dystonia musculorum deformans

Summary

Summary: A condition characterized by focal DYSTONIA that progresses to involuntary spasmodic contractions of the muscles of the legs, trunk, arms, and face. The hands are often spared, however, sustained axial and limb contractions may lead to a state where the body is grossly contorted. Onset is usually in the first or second decade. Familial patterns of inheritance, primarily autosomal dominant with incomplete penetrance, have been identified. (Adams et al., Principles of Neurology, 6th ed, p1078)

Top Publications

  1. Leung J, Klein C, Friedman J, Vieregge P, Jacobs H, Doheny D, et al. Novel mutation in the TOR1A (DYT1) gene in atypical early onset dystonia and polymorphisms in dystonia and early onset parkinsonism. Neurogenetics. 2001;3:133-43 pubmed
    ..This 18-bp deletion is the first additional mutation, beyond the GAG-deletion (Glu302/303del), to be found in the TOR1A gene, and is associated with a distinct type of early onset dystonia...
  2. Duchen L, Strich S, Falconer D. CLINICAL AND PATHOLOGICAL STUDIES OF AN HEREDITARY NEUROPATHY IN MICE (DYSTONIA MUSCULORUM). Brain. 1964;87:367-78 pubmed
  3. Yokoi F, Dang M, Mitsui S, Li J, Li Y. Motor deficits and hyperactivity in cerebral cortex-specific Dyt1 conditional knockout mice. J Biochem. 2008;143:39-47 pubmed
    ..Developing drugs targeting the cerebral cortex may produce novel medical treatments for DYT1 dystonia patients...
  4. Goodchild R, Kim C, Dauer W. Loss of the dystonia-associated protein torsinA selectively disrupts the neuronal nuclear envelope. Neuron. 2005;48:923-32 pubmed
    ..These observations demonstrate that neurons have a unique requirement for nuclear envelope localized torsinA function and suggest that loss of this activity is a key molecular event in the pathogenesis of DYT1 dystonia...
  5. Ozelius L, Bressman S. Genetic and clinical features of primary torsion dystonia. Neurobiol Dis. 2011;42:127-35 pubmed publisher
    ..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"...
  6. Naismith T, Dalal S, Hanson P. Interaction of torsinA with its major binding partners is impaired by the dystonia-associated DeltaGAG deletion. J Biol Chem. 2009;284:27866-74 pubmed publisher
    ..Impaired interaction of torsinA with LULL1 and/or LAP1 may thus contribute to the development of dystonia...
  7. Burdette A, Churchill P, Caldwell G, Caldwell K. The early-onset torsion dystonia-associated protein, torsinA, displays molecular chaperone activity in vitro. Cell Stress Chaperones. 2010;15:605-17 pubmed publisher
  8. Augood S, Hollingsworth Z, Albers D, Yang L, Leung J, Muller B, et al. Dopamine transmission in DYT1 dystonia: a biochemical and autoradiographical study. Neurology. 2002;59:445-8 pubmed
  9. Brown A, Bernier G, Mathieu M, Rossant J, Kothary R. The mouse dystonia musculorum gene is a neural isoform of bullous pemphigoid antigen 1. Nat Genet. 1995;10:301-6 pubmed
    ..We also demonstrate abnormal dystonin transcripts in a second dt mutant, dt24J. We conclude that mutations in the dystonin gene are the primary genetic lesion in dt mice...

More Information

Publications62

  1. Khan N, Wood N, Bhatia K. Autosomal recessive, DYT2-like primary torsion dystonia: a new family. Neurology. 2003;61:1801-3 pubmed
    ..There were no other abnormal signs, apart from dystonia and jerky tremor over a 12-year follow-up. All investigations for other causes of primary and secondary dystonia had normal results...
  2. Ahmad F, Davis M, Waddy H, Oley C, Marsden C, Harding A. Evidence for locus heterogeneity in autosomal dominant torsion dystonia. Genomics. 1993;15:9-12 pubmed
    ..This study provides evidence for locus heterogeneity in autosomal dominant ITD and also gives additional information on gene order in chromosome 9q...
  3. Ozelius L, Hewett J, Page C, Bressman S, Kramer P, Shalish C, et al. The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nat Genet. 1997;17:40-8 pubmed
    ..This protein has homologues in nematode, rat, mouse and humans, with some resemblance to the family of heat-shock proteins and Clp proteases...
  4. Almasy L, Bressman S, Raymond D, Kramer P, Greene P, Heiman G, et al. Idiopathic torsion dystonia linked to chromosome 8 in two Mennonite families. Ann Neurol. 1997;42:670-3 pubmed
    ..An identical haplotype spanning 40-cM segregates with ITD in these families, suggesting a shared mutation from the recent past...
  5. Eidelberg D, Moeller J, Antonini A, Kazumata K, Nakamura T, Dhawan V, et al. Functional brain networks in DYT1 dystonia. Ann Neurol. 1998;44:303-12 pubmed
    ..These findings indicate the penetrance of the DYT1 gene is considerably greater than previously assumed. ITD is mediated through the interaction of functional brain networks relating separately to gene status and to abnormal movement...
  6. Hjermind L, Werdelin L, Sørensen S. Inherited and de novo mutations in sporadic cases of DYT1-dystonia. Eur J Hum Genet. 2002;10:213-6 pubmed
    ..None of the probands in our study with other types of dystonia had the GAG-deletion as reported in other studies. The difficulties in genetic counselling concerning the heterogeneity of dystonia exemplified by DYT1-dystonia are outlined...
  7. Tseng K, Chau Y, Yang M, Lu K, Chien C. Abnormal cellular translocation of alpha-internexin in spinal motor neurons of Dystonia musculorum mice. J Comp Neurol. 2008;507:1053-64 pubmed
  8. Rostasy K, Augood S, Hewett J, Leung J, Sasaki H, Ozelius L, et al. TorsinA protein and neuropathology in early onset generalized dystonia with GAG deletion. Neurobiol Dis. 2003;12:11-24 pubmed
  9. Lalonde R, Marchetti N, Strazielle C. Primary neurologic screening and motor coordination of Dstdt-J mutant mice (dystonia musculorum) with spinocerebellar atrophy. Physiol Behav. 2005;86:46-51 pubmed
    ..The neurologic screening battery delineated the functional integrity of some sensorimotor pathways in a spinocerebellar mutant whose severe phenotype prevents a more elaborate evaluation...
  10. Bragg D, Camp S, Kaufman C, Wilbur J, Boston H, Schuback D, et al. Perinuclear biogenesis of mutant torsin-A inclusions in cultured cells infected with tetracycline-regulated herpes simplex virus type 1 amplicon vectors. Neuroscience. 2004;125:651-61 pubmed
    ..These nuclear-associated membrane structures enriched in mutant torsinA may therefore be of greater relevance to understanding how the dystonia-related mutation compromises cellular physiology...
  11. Naismith T, Heuser J, Breakefield X, Hanson P. TorsinA in the nuclear envelope. Proc Natl Acad Sci U S A. 2004;101:7612-7 pubmed
    ..These results suggest that changes in interactions involving torsinA in the NE could be important for the pathogenesis of dystonia and point to torsinA and related proteins as a class of ATPases that may operate in the NE...
  12. Bernier G, Kothary R. Prenatal onset of axonopathy in Dystonia musculorum mice. Dev Genet. 1998;22:160-8 pubmed
    ..They also suggest that axonal transport defects, through microtubule network perturbation, may be the primary mechanism of neurodegeneration in dt mice...
  13. Hewett J, Nery F, Niland B, Ge P, Tan P, Hadwiger P, et al. siRNA knock-down of mutant torsinA restores processing through secretory pathway in DYT1 dystonia cells. Hum Mol Genet. 2008;17:1436-45 pubmed publisher
    ..The ability of allele-specific siRNA for torsinADeltaE to normalize secretory function in DYT1 patient cells supports its potential role as a therapeutic agent in early onset torsion dystonia...
  14. Playford E, Fletcher N, Sawle G, Marsden C, Brooks D. Striatal [18F]dopa uptake in familial idiopathic dystonia. Brain. 1993;116 ( Pt 5):1191-9 pubmed
    ..In addition, we studied three presumed carriers of the ITD gene. These subjects all had normal striatal [18F]dopa influx constants suggesting that [18F]dopa PET is unsuitable as a screening tool for ITD...
  15. Blanchard A, Ea V, Roubertie A, Martin M, Coquart C, Claustres M, et al. DYT6 dystonia: review of the literature and creation of the UMD Locus-Specific Database (LSDB) for mutations in the THAP1 gene. Hum Mutat. 2011;32:1213-24 pubmed publisher
  16. Boudreau Larivière C, Kothary R. Differentiation potential of primary myogenic cells derived from skeletal muscle of dystonia musculorum mice. Differentiation. 2002;70:247-56 pubmed
    ..Together, these findings demonstrate that the early phases of myogenic differentiation occur independently of Bpag1...
  17. Dang M, Yokoi F, Cheetham C, Lu J, Vo V, Lovinger D, et al. An anticholinergic reverses motor control and corticostriatal LTD deficits in Dyt1 ?GAG knock-in mice. Behav Brain Res. 2012;226:465-72 pubmed publisher
  18. Leube B, Rudnicki D, Ratzlaff T, Kessler K, Benecke R, Auburger G. Idiopathic torsion dystonia: assignment of a gene to chromosome 18p in a German family with adult onset, autosomal dominant inheritance and purely focal distribution. Hum Mol Genet. 1996;5:1673-7 pubmed
    ..17 to the region telomeric of D18S1153 on chromosome 18p...
  19. McNaught K, Kapustin A, Jackson T, Jengelley T, Jnobaptiste R, Shashidharan P, et al. Brainstem pathology in DYT1 primary torsion dystonia. Ann Neurol. 2004;56:540-7 pubmed
    ..and cuneiform nuclei, and related brainstem brainstem structures, in mediating motor activity and controlling muscle tone suggests that alterations in these structures could underlie the pathophysiology of DYT1 dystonia [corrected]..
  20. Torres G, Sweeney A, Beaulieu J, Shashidharan P, Caron M. Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated DeltaE-torsinA mutant. Proc Natl Acad Sci U S A. 2004;101:15650-5 pubmed
    ..These properties may contribute to the autosomal dominant nature of the condition...
  21. Cao S, Hewett J, Yokoi F, Lu J, Buckley A, Burdette A, et al. Chemical enhancement of torsinA function in cell and animal models of torsion dystonia. Dis Model Mech. 2010;3:386-96 pubmed publisher
  22. Pool M, Boudreau Larivière C, Bernier G, Young K, Kothary R. Genetic alterations at the Bpag1 locus in dt mice and their impact on transcript expression. Mamm Genome. 2005;16:909-17 pubmed
    ..Such alterations likely result in reduced or absent dystonin/Bpag1 protein levels. Thus, distinct genetic defects lead to a common outcome of reduced transcript expression causing the same phenotype in multiple dt alleles...
  23. Granata A, Watson R, Collinson L, Schiavo G, Warner T. The dystonia-associated protein torsinA modulates synaptic vesicle recycling. J Biol Chem. 2008;283:7568-79 pubmed publisher
    ..This may affect neuronal uptake of neurotransmitters, such as dopamine, playing a role in the development of dystonic movements...
  24. De Repentigny Y, Ferrier A, Ryan S, Sato T, Kothary R. Motor unit abnormalities in Dystonia musculorum mice. PLoS ONE. 2011;6:e21093 pubmed publisher
    ..This study reveals neuromuscular defects that likely contribute to the dt(27J) pathology and identifies a critical role for dystonin outside of sensory neurons...
  25. Asanuma K, Ma Y, Okulski J, Dhawan V, Chaly T, Carbon M, et al. Decreased striatal D2 receptor binding in non-manifesting carriers of the DYT1 dystonia mutation. Neurology. 2005;64:347-9 pubmed
    ..D2 receptor binding was reduced by approximately 15% in caudate and putamen (p < 0.005). These results suggest that striatal D2 binding reductions are a trait feature of the DYT1 genotype...
  26. Rechitsky S, Verlinsky O, Kuliev A, Ozen S, Laziuk K, Beck R, et al. Preimplantation genetic diagnosis for early-onset torsion dystonia. Reprod Biomed Online. 2004;8:224-8 pubmed
    ..This is the first PGD for primary torsion dystonia, providing an alternative for those at-risk couples who cannot accept prenatal diagnosis and termination of pregnancy as an option for avoiding early onset torsion dystonia...
  27. Goodchild R, Dauer W. Mislocalization to the nuclear envelope: an effect of the dystonia-causing torsinA mutation. Proc Natl Acad Sci U S A. 2004;101:847-52 pubmed
    ..DYT1 dystonia appears to be a previously uncharacterized NE disease and the first, to our knowledge, to selectively affect CNS function...
  28. Breakefield X, Kamm C, Hanson P. TorsinA: movement at many levels. Neuron. 2001;31:9-12 pubmed
    ..Torsins are members of the AAA(+) superfamily of ATPases and are present in all multicellular organisms. Initial studies suggest that torsinA is an ER protein involved in chaperone functions and/or membrane movement...
  29. Eyer J, Cleveland D, Wong P, Peterson A. Pathogenesis of two axonopathies does not require axonal neurofilaments. Nature. 1998;391:584-7 pubmed
    ..By specifically excluding a necessary role for axonal neurofilaments, our observations redefine the components of the pathogenic pathway leading to axon disruption in these two degenerative diseases...
  30. Kakazu Y, Koh J, Iwabuchi S, Gonzalez Alegre P, Harata N. Miniature release events of glutamate from hippocampal neurons are influenced by the dystonia-associated protein torsinA. Synapse. 2012;66:807-22 pubmed publisher
    ..Moreover, qualitative differences between heterozygous and homozygous neurons with respect to certain synaptic properties indicate that the abnormalities observed in homozygotes may reflect more than a simple gene dosage effect...
  31. Janota I. Ultrastructural studies of an hereditary sensory neuropathy in mice (dystonia musculorum). Brain. 1972;95:529-36 pubmed
  32. Hewett J, Zeng J, Niland B, Bragg D, Breakefield X. Dystonia-causing mutant torsinA inhibits cell adhesion and neurite extension through interference with cytoskeletal dynamics. Neurobiol Dis. 2006;22:98-111 pubmed
  33. Lalonde R, Joyal C, Cote C. Swimming activity in dystonia musculorum mutant mice. Physiol Behav. 1993;54:119-20 pubmed
    ..It is not excluded that a measure tracing their path may find a mild deviation from the goal...
  34. Pham P, Frei K, Woo W, Truong D. Molecular defects of the dystonia-causing torsinA mutation. Neuroreport. 2006;17:1725-8 pubmed
    ..We also demonstrated that purified torsinA protein is an ATPase, which forms a multimeric complex in vitro and that the DeltaGAG mutation disrupts the formation of multimeric complex and decreases torsinA's ATPase activity...
  35. Balcioglu A, Kim M, Sharma N, Cha J, Breakefield X, Standaert D. Dopamine release is impaired in a mouse model of DYT1 dystonia. J Neurochem. 2007;102:783-8 pubmed
    ..The defect in DA release as observed may contribute to the abnormalities in motor learning as previously documented in this transgenic mouse model, and may contribute to the clinical symptoms of the human disorder...
  36. Brown A, Lemieux N, Rossant J, Kothary R. Human homolog of a mouse sequence from the dystonia musculorum locus is on chromosome 6p12. Mamm Genome. 1994;5:434-7 pubmed
    ..Mapping the human homolog of the mouse dt gene enables us to initiate linkage studies to identify neurodegenerative disorders that may be caused by mutations in this gene...
  37. Duchen L. Dystonia musculorum--an inherited disease of the nervous system in the mouse. Adv Neurol. 1976;14:353-65 pubmed
  38. Zhao C, Brown R, Chase A, Eisele M, Schlieker C. Regulation of Torsin ATPases by LAP1 and LULL1. Proc Natl Acad Sci U S A. 2013;110:E1545-54 pubmed publisher
    ..The dystonia-causing mutant of TorsinA is defective in this activation mechanism, suggesting a loss-of-function mechanism for this congenital disorder...
  39. Elia A, Filippini G, Bentivoglio A, Fasano A, Ialongo T, Albanese A. Onset and progression of primary torsion dystonia in sporadic and familial cases. Eur J Neurol. 2006;13:1083-8 pubmed
    ..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...
  40. Tojo K, Sekijima Y, Suzuki T, Suzuki N, Tomita Y, Yoshida K, et al. Dystonia, mental deterioration, and dyschromatosis symmetrica hereditaria in a family with ADAR1 mutation. Mov Disord. 2006;21:1510-3 pubmed
    ..Further investigation of ADAR1 mutations will shed light on the genotype-phenotype correlation in DSH...
  41. Tamiya G. [Genetic dissection of dystonia]. No To Shinkei. 2005;57:935-44 pubmed
  42. Carbon M, Kingsley P, Tang C, Bressman S, Eidelberg D. Microstructural white matter changes in primary torsion dystonia. Mov Disord. 2008;23:234-9 pubmed
    ..Our data thus support the possibility of a disturbance in cerebello-thalamo-cortical pathways as a cause of the clinical manifestations of PTD...
  43. Nery F, Zeng J, Niland B, Hewett J, Farley J, Irimia D, et al. TorsinA binds the KASH domain of nesprins and participates in linkage between nuclear envelope and cytoskeleton. J Cell Sci. 2008;121:3476-86 pubmed publisher
  44. Brancati F, Defazio G, Caputo V, Valente E, Pizzuti A, Livrea P, et al. Novel Italian family supports clinical and genetic heterogeneity of primary adult-onset torsion dystonia. Mov Disord. 2002;17:392-7 pubmed
    ..These findings support genetic heterogeneity of PTD and indicate that a novel unassigned gene is responsible for focal dystonia in this family...
  45. Ryan S, Ferrier A, Sato T, O Meara R, De Repentigny Y, Jiang S, et al. Neuronal dystonin isoform 2 is a mediator of endoplasmic reticulum structure and function. Mol Biol Cell. 2012;23:553-66 pubmed publisher
    ..This study provides insight into the mechanism of dt neuropathology and proposes a role for dystonin-a2 as a mediator of normal ER structure and function...
  46. Yokochi F. [Hereditary dystonia -- phenotype of DYT1]. Rinsho Shinkeigaku. 2012;52:1071-3 pubmed
    ..The penetration of DYT1 gene in Japan is low and the symptoms in the early-onset patients are variable...
  47. Pisani A, Martella G, Tscherter A, Bonsi P, Sharma N, Bernardi G, et al. Altered responses to dopaminergic D2 receptor activation and N-type calcium currents in striatal cholinergic interneurons in a mouse model of DYT1 dystonia. Neurobiol Dis. 2006;24:318-25 pubmed
    ..Our data support the existence of an imbalance between striatal dopaminergic and cholinergic signaling in DYT1 dystonia...
  48. Bradley D, Whelan R, Kimmich O, O Riordan S, Mulrooney N, Brady P, et al. Temporal discrimination thresholds in adult-onset primary torsion dystonia: an analysis by task type and by dystonia phenotype. J Neurol. 2012;259:77-82 pubmed publisher
    ..Temporal discrimination threshold results were comparable across common adult-onset primary torsion dystonia phenotypes, with lower sensitivity in the musicians...
  49. Ikeuchi T, Shimohata T, Nakano R, Koide R, Takano H, Tsuji S. A case of primary torsion dystonia in Japan with the 3-bp (GAG) deletion in the DYT1 gene with a unique clinical presentation. Neurogenetics. 1999;2:189-90 pubmed
  50. Carbon M, Trost M, Ghilardi M, Eidelberg D. Abnormal brain networks in primary torsion dystonia. Adv Neurol. 2004;94:155-61 pubmed
  51. Kuehler A, Henrich G, Schroeder U, Conrad B, Herschbach P, Ceballos Baumann A. A novel quality of life instrument for deep brain stimulation in movement disorders. J Neurol Neurosurg Psychiatry. 2003;74:1023-30 pubmed
    ..To develop a short instrument to examine quality of life (QoL) which specifically addresses patients with movement disorders treated by deep brain stimulation (DBS)...
  52. Hayashi M, Koide H. Idiopathic torsion dystonia and writing tremor within a family. Brain Dev. 1997;19:556-8 pubmed
    ..The simultaneous occurrence of dystonia and writing tremor within one family, and the presence of the paradoxical contraction in both cases suggest that a certain type of dystonia and writing tremor may be pathogenetically linked...
  53. Risch N, Bressman S, deLeon D, Brin M, Burke R, Greene P, et al. Segregation analysis of idiopathic torsion dystonia in Ashkenazi Jews suggests autosomal dominant inheritance. Am J Hum Genet. 1990;46:533-8 pubmed
    ..The high incidence and dominant inheritance of early-onset idiopathic torsion dystonia in Ashkenazi Jews suggests genetic homogeneity within this population, making it especially useful for linkage studies of this disorder...