Brain Advance Access originally published online on February 4, 2007
Brain 2007 130(3):828-835; doi:10.1093/brain/awl340
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The phenotypic spectrum of rapid-onset dystonia–parkinsonism (RDP) and mutations in the ATP1A3 gene
1Department of Neurology, Wake Forest University, Winston Salem, NC, 2Departments of Human Genetics, Neurology and Pediatrics, The University of Chicago, Chicago, IL, 3Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, 4Department of Neurology, Beth Israel Medical Center, New York, NY, 5Meritcare Neuroscience, Fargo, ND, 6Department of Neurology, University Hospital of Cleveland, Cleveland, OH, USA, 7Department of Neurology and Neurosurgery, Instituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo-SP, Brazil, 8Service de Neurologie Centre Hospitalier, Universitaire de Nice, Nice, France, 9Department of Neurology, University Medical Centre Utrecht, The Netherlands, 10Department of Neurology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands, 11National Center for Medical Genetics, Our Lady's Hospital, Crumlin, Dublin, Ireland, 12Pediatric Neurology, Our Lady's Hospital, Crumlin, Northern Ireland, UK, 13Hospital De Egas Moniz, Universidade Nova de Lisboa, Lisboa, Portugal, 14Department of Neurology, Medical University of Lübeck, Lübeck, Germany, 15Department of Neurology, University of Hamburg, Hamburg, Germany, 16Centro de Investigación Parkinson, Policlínica Gipuzkoa, San Sebastián, Spain and 17Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland
Corresponding author: Allison Brashear, MD, Department of Neurology, Wake Forest University, Meads Hall 3rd Floor, Medical Center Boulevard, Winston Salem, NC 27157, USA E-mail: abrashea{at}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.
Key Words: ATP1A3; dystonia; Na+/K+-ATPase; parkinsonism; rapid-onset dystonia–parkinsonism; RDP
Received July 26, 2006. Revised September 26, 2006. Accepted November 9, 2006.
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