Rapid-onset dystonia-parkinsonism: A fourth family consistent with linkage to chromosome 19q13
ABSTRACT Rapid-onset dystonia-parkinsonism (RDP, DYT12, MIM 128235) is a rare autosomal dominant movement disorder characterized by abrupt onset of slow, dystonic movements and prominent bulbar features. Three families and 1 isolated case have been described in the literature, and linkage to markers on chromosome 19q13 have been reported. Here, we describe the clinical features in a fourth family (the second in Europe) with 4 affected members, suggesting that RDP may be misdiagnosed for years and/or may mimic other dystonic/parkinsonian syndromes. By using haplotype analysis, we show that the family is consistent with linkage to markers on chromosome 19q13.
SourceAvailable from: Greer Kirshenbaum[Show abstract] [Hide abstract]
ABSTRACT: Genetic research has shown that mutations that modify the protein-coding sequence of ATP1A3, the gene encoding the α3 subunit of Na(+)/K(+)-ATPase, cause both rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood. These discoveries link two clinically distinct neurological diseases to the same gene, however, ATP1A3 mutations are, with one exception, disease-specific. Although the exact mechanism of how these mutations lead to disease is still unknown, much knowledge has been gained about functional consequences of ATP1A3 mutations using a range of in-vitro and animal model systems, and the role of Na(+)/K(+)-ATPases in the brain. Researchers and clinicians are attempting to further characterise neurological manifestations associated with mutations in ATP1A3, and to build on the existing molecular knowledge to understand how specific mutations can lead to different diseases.The Lancet Neurology 05/2014; 13(5):503-514. DOI:10.1016/S1474-4422(14)70011-0 · 21.82 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Dystonia is a neurological disorder characterized by abnormal involuntary movements that are prolonged and often cause twisting and turning. Several genetically modified worms, fruit flies, and rodents have been generated as models of genetic dystonias, in particular DYT1, DYT11, and DYT12 dystonias. Although these models do not show overt dystonic symptoms, the rodent models exhibit motor deficits in specialized behavioral tasks, such as the rotarod and beam-walking tests. For example, in a rodent model of DYT12 dystonia, which is generally stress triggered, motor deficits are observed only after the animal is stressed. Moreover, in a rodent model of DYT1 dystonia, the motor and electrophysiological deficits can be rescued by trihexyphenidyl, a common anticholinergic medication used to treat dystonic symptoms in human patients. Biochemically, the DYT1 and DYT11 animal models also share some similarities to patients, such as a reduction in striatal D2 dopamine receptor and binding activities. In addition, conditional knockout mouse models for DYT1 and DYT11 dystonia demonstrate that loss of the causal dystonia-related proteins in the striatum leads to motor deficits. Interestingly, loss of the DYT1 dystonia causal protein in Purkinje cells shows an improvement in motor performance, suggesting that gene therapy targeting of the cerebellum or intervention in its downstream pathways may be useful. Finally, recent studies using DYT1 dystonia worm and mouse models led to a potential novel therapeutic agent, which is currently undergoing clinical trials. These results indicate that genetic animal models are powerful tools to elucidate the pathophysiology and to further develop new therapeutics for dystonia. © 2013 Movement Disorder Society.Movement Disorders 06/2013; 28(7):990-1000. DOI:10.1002/mds.25583 · 5.63 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: We aimed to delineate the clinical and genetic spectrum of ATP1A3-related disorders and recognition of a potential genotype-phenotype correlation. We identified 16 new patients with alternating hemiplegia of childhood (AHC) and 3 new patients with rapid-onset dystonia-parkinsonism (RDP) and included these as well as the clinical and molecular findings of all previously reported 164 patients with mutation-positive AHC and RDP in our analyses. Major clinical characteristics shared in common by AHC and RDP comprise a strikingly asymmetric, predominantly dystonic movement disorder with rostrocaudal gradient of involvement and physical, emotional, or chemical stressors as triggers. The clinical courses include an early-onset polyphasic for AHC, a later-onset mono- or biphasic for RDP, as well as intermediate forms. Meta-analysis of the 8 novel and 38 published ATP1A3 mutations shows that the ones affecting transmembrane and functional domains tend to be associated with AHC as the more severe phenotype. The majority of mutations are located in exons 8, 14, 17, and 18. AHC and RDP constitute clinical prototypes in a continuous phenotypic spectrum of ATP1A3-related disorders. Intermediate phenotypes combining criteria of both conditions are increasingly recognized. Efficient stepwise mutation analysis of the ATP1A3 gene may prioritize those exons where current state of knowledge indicates mutational clusters.Neurology 02/2014; 82(11). DOI:10.1212/WNL.0000000000000212 · 8.30 Impact Factor