Rapid-onset dystonia-parkinsonism associated with the I758S mutation of the ATP1A3 gene

A neuropathologic and neuroanatomical study of four siblings

Adrian L. Oblak, Matthew C. Hagen, Kathleen J. Sweadner, Ihtsham Haq, Christopher T. Whitlow, Joseph A. Maldjian, Francine Epperson, Jared F. Cook, Mark Stacy, Jill R. Murrell, Laurie J. Ozelius, Allison Brashear, Bernardino Ghetti

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)81-98
Number of pages18
JournalActa Neuropathologica
Volume128
Issue number1
DOIs
StatePublished - 2014

Fingerprint

Siblings
Mutation
Genes
Olivary Nucleus
Red Nucleus
Cerebrovascular Disorders
Cerebellar Nuclei
Subthalamic Nucleus
Globus Pallidus
Purkinje Cells
Movement Disorders
Dystonia 12
Cell Nucleus
Psychological Stress
Signs and Symptoms
Spinal Cord
Alzheimer Disease
Central Nervous System
Maintenance
Pathology

Keywords

  • DYT12
  • Neuropathology
  • Rapid-onset dystonia-parkinsonism
  • RDP

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Rapid-onset dystonia-parkinsonism associated with the I758S mutation of the ATP1A3 gene : A neuropathologic and neuroanatomical study of four siblings. / Oblak, Adrian L.; Hagen, Matthew C.; Sweadner, Kathleen J.; Haq, Ihtsham; Whitlow, Christopher T.; Maldjian, Joseph A.; Epperson, Francine; Cook, Jared F.; Stacy, Mark; Murrell, Jill R.; Ozelius, Laurie J.; Brashear, Allison; Ghetti, Bernardino.

In: Acta Neuropathologica, Vol. 128, No. 1, 2014, p. 81-98.

Research output: Contribution to journalArticle

Oblak, AL, Hagen, MC, Sweadner, KJ, Haq, I, Whitlow, CT, Maldjian, JA, Epperson, F, Cook, JF, Stacy, M, Murrell, JR, Ozelius, LJ, Brashear, A & Ghetti, B 2014, 'Rapid-onset dystonia-parkinsonism associated with the I758S mutation of the ATP1A3 gene: A neuropathologic and neuroanatomical study of four siblings', Acta Neuropathologica, vol. 128, no. 1, pp. 81-98. https://doi.org/10.1007/s00401-014-1279-x
Oblak, Adrian L. ; Hagen, Matthew C. ; Sweadner, Kathleen J. ; Haq, Ihtsham ; Whitlow, Christopher T. ; Maldjian, Joseph A. ; Epperson, Francine ; Cook, Jared F. ; Stacy, Mark ; Murrell, Jill R. ; Ozelius, Laurie J. ; Brashear, Allison ; Ghetti, Bernardino. / Rapid-onset dystonia-parkinsonism associated with the I758S mutation of the ATP1A3 gene : A neuropathologic and neuroanatomical study of four siblings. In: Acta Neuropathologica. 2014 ; Vol. 128, No. 1. pp. 81-98.
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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.",
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AU - Brashear, Allison

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