G2Cdb::Human Disease report

Disease id
D00000192
Name
Dystonia parkinsonism (rapid onset)
Nervous system disease
yes

Genes (3)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00001313 GRM5
glutamate receptor, metabotropic 5
Y (15254951) No mutation found (N) N
G00001323 ATP1A3
ATPase, Na+/K+ transporting, alpha 3 polypeptide
Y (17282997) Unknown (?) Y
G00001323 ATP1A3
ATPase, Na+/K+ transporting, alpha 3 polypeptide
Y (16161139) Microinsertion (MI) Y
G00001323 ATP1A3
ATPase, Na+/K+ transporting, alpha 3 polypeptide
Y (15897512) No mutation found (N) N
G00001323 ATP1A3
ATPase, Na+/K+ transporting, alpha 3 polypeptide
Y (15260953) Microinsertion (MI) Y
G00001324 ATP1A1
ATPase, Na+/K+ transporting, alpha 1 polypeptide
Y (15260953) Microinsertion (MI) Y
G00001324 ATP1A1
ATPase, Na+/K+ transporting, alpha 1 polypeptide
Y (15260948) Microinsertion (MI) Y

References

  • The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A3 gene.

    Brashear A, Dobyns WB, de Carvalho Aguiar P, Borg M, Frijns CJ, Gollamudi S, Green A, Guimaraes J, Haake BC, Klein C, Linazasoro G, Münchau A, Raymond D, Riley D, Saunders-Pullman R, Tijssen MA, Webb D, Zaremba J, Bressman SB and Ozelius LJ

    Department of Neurology, Wake Forest University, Winston Salem, NC 27157, USA. abrashea@wfubmc.edu

    Rapid-onset dystonia-parkinsonism (RDP) (also known as DYT12) is characterized by the abrupt onset of dystonia and parkinsonism and is caused by mutations in the ATP1A3 gene. We obtained clinical data and sequenced the ATP1A3 gene in 49 subjects from 21 families referred with 'possible' RDP, and performed a genotype-phenotype analysis. Of the new families referred for study only 3 of 14 families (21%) demonstrated a mutation in the ATP1A3 gene, but no new mutations were identified beyond our earlier report of 6. Adding these to previously reported families, we found mutations in 36 individuals from 10 families including 4 de novo mutations and excluded mutations in 13 individuals from 11 families. The phenotype in mutation positive patients included abrupt onset of dystonia with features of parkinsonism, a rostrocaudal gradient, and prominent bulbar findings. Other features found in some mutation carriers included common reports of triggers, minimal or no tremor at onset, occasional mild limb dystonia before the primary onset, lack of response to dopaminergic medications, rare abrupt worsening of symptoms later in life, stabilization of symptoms within a month and minimal improvement overall. In comparing ATP1A3 mutation positive and negative patients, we found that tremor at onset of symptoms, a reversed rostrocaudal gradient, and significant limb pain exclude a diagnosis of RDP. A positive family history is not required. Genetic testing for the ATP1A3 gene is recommended when abrupt onset, rostrocaudal gradient and prominent bulbar findings are present.

    Funded by: NINDS NIH HHS: K23 NS 047256, NS26636

    Brain : a journal of neurology 2007;130;Pt 3;828-35

  • Sporadic rapid-onset dystonia-parkinsonism presenting as Parkinson's disease.

    Kamphuis DJ, Koelman H, Lees AJ and Tijssen MA

    Department of Neurology, Reinier de Graaf Groep, Delft, The Netherlands. kamphuis@rdgg.nl

    We report on a 38-year-old patient with rapid-onset dystonia-parkinsonism (RDP) with a missense mutation in the Na/K-ATPase alpha3 subunit (ATP1A3). Asymmetrical parkinsonian symptoms evolved over a year. After a stable episode of another 2.5 years, overnight he developed oromandibular dystonia and more severe parkinsonian symptoms. We conclude that RDP should be considered as a rare cause of levodopa-unresponsive parkinsonism even if there is no family history and the classic presentation is lacking.

    Movement disorders : official journal of the Movement Disorder Society 2006;21;1;118-9

  • Genetic heterogeneity in rapid onset dystonia-parkinsonism: description of a new family.

    Kabakci K, Isbruch K, Schilling K, Hedrich K, de Carvalho Aguiar P, Ozelius LJ, Kramer PL, Schwarz MH and Klein C

    Department of Neurology, University of Lübeck, Lübeck, Germany.

    Rapid onset dystonia-parkinsonism (RDP) is a rare movement disorder with autosomal dominant inheritance, characterised by sudden onset of dystonic spasms and slowness of movement. To date, three families have been described that share linkage to the same location on chromosome 19q13, designated DYT12. Very recently, mutations in the ATP1A3 gene at the DYT12 locus have been demonstrated in seven unrelated patients, including the three previously linked families. A large RDP family is reported here, with eight definitely and one possibly affected members, that is not linked to the DYT12 region and has no mutation in the ATP1A3 gene. Predominant cranial-cervical involvement of dystonia occurred in this family, which has also been described in patients with idiopathic torsion dystonia linked to the DYT6 region on chromosome 8 and is a rare finding in DYT1 dystonia. Molecular genetic analysis also excluded linkage to the DYT6 locus and the GAG deletion in DYT1, suggesting at least one additional RDP gene.

    Journal of neurology, neurosurgery, and psychiatry 2005;76;6;860-2

  • Mutations in the Na+/K+ -ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism.

    de Carvalho Aguiar P, Sweadner KJ, Penniston JT, Zaremba J, Liu L, Caton M, Linazasoro G, Borg M, Tijssen MA, Bressman SB, Dobyns WB, Brashear A and Ozelius LJ

    Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

    Rapid-onset dystonia-parkinsonism (RDP, DYT12) is a distinctive autosomal-dominant movement disorder with variable expressivity and reduced penetrance characterized by abrupt onset of dystonia, usually accompanied by signs of parkinsonism. The sudden onset of symptoms over hours to a few weeks, often associated with physical or emotional stress, suggests a trigger initiating a nervous system insult resulting in permanent neurologic disability. We report the finding of six missense mutations in the gene for the Na+/K+ -ATPase alpha3 subunit (ATP1A3) in seven unrelated families with RDP. Functional studies and structural analysis of the protein suggest that these mutations impair enzyme activity or stability. This finding implicates the Na+/K+ pump, a crucial protein responsible for the electrochemical gradient across the cell membrane, in dystonia and parkinsonism.

    Funded by: NHLBI NIH HHS: HL36251; NIA NIH HHS: AG10133; NIGMS NIH HHS: GM28835; NINDS NIH HHS: NS26636

    Neuron 2004;43;2;169-75

  • Paying the price at the pump: dystonia from mutations in a Na+/K+ -ATPase.

    Cannon SC

    Department of Neurology, UT Southwestern Medical Center at Dallas, TX 75390, USA.

    Dystonia is a disorder of involuntary sustained muscle contraction, which usually affects a focal region of the body but may be generalized and results in twisting contorted movements or abnormal postures. Several clinical subtypes of dystonia have been delineated and many have a strong inherited basis. In this issue of Neuron, de Carvalho Aguiar and colleagues report the identification of missense mutations in the gene for the Na+/K+ -ATPase alpha3 subunit (ATP1A3) as a cause of rapid-onset dystonia-parkinsonism (RDP, DYT12).

    Neuron 2004;43;2;153-4

  • Refined linkage to the RDP/DYT12 locus on 19q13.2 and evaluation of GRIK5 as a candidate gene.

    Kamm C, Leung J, Joseph S, Dobyns WB, Brashear A, Breakefield XO and Ozelius LJ

    Molecular Neurogenetics Unit, Departments of Neurology and Radiology and Neuroscience Program, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    By examining two previously described families with rapid-onset dystonia parkinsonism, we have identified a key recombination event that places the disease locus (DYT12) into a 5.9 cM interval flanked by markers D19S224 and D19S900. Evaluation of a positional candidate gene, the glutamate receptor subunit GRIK5, revealed no mutations.

    Funded by: NINDS NIH HHS: NS38372

    Movement disorders : official journal of the Movement Disorder Society 2004;19;7;845-847

Literature (6)

Pubmed - human_disease

  • Sporadic rapid-onset dystonia-parkinsonism presenting as Parkinson's disease.

    Kamphuis DJ, Koelman H, Lees AJ and Tijssen MA

    Department of Neurology, Reinier de Graaf Groep, Delft, The Netherlands. kamphuis@rdgg.nl

    We report on a 38-year-old patient with rapid-onset dystonia-parkinsonism (RDP) with a missense mutation in the Na/K-ATPase alpha3 subunit (ATP1A3). Asymmetrical parkinsonian symptoms evolved over a year. After a stable episode of another 2.5 years, overnight he developed oromandibular dystonia and more severe parkinsonian symptoms. We conclude that RDP should be considered as a rare cause of levodopa-unresponsive parkinsonism even if there is no family history and the classic presentation is lacking.

    Movement disorders : official journal of the Movement Disorder Society 2006;21;1;118-9

  • Genetic heterogeneity in rapid onset dystonia-parkinsonism: description of a new family.

    Kabakci K, Isbruch K, Schilling K, Hedrich K, de Carvalho Aguiar P, Ozelius LJ, Kramer PL, Schwarz MH and Klein C

    Department of Neurology, University of Lübeck, Lübeck, Germany.

    Rapid onset dystonia-parkinsonism (RDP) is a rare movement disorder with autosomal dominant inheritance, characterised by sudden onset of dystonic spasms and slowness of movement. To date, three families have been described that share linkage to the same location on chromosome 19q13, designated DYT12. Very recently, mutations in the ATP1A3 gene at the DYT12 locus have been demonstrated in seven unrelated patients, including the three previously linked families. A large RDP family is reported here, with eight definitely and one possibly affected members, that is not linked to the DYT12 region and has no mutation in the ATP1A3 gene. Predominant cranial-cervical involvement of dystonia occurred in this family, which has also been described in patients with idiopathic torsion dystonia linked to the DYT6 region on chromosome 8 and is a rare finding in DYT1 dystonia. Molecular genetic analysis also excluded linkage to the DYT6 locus and the GAG deletion in DYT1, suggesting at least one additional RDP gene.

    Journal of neurology, neurosurgery, and psychiatry 2005;76;6;860-2

  • Paying the price at the pump: dystonia from mutations in a Na+/K+ -ATPase.

    Cannon SC

    Department of Neurology, UT Southwestern Medical Center at Dallas, TX 75390, USA.

    Dystonia is a disorder of involuntary sustained muscle contraction, which usually affects a focal region of the body but may be generalized and results in twisting contorted movements or abnormal postures. Several clinical subtypes of dystonia have been delineated and many have a strong inherited basis. In this issue of Neuron, de Carvalho Aguiar and colleagues report the identification of missense mutations in the gene for the Na+/K+ -ATPase alpha3 subunit (ATP1A3) as a cause of rapid-onset dystonia-parkinsonism (RDP, DYT12).

    Neuron 2004;43;2;153-4

Pubmed - other

  • The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A3 gene.

    Brashear A, Dobyns WB, de Carvalho Aguiar P, Borg M, Frijns CJ, Gollamudi S, Green A, Guimaraes J, Haake BC, Klein C, Linazasoro G, Münchau A, Raymond D, Riley D, Saunders-Pullman R, Tijssen MA, Webb D, Zaremba J, Bressman SB and Ozelius LJ

    Department of Neurology, Wake Forest University, Winston Salem, NC 27157, USA. abrashea@wfubmc.edu

    Rapid-onset dystonia-parkinsonism (RDP) (also known as DYT12) is characterized by the abrupt onset of dystonia and parkinsonism and is caused by mutations in the ATP1A3 gene. We obtained clinical data and sequenced the ATP1A3 gene in 49 subjects from 21 families referred with 'possible' RDP, and performed a genotype-phenotype analysis. Of the new families referred for study only 3 of 14 families (21%) demonstrated a mutation in the ATP1A3 gene, but no new mutations were identified beyond our earlier report of 6. Adding these to previously reported families, we found mutations in 36 individuals from 10 families including 4 de novo mutations and excluded mutations in 13 individuals from 11 families. The phenotype in mutation positive patients included abrupt onset of dystonia with features of parkinsonism, a rostrocaudal gradient, and prominent bulbar findings. Other features found in some mutation carriers included common reports of triggers, minimal or no tremor at onset, occasional mild limb dystonia before the primary onset, lack of response to dopaminergic medications, rare abrupt worsening of symptoms later in life, stabilization of symptoms within a month and minimal improvement overall. In comparing ATP1A3 mutation positive and negative patients, we found that tremor at onset of symptoms, a reversed rostrocaudal gradient, and significant limb pain exclude a diagnosis of RDP. A positive family history is not required. Genetic testing for the ATP1A3 gene is recommended when abrupt onset, rostrocaudal gradient and prominent bulbar findings are present.

    Funded by: NINDS NIH HHS: K23 NS 047256, NS26636

    Brain : a journal of neurology 2007;130;Pt 3;828-35

  • Mutations in the Na+/K+ -ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism.

    de Carvalho Aguiar P, Sweadner KJ, Penniston JT, Zaremba J, Liu L, Caton M, Linazasoro G, Borg M, Tijssen MA, Bressman SB, Dobyns WB, Brashear A and Ozelius LJ

    Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

    Rapid-onset dystonia-parkinsonism (RDP, DYT12) is a distinctive autosomal-dominant movement disorder with variable expressivity and reduced penetrance characterized by abrupt onset of dystonia, usually accompanied by signs of parkinsonism. The sudden onset of symptoms over hours to a few weeks, often associated with physical or emotional stress, suggests a trigger initiating a nervous system insult resulting in permanent neurologic disability. We report the finding of six missense mutations in the gene for the Na+/K+ -ATPase alpha3 subunit (ATP1A3) in seven unrelated families with RDP. Functional studies and structural analysis of the protein suggest that these mutations impair enzyme activity or stability. This finding implicates the Na+/K+ pump, a crucial protein responsible for the electrochemical gradient across the cell membrane, in dystonia and parkinsonism.

    Funded by: NHLBI NIH HHS: HL36251; NIA NIH HHS: AG10133; NIGMS NIH HHS: GM28835; NINDS NIH HHS: NS26636

    Neuron 2004;43;2;169-75

  • Refined linkage to the RDP/DYT12 locus on 19q13.2 and evaluation of GRIK5 as a candidate gene.

    Kamm C, Leung J, Joseph S, Dobyns WB, Brashear A, Breakefield XO and Ozelius LJ

    Molecular Neurogenetics Unit, Departments of Neurology and Radiology and Neuroscience Program, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    By examining two previously described families with rapid-onset dystonia parkinsonism, we have identified a key recombination event that places the disease locus (DYT12) into a 5.9 cM interval flanked by markers D19S224 and D19S900. Evaluation of a positional candidate gene, the glutamate receptor subunit GRIK5, revealed no mutations.

    Funded by: NINDS NIH HHS: NS38372

    Movement disorders : official journal of the Movement Disorder Society 2004;19;7;845-847

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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