The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A3 gene.
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.
Brashear
Allison
A
Department of Neurology, Wake Forest University, Winston Salem, NC 27157, USA. abrashea@wfubmc.edu
Dobyns
William B
WB
de Carvalho Aguiar
Patricia
P
Borg
Michel
M
Frijns
C J M
CJ
Gollamudi
Seema
S
Green
Andrew
A
Guimaraes
João
J
Haake
Bret C
BC
Klein
Christine
C
Linazasoro
Gurutz
G
Münchau
Alexander
A
Raymond
Deborah
D
Riley
David
D
Saunders-Pullman
Rachel
R
Tijssen
Marina A J
MA
Webb
David
D
Zaremba
Jacek
J
Bressman
Susan B
SB
Ozelius
Laurie J
LJ
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
C488756:ATP1A3 protein, human; D000254:Sodium-Potassium-Exchanging ATPase