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.

Recent Advances in the Molecular Pathogenesis of Dystonia-Plus Syndromes and Heredodegenerative Dystonias

“…There are many similarities between DYT16 and DYT12 , such as prominent bulbar signs and rostro-caudal gradient; however, DYT12 has an abrupt onset and a clear autosomal dominant mode of inheritance [39]. …”

α3Na+/K+-ATPase Deficiency Causes Brain Ventricle Dilation and Abrupt Embryonic Motility in Zebrafish

“…In the brain, the ATP1␣ 3 subunit is present exclusively in neurons (8). Mutations in the gene cause the neurological disorder rapid-onset dystonia-parkinsonism (RDP) 2 (9, 10), a rare movement disorder with an abrupt onset and rapid (hours to weeks) development of dystonia parkinsonism, primarily bradykinesia and postural instability (10,11).…”

Alternative Approaches to Modeling Hereditary Dystonias

“…The disorder has since been found in at least 21 families throughout the world [85]. DYT12 is characterized by a normal or near-normal childhood with the onset of severe dystonia and parkinsonism after a stressful event [84].…”

“…DYT12 is characterized by a normal or near-normal childhood with the onset of severe dystonia and parkinsonism after a stressful event [84]. The triggers are variable and include head trauma, childbirth, and prolonged exposure to heat or exercise [85]. However, even severe emotional stress can bring on symptoms [86].…”

“…However, even severe emotional stress can bring on symptoms [86]. Importantly, once DYT12 patients become symptomatic, their disability persists and patients largely do not recover function with time [85]. In 2004, the causative gene in DYT12 was identified as ATP1A3, which codes for the α 3 isoform of the sodium pump [75].…”