New triggers and non-motor findings in a family with rapid-onset dystonia-parkinsonism
ABSTRACT 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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ABSTRACT: Rapid-onset dystonia-parkinsonism (RDP) is a movement disorder associated with mutations in the ATP1A3 gene. Signs and symptoms of RDP commonly occur in adolescence or early adulthood and can be triggered by physical or psychological stress. Mutations in ATP1A3 are also associated with alternating hemiplegia of childhood (AHC). The neuropathologic substrate of these conditions is unknown. The central nervous system of four siblings, three affected by RDP and one asymptomatic, all carrying the I758S mutation in the ATP1A3 gene, was analyzed. This neuropathologic study is the first carried out in ATP1A3 mutation carriers, whether affected by RDP or AHC. Symptoms began in the third decade of life for two subjects and in the fifth for another. The present investigation aimed at identifying, in mutation carriers, anatomical areas potentially affected and contributing to RDP pathogenesis. Comorbid conditions, including cerebrovascular disease and Alzheimer disease, were evident in all subjects. We evaluated areas that may be relevant to RDP separately from those affected by the comorbid conditions. Anatomical areas identified as potential targets of I758S mutation were globus pallidus, subthalamic nucleus, red nucleus, inferior olivary nucleus, cerebellar Purkinje and granule cell layers, and dentate nucleus. Involvement of subcortical white matter tracts was also evident. Furthermore, in the spinal cord, a loss of dorsal column fibers was noted. This study has identified RDP-associated pathology in neuronal populations, which are part of complex motor and sensory loops. Their involvement would cause an interruption of cerebral and cerebellar connections which are essential for maintenance of motor control.Acta Neuropathologica 05/2014; 128(1). DOI:10.1007/s00401-014-1279-x · 9.78 Impact Factor
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ABSTRACT: This article will highlight recent advances in dystonia with focus on clinical aspects such as the new classification, syndromic approach, new gene discoveries and genotype-phenotype correlations. Broadening of phenotype of some of the previously described hereditary dystonias and environmental risk factors and trends in treatment will be covered.
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ABSTRACT: ATP1A3 mutations have now been recognized in infants and children presenting with a diverse group of neurological phenotypes, including Rapid-onset Dystonia-Parkinsonism (RDP), Alternating Hemiplegia of Childhood (AHC), and most recently, Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss (CAPOS) syndrome. Existing literature on ATP1A3-related disorders in the pediatric population were reviewed, with attention to clinical features and associated genotypes among those with RDP, AHC, or CAPOS syndrome phenotypes. While classically defined phenotypes associated with AHC, RDP, and CAPOS syndromes are distinct, common elements among ATP1A3-related neurological disorders include characteristic episodic neurological symptoms and signs that vary in severity, duration, and frequency of occurrence. Affected children typically present in the context of an acute onset of paroxysmal, episodic neurological symptoms ranging from oculomotor abnormalities, hypotonia, paralysis, dystonia, ataxia, seizure-like episodes, or encephalopathy. Neurodevelopmental delays or persistence of dystonia, chorea, or ataxia after resolution of an initial episode are common, providing important clues for diagnosis. The phenotypic spectrum of ATP1A3-related neurological disorders continues to expand beyond the distinct yet overlapping phenotypes in patients with AHC, RDP, and CAPOS syndromes. ATP1A3 mutation analysis is appropriate to consider in the diagnostic algorithm for any child presenting with episodic or fluctuating ataxia, weakness or dystonia whether they manifest persistence of neurological symptoms between episodes. Additional work is needed to better identify and classify affected patients and develop targeted treatment approaches. Copyright © 2014 Elsevier Inc. All rights reserved.Pediatric Neurology 10/2014; 52(1). DOI:10.1016/j.pediatrneurol.2014.09.015 · 1.50 Impact Factor