title: The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A3 gene.
abstract: 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.
authors.affiliation: Department of Neurology, Wake Forest University, Winston Salem, NC 27157, USA. abrashea@wfubmc.edu
authors.forename: Allison
authors.initials: A
authors.lastname: Brashear
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: Patricia
authors.initials: P
authors.lastname: de Carvalho Aguiar
authors.forename: Michel
authors.initials: M
authors.lastname: Borg
authors.forename: C J M
authors.initials: CJ
authors.lastname: Frijns
authors.forename: Seema
authors.initials: S
authors.lastname: Gollamudi
authors.forename: Andrew
authors.initials: A
authors.lastname: Green
authors.forename: João
authors.initials: J
authors.lastname: Guimaraes
authors.forename: Bret C
authors.initials: BC
authors.lastname: Haake
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.forename: Gurutz
authors.initials: G
authors.lastname: Linazasoro
authors.forename: Alexander
authors.initials: A
authors.lastname: Münchau
authors.forename: Deborah
authors.initials: D
authors.lastname: Raymond
authors.forename: David
authors.initials: D
authors.lastname: Riley
authors.forename: Rachel
authors.initials: R
authors.lastname: Saunders-Pullman
authors.forename: Marina A J
authors.initials: MA
authors.lastname: Tijssen
authors.forename: David
authors.initials: D
authors.lastname: Webb
authors.forename: Jacek
authors.initials: J
authors.lastname: Zaremba
authors.forename: Susan B
authors.initials: SB
authors.lastname: Bressman
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Ozelius
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D004421:Dystonia / Q000150:complications / Q000235:genetics*; D005121:Extremities; D005192:Family Health; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D009069:Movement Disorders / Q000209:etiology / Q000235:genetics; D009154:Mutation / Q000235:genetics; D020734:Parkinsonian Disorders / Q000150:complications / Q000235:genetics*; D010641:Phenotype; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics*; D014202:Tremor / Q000209:etiology / Q000235:genetics
chemical_list: C488756:ATP1A3 protein, human; D000254:Sodium-Potassium-Exchanging ATPase