DYT6/THAP1), the detection of subclinical alterations caused by mutations in PTD genes in some healthy non-penetrant individuals, and functional studies on TOR1A and THAP1 protein products have significantly improved mutation detection, genotype-phenotype correlates, and our understanding of the cellular mechanisms underlying the development of Dystonia.
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atypical phenotypes and clinical variability in a large italian family with dyt1 primary Torsion Dystonia
Movement Disorders, 2006Co-Authors: Mattia Gambarin, Enza Maria Valente, Bruno Dallapiccola, Paolo Liberini, Giuseppe Barrano, Alberto Bonizzato, Alessandro Padovani, Giuseppe Moretto, Mirta Fiorio, Nicola SmaniaAbstract:The GAG deletion in the DYT1 gene usually causes a typical form of primary Torsion Dystonia (PTD) with early onset in a limb, rapid generalization, and sparing of cranial-cervical muscles, but atypical phenotypes have often been reported. Here, we describe a large DYT1 Italian family with phenotypically heterogeneous PTD that recapitulates all the atypical features associated with the DYT1 mutation, including late age at onset, focal or segmental phenotypes, onset or spreading of Dystonia to the cranial-cervical muscles. Of 38 healthy family members, 15 also carried the DYT1 mutation, with an estimated penetrance of 21%. A literature review of atypical familial cases of DYT1-PTD showed that late onset, cervical involvement, and limited progression of Dystonia are features frequently seen in DYT1 families. However, nearly all of these atypical patients fall within at least one of the clinical categories that best predict the DYT1 carrier status, namely, early onset, onset in a limb, and family history positive for early-onset Dystonia.
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phenotypic characterization of dyt13 primary Torsion Dystonia
Movement Disorders, 2004Co-Authors: Anna Rita Bentivoglio, Enza Maria Valente, Tamara Ialongo, Fiorella M Contarino, Alberto AlbaneseAbstract:We describe the phenotype of DYT13 primary Torsion Dystonia (PTD) in a family first examined in 1994. A complete neurological evaluation was performed on all available family members: 8 individuals were definitely affected by Dystonia. The family was re-evaluated in March 2000: at that time, 3 more individuals had developed symptoms of Dystonia. Inheritance of PTD was autosomal dominant, with affected individuals spanning three consecutive generations and male-to-male transmission. Age at onset ranged from 5 to 43 years. Onset occurred either in the craniocervical region or in upper limbs. Progression was mild, and the disease course was benign in most affected individuals; generalization occurred only in 2 cases. We did not find anticipation of age at onset or of disease severity through generations. Most subjects presented with jerky, myoclonic-like dystonic movements of the neck or shoulders. DYT13-PTD is an autosomal dominant disease, with incomplete penetrance (58%). Clinical presentation and age at onset were more variable than in DYT1-PTD, and the neck was involved in most of those affected. Moreover, the individuals with generalised Dystonia were not severely disabled and were able to lead independent lives. To date, this is the only family with DYT13-PTD.
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Opioid binding in DYT1 primary Torsion Dystonia: an 11C-diprenorphine PET study.
Movement disorders : official journal of the Movement Disorder Society, 2004Co-Authors: Alan L Whone, Alexander Hammers, Sarah Von Spiczak, Mark J. Edwards, Enza Maria Valente, Kailash P. Bhatia, David J. BrooksAbstract:The opioid transmitters enkephalin and dynorphin are known to regulate pallidal output and consequently cortical excitability. Indeed, abnormal basal ganglia opioid transmission has been reported in several involuntary movement disorders, including levodopa-induced dyskinesias in Parkinson's disease (PD), tardive dyskinesias/Dystonia, Huntington's disease, and Tourette's syndrome. Moreover, a previous C-11-diprenorphine PET study investigating levodopa-induced dyskinesias found reduced opioid receptor availability in PD with but not without dyskinesias. We wished to investigate if a similar alteration in basal ganglia opioid binding was present in DYT1 primary Torsion Dystonia (PTD). Regional cerebral C-11-diprenorphine binding was investigated in 7 manifesting carriers of the DYT1 gene and 15 age-matched normal controls using a region-of-interest (ROI) approach and statistical parametric mapping (SPM). No difference in regional mean C-11-diprenorphine binding was found between DYT1-PTD and controls, and no correlation between the severity of Dystonia and opioid binding was seen. We conclude that aberrant opioid transmission is unlikely to be present in DYT1-PTD and altered opioid transmission is not a common mechanism underlying all disorders of involuntary movement. (C) 2004 Movement Disorder Society.
Michael Hutchinson - One of the best experts on this subject based on the ideXlab platform.
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sporadic adult onset primary Torsion Dystonia is a genetic disorder by the temporal discrimination test
Brain, 2011Co-Authors: Okka Kimmich, David Bradley, Robert Whelan, Nicola Mulrooney, Richard B Reilly, Siobhan Hutchinson, Sean Oriordan, Michael HutchinsonAbstract:Adult-onset primary Torsion Dystonia is an autosomal dominant disorder with markedly reduced penetrance; patients with sporadic adult-onset primary Torsion Dystonia are much more prevalent than familial. The temporal discrimination threshold is the shortest time interval at which two stimuli are detected to be asynchronous and has been shown to be abnormal in adult-onset primary Torsion Dystonia. The aim was to determine the frequency of abnormal temporal discrimination thresholds in patients with sporadic adult-onset primary Torsion Dystonia and their first-degree relatives. We hypothesized that abnormal temporal discrimination thresholds in first relatives would be compatible with an autosomal dominant endophenotype. Temporal discrimination thresholds were examined in 61 control subjects (39 subjects 50 years of age), 32 patients with sporadic adult-onset primary Torsion Dystonia (cervical Dystonia n = 30, spasmodic dysphonia n = 1 and Meige's syndrome n = 1) and 73 unaffected first-degree relatives (36 siblings, 36 offspring and one parent) using visual and tactile stimuli. Z- scores were calculated for all subjects; a Z > 2.5 was considered abnormal. Abnormal temporal discrimination thresholds were found in 1/61 (2%) control subjects, 27/32 (84%) patients with adult-onset primary Torsion Dystonia and 32/73 (44%) unaffected relatives [siblings (20/36; 56%), offspring (11/36; 31%) and one parent]. When two or more relatives were tested in any one family, 22 of 24 families had at least one first-degree relative with an abnormal temporal discrimination threshold. The frequency of abnormal temporal discrimination thresholds in first-degree relatives of patients with sporadic adult-onset primary Torsion Dystonia is compatible with an autosomal dominant disorder and supports the hypothesis that apparently sporadic adult-onset primary Torsion Dystonia is genetic in origin. * Abbreviations : AOPTD : adult-onset primary Torsion Dystonia
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comparing endophenotypes in adult onset primary Torsion Dystonia
Movement Disorders, 2010Co-Authors: David Bradley, Robert Whelan, Richard B Reilly, Siobhan Hutchinson, Richard A Walsh, Fiona Molloy, John P Odwyer, Michael HutchinsonAbstract:Adult-onset primary Torsion Dystonia (AOPTD) has an autosomal dominant pattern of inheritance with markedly reduced penetrance; the genetic causes of most forms of AOPTD remain unknown. Endophenotypes, markers of sub-clinical gene carriage, may be of use detecting non-manifesting gene carriers in relatives of AOPTD patients. The aim of this study was to compare the utility of the spatial discrimination threshold (SDT) and temporal discrimination threshold (TDT) as potential endophenotypes in AOPTD. Data on other published candidate endophenotypes are also considered. Both SDT and TDT testing were performed in 24 AOPTD patients and 34 of their unaffected first degree relatives; results were compared with normal values from a control population. Of the 24 AOPTD patients 5 (21%) had abnormal SDTs and 20 (83%) had abnormal TDTs. Of the 34 first degree relatives 17 (50%) had abnormal SDTs and 14 (41%) had abnormal TDTs. Discordant results on SDT and TDT testing were found in 16 (67%) AOPTD patients and 21 (62%) first degree relatives. TDT testing has superior sensitivity compared to SDT testing in AOPTD patients; although false positive TDTs are recognised, the specificity of TDT testing in unaffected relatives is not determinable. The high level of discordance between the two tests probably relates methodological difficulties with SDT testing. The SDT is an unreliable AOPTD endophenotype; TDT testing fulfils criteria for a reliable endophenotype with a high sensitivity. © 2009 Movement Disorder Society
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temporal discrimination threshold vbm evidence for an endophenotype in adult onset primary Torsion Dystonia
Brain, 2009Co-Authors: David Bradley, Robert Whelan, Richard B Reilly, Siobhan Hutchinson, Richard A Walsh, Fiona Molloy, Michael HutchinsonAbstract:Familial adult-onset primary Torsion Dystonia is an autosomal dominant disorder with markedly reduced penetrance. Most adult-onset primary Torsion Dystonia patients are sporadic cases. Disordered sensory processing is found in adult-onset primary Torsion Dystonia patients; if also present in their unaffected relatives this abnormality may indicate non-manifesting gene carriage. Temporal discrimination thresholds (TDTs) are abnormal in adult-onset primary Torsion Dystonia, but their utility as a possible endophenotype has not been examined. We examined 35 adult-onset primary Torsion Dystonia patients (17 familial, 18 sporadic), 42 unaffected first-degree relatives of both familial and sporadic adult-onset primary Torsion Dystonia patients, 32 unaffected second-degree relatives of familial adult-onset primary Torsion Dystonia (AOPTD) patients and 43 control subjects. TDT was measured using visual and tactile stimuli. In 33 unaffected relatives, voxel-based morphometry was used to compare putaminal volumes between relatives with abnormal and normal TDTs. The mean TDT in 26 control subjects under 50 years of age was 22.85 ms (SD 8.00; 95% CI: 19.62-26.09 ms). The mean TDT in 17 control subjects over 50 years was 30.87 ms (SD 5.48; 95% CI: 28.05-33.69 ms). The upper limit of normal, defined as control mean + 2.5 SD, was 42.86 ms in the under 50 years group and 44.58 ms in the over 50 years group. Thirty out of thirty-five (86%) AOPTD patients had abnormal TDTs with similar frequencies of abnormalities in sporadic and familial patients. Twenty-two out of forty-two (52%) unaffected first-degree relatives had abnormal TDTs with similar frequencies in relatives of sporadic and familial AOPTD patients. Abnormal TDTs were found in 16/32 (50%) of second-degree relatives. Voxel-based morphometry analysis comparing 13 unaffected relatives with abnormal TDTs and 20 with normal TDTs demonstrated a bilateral increase in putaminal grey matter in unaffected relatives with abnormal TDTs. The prevalence of abnormal TDTs in sporadic and familial AOPTD patients and their first-degree relatives follows the rules for a useful endophenotype. A structural correlate of abnormal TDTs in unaffected first-degree relatives was demonstrated using voxel-based morphometry. Voxel-based morphometry findings indicate that putaminal enlargement in AOPTD is a primary phenomenon. TDTs may be an effective tool in AOPTD research with particular relevance to genetic studies of the disorder.
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age at onset as a factor in determining the phenotype of primary Torsion Dystonia
Neurology, 2004Co-Authors: Sean Oriordan, Deborah Raymond, Rachel Saunderspullman, Susan Bressman, Timothy Lynch, L Daly, Michael HutchinsonAbstract:Background: The genetic basis of most forms of primary Torsion Dystonia (PTD) is unknown; multiplex families are uncommon due to low penetrance. Intrafamilial, age-related, phenotypic heterogeneity was noted in 14 PTD families. The authors hypothesized that the clinical presentation of PTD was modulated by the age at onset of the Dystonia, irrespective of the genotype. Methods: This hypothesis was addressed in a study of 14 PTD families and a meta-analysis of 83 published series of PTD. Results: In 12 families with adult-onset PTD, the index cases presented with cervical Dystonia (CD); of the 22 affected relatives, 17 had CD, 2 had writer’s cramp, 1 had blepharospasm, and 2 had spasmodic dysphonia. In the two other PTD families, the probands and all 10 symptomatic relatives had limb-onset Dystonia at p = 0.0037). Analysis of 83 published series including 5,057 patients indicated significant differences in the mean age at onset of five phenotypes of PTD (mean age at onset; 95% CI): DYT1 Dystonia (11.3 years; 10.3 to 12.2), writer’s cramp (38.4; 36.9 to 39.9), CD (40.8; 40.3 to 41.3), spasmodic dysphonia (43.0; 42.2 to 43.9), and blepharospasm–oromandibular Dystonia (55.7; 55.1 to 56.4). Conclusion: Phenotypic variation in PTD presentation is due to the effect of age at onset modulating the expression of a genetic disorder with a caudal-to-rostral change in the site of onset.