Mutations in the Na+/K+-ATPase α3 Gene ATP1A3 Are Associated with Rapid-Onset Dystonia Parkinsonism

AbstractRapid-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 α3 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

Alzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects

In a large multicentre study, Toledo et al. examine core Alzheimer's disease CSF biomarkers in 1233 cognitively normal subjects aged 40-85 years. Alzheimer disease-like changes in Aβ1-42 are seen as early as middle age, while APOE genotype strongly modifies age-related effects on both Aβ1-42 and phosphorylated/total ta

A multi-centre, randomized, double-blind, placebo-controlled, parallel-group, multiple oral dose study to assess the efficacy, safety and tolerability of AQW051 in Parkinson’s patients with L-dopa induced dyskinesias

In this study, administrationof AQW051 did not show any efect on dyskinesias or artiparkinsonian effect. However, The results of cognition assessments for the PD population indicated that the study drug AQW051 wasnot associated with statistically significant benefits to any cognitive domain or individual cognitive function. However when the magnitude of change under drug was compared to that under placebo,moderate to large effects were observed for the Memory Composite scores and the tasks comprisingthe Memory Composite score (ONB and ISLT), which were also found significant in the Safetypopulation for 50 mg versus placebo for ISLT and the Memory Composite score. Psychiatric and sleep problems are observed in 30-40% of PD patients. Some of the study patients showed mild to moderate depression at baseline, and mild sleep abnormalities. However, there was no overall effect of AQW051 in regards of SCOPA, BDI and PDSS results during the study. Exposure to AQW051 in patients with Parkinson’s disease was as expected in an elderly population. In regard to safety, administration of AQW051 showed good tolerability as in previous AQW051 studies, and the majority of AEs were mild to moderate in severity. Seven AEs were reported to be severe in intensity of which 2 events were suspected to be related to study medication

The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATPIA3 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 presen