New triggers and non-motor findings in a family with rapid-onset dystonia-parkinsonism

Department of Neurology, University of Rochester School of Medicine, Rochester, NY, USA.
Parkinsonism & Related Disorders (Impact Factor: 3.97). 04/2012; 18(6):737-41. DOI: 10.1016/j.parkreldis.2012.03.020
Source: PubMed


A woman from Italy presented with dystonic leg symptoms at the age of 59. Rapid-onset dystonia-parkinsonism (RDP) was not suspected until 3 affected children (2 male, 1 female) with presentations consistent with the disorder were recognized.
The mother and four of her children (3 with and 1 without dystonia) were evaluated with an extensive battery including standardized history questionnaire and rating scales. In addition, all four children had cognitive testing and three of the four children had psychiatric interviews.
In this family, a T613M mutation in the ATP1A3 gene was confirmed, the most common mutation present in patients with RDP. The proband's limb dystonia was atypical of RDP, symptoms of the others affected included dysarthria, asymmetric limb dystonia, and dysphagia more consistent with RDP. The two sons developed dystonia-parkinsonism in adolescence after consuming large amounts of alcohol. All 3 of those with psychiatric interviews reached diagnosable thresholds for mood disorder (bipolar or dysthymia) and some form of anxiety disorder.
The phenotype and age of onset is broader than previously reported in RDP, suggesting that it could be under-reported. Prior to this study, neuropsychologic symptoms associated with RDP were under-appreciated. Those patients who are at risk or suspected of having RDP should be cautioned to avoid excessive alcohol intake. Further study is needed to assess if the cognitive and psychiatric features are part of a broader RDP phenotype and this may have implications for future research into genetic susceptibility for psychiatric disease.

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    • "As with other forms of dystonia (Stamelou, Edwards, Hallett, & Bhatia, 2012; Walterfang & van de Warrenburg, 2014), there is growing evidence for an important nonmotor component to RDP (Barbano et al., 2012). Cognitive impairments in verbal fluency and executive functioning tasks have been exhibited by RDP patients and an asymptomatic relative, all carrying a T613M mutation (Barbano et al., 2012). Three RDP mutations and one additional mutation have been identified in patients with an intermediate AHC/RDP presentation (Boelman et al., 2014; Heinzen et al., 2014; Rosewich et al., 2014; Roubergue et al., 2013; Sasaki, Ishii, Saito, & Hirose, 2014). "
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    ABSTRACT: Cognitive impairment is a prominent feature in a range of different movement disorders. Children with Alternating Hemiplegia of Childhood are prone to developmental delay, with deficits in cognitive functioning becoming progressively more evident as they grow older. Heterozygous mutations of the ATP1A3 gene, encoding the Na+,K+-ATPase α3 subunit, have been identified as the primary cause of Alternating Hemiplegia. Heterozygous Myshkin mice have an amino acid change (I810N) in Na+,K+-ATPase α3 that is also found in Alternating Hemiplegia. To investigate whether Myshkin mice exhibit learning and memory deficits resembling the cognitive impairments of patients with Alternating Hemiplegia, we subjected them to a range of behavioral tests that interrogate various cognitive domains. Myshkin mice showed impairments in spatial memory, spatial habituation, locomotor habituation, object recognition, social recognition, and trace fear conditioning, as well as in the visible platform version of the Morris water maze. Increasing the duration of training ameliorated the deficit in social recognition but not in spatial habituation. The deficits of Myshkin mice in all of the learning and memory tests used are consistent with the cognitive impairment of the vast majority of AHC patients. These mice could thus help advance our understanding of the underlying neural mechanisms influencing cognitive impairment in patients with ATP1A3-related disorders. (PsycINFO Database Record
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  • The Lancet Neurology 08/2012; 11(9):741-3. DOI:10.1016/S1474-4422(12)70185-0 · 21.90 Impact Factor
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    ABSTRACT: Rapid-onset dystonia-parkinsonism (RDP) occurs in children over 18 months of age, teens, and adults, and alternating hemiplegia of childhood (AHC) occurs in children less than 18 months. They appear to be different diseases, but both are caused by mutations in ATP1A3.(1-4) ATP1A3 encodes the α subunit of the Na(+)/K(+)-ATPase that is partially responsible for maintaining the electrical gradient in neurons. Motor symptoms, particularly dystonia, are obvious in both RDP and AHC, but RDP is predominantly fixed and AHC is known for its episodic and fluctuating course. There is now a broader phenotypic spectrum of RDP than originally described in 1993,(5,6) including psychosis,(7) new phenotypes in children,(8) and late onset.(9) The nonmotor phenotypes of both RDP (cognitive and psychiatric) and AHC (developmental delay, cognitive, and behavioral)(10,11) suggest that ATP1A3 mutations may play a role in other neurologic and psychiatric disorders. Mutations causing RDP or AHC cause symptoms such as dystonia, parkinsonism, epilepsy (including status epilepticus), hemiplegic episodes, abnormal ocular movements, developmental delay, psychosis, depression, anxiety, and gait disorders in ages ranging from newborns to age 87 years. It is likely that there will be a broad continuum of patients found, and even a role for the gene in polygenic disorders.
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