Rapid-onset dystonia-parkinsonism: A fourth family consistent with linkage to chromosome 19q13

Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.
Movement Disorders (Impact Factor: 5.68). 12/2004; 19(12):1506-10. DOI: 10.1002/mds.20258
Source: PubMed


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.

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    • "No statistical difference was observed in both non-stressed male and female Het mice when compared to non-stressed wild-type (WT) mice (p>0.05, Figure 2A). As the symptoms of DYT12 dystonia are absent until triggered by a physiological stressor (Brashear et al., 2007; Dobyns et al., 1993; Kamm et al., 2004; Linazasoro et al., 2002; Pittock et al., 2000; Zaremba et al., 2004), the effects of stress on motor behavior was examined. Mice were exposed to a restraint stress for five days followed by a two-week rest period. "
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    ABSTRACT: Rapid-onset dystonia with parkinsonism (RDP) or DYT12 dystonia is a rare form of primary, generalized dystonia. Patients do not present with any symptoms until triggered by a physiological stressor. Within days, patients will show both dystonia and parkinsonism. Mutations resulting in a loss of function in the ATP1A3 gene have been identified as the cause of RDP. ATP1A3 encodes the α3 subunit of the Na(+)/K(+)-ATPase, which is exclusively expressed in neurons and cardiac cells. We have previously created a line of mice harboring a point mutation of the Atp1a3 gene (mouse homolog of the human ATP1A3 gene) that results in a loss of function of the α3 subunit. The Atp1a3 mutant mice showed hyperactivity, spatial learning and memory deficits, and increased locomotion induced by methamphetamine. However, the full spectrum of the motor phenotype has not been characterized in the mutant mice and it is not known whether triggers such as restraint stress affect the motor phenotype. Here, we characterized the motor phenotype in normal heterozygous Atp1a3 mutant mice and heterozygous Atp1a3 mutant mice that have been exposed to a restraint stress. We found that this type of trigger induced significant deficits in motor coordination and balance in the mutant mice, characteristic of other genotypic dystonia mouse models. Furthermore, stressed mutant mice also had a decreased thermal sensitivity and alterations in monoamine metabolism. These results suggest that the Atp1a3 mutant mouse models several characteristics of RDP and further analysis of this mouse model will provide great insight into pathogenesis of RDP.
    Full-text · Article · Jan 2011 · Behavioural brain research
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    • "To date, RDP has been described in a small number of families [1] [2] [4] [6] [11] [12], but sporadic cases have also been reported [9,13–15]. Levels of dopamine metabolite homovanillic acid (HVA) have been found to be reduced in many RDP patients and also in asymptomatic gene carriers [3] [16], pointing to a potential dopaminergic involvement in RDP pathogenesis. "
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    ABSTRACT: Rapid-onset dystonia-parkinsonism (RDP) is a rare, autosomal-dominantly inherited syndrome characterized by abrupt onset, over hours to days, of dystonic and parkinsonian symptoms. To date, RDP has been described in a small number of families, and in only four sporadic cases. We here report a new sporadic case of RDP who has a novel de novo mutation in the ATP1A3 gene. Striatal dopamine transporters have been assessed quantitatively using [123I]-FP-CIT SPECT. A volume of interest (VOI) was drawn within the occipital cortex to obtain non-specific activity and specific to non-specific binding ratios (BR) were calculated. A single template of predefined VOI 3D-drawn on right and left caudate nucleus and putamen was applied to the spatially normalized BR images. BR values were compared to those obtained from an age-matched control group and from a group of patients suffering from Parkinson's disease (Hoehn and Yahr score 2 or 3). A [99mTc]-HMPAO cerebral blood flow study was also performed. In the control group, BR values (mean+/-Standard Deviation) were 3.5+/-0.4 for the left striatum and 3.3+/-0.3 for the right one. RDP patient's values were 3 and 2.7, respectively. In the Parkinson group, values were 1.6+/-0.3 and 1.7+/-0.4, respectively. [99mTc]-HMPAO scan showed homogeneous cortical and sub-cortical perfusion. Quantification of striatal [123I]-FP-CIT uptake in a new sporadic case of RDP with a novel mutation in the ATP1A3 gene showed values just within the range of normality. [99mTc]-HMPAO scan was normal.
    Full-text · Article · Nov 2008 · Journal of the Neurological Sciences
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    • "Table 1. Clinical Characteristics and Mutations in RDP Families Age of Onset in Onset Period in Number RDP Severity Codon Probands in Years Proband (Range Affected Scale Range Family Mutation a Change (Range in Family) in Family) in Family in Family b Reference 1 T821C I274T 37 14 days 1 3 2 G829A E277K 20 1 day 1 4 3 C1838T T613M 17 2 days 1 2 1 4 C1838T T613M 17 (16–28) Several hours 4 3 2 (mins to 30 days) 5 T2273G I758S 14 (14–45) 30 days 12 2–4 3 (1 hr to 30 days) 6 T2338C F780L 35 (16–35) 30 days 2 3–4 (30–90 days) 7 G2401T D801Y 23 (12–23) 2–3 days 4 2–4 4 References: 1, Linazasoro et al., 2002; 2, Zaremba et al., 2004; 3, Dobyns et al., 1993; 4, Brashear et al., 1997. a Nucleotide numbering is based on using the A in the start ATG as position 1. "
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    ABSTRACT: Rapid-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 alpha3 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.
    Full-text · Article · Aug 2004 · Neuron
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