Early-Onset Parkinsonism Is a Manifestation of the PPP2R5D p.E200K Mutation

Christine Y Kim; Thomas Wirth; Cécile Hubsch; Andrea H Németh; Volkan Okur; Mathieu Anheim; Nathalie Drouot; Christine Tranchant; Gabrielle Rudolf; Jamel Chelly; Katrina Tatton-Brown; Cornelis Blauwendraat; Jean Paul G Vonsattel; Etty Cortes; Roy N Alcalay; Wendy K Chung

doi:10.1002/ana.25863

Early-Onset Parkinsonism Is a Manifestation of the PPP2R5D p.E200K Mutation

Ann Neurol. 2020 Nov;88(5):1028-1033. doi: 10.1002/ana.25863. Epub 2020 Aug 22.

Authors

Christine Y Kim^#^{1

2}, Thomas Wirth^#^{3

4

5}, Cécile Hubsch⁶, Andrea H Németh⁷, Volkan Okur⁸, Mathieu Anheim^{4

5

9}, Nathalie Drouot⁵, Christine Tranchant^{4

5

9}, Gabrielle Rudolf^{4

5

9}, Jamel Chelly^{4

5

10}, Katrina Tatton-Brown¹¹, Cornelis Blauwendraat¹², Jean Paul G Vonsattel¹³, Etty Cortes¹⁴, Roy N Alcalay^{15

16}, Wendy K Chung^{8

17}

Affiliations

¹ Department of Neurology, Yale School of Medicine, Yale University, New Haven, CT, USA.
² Center for Neuroepidemiology and Clinical Neurological Research, Yale School of Medicine, Yale University, New Haven, CT, USA.
³ Unit of Functional Neurosurgery, National Hospital for Neurology and Neurosurgery, University College London Hospital, London, UK.
⁴ Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
⁵ Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Illkirch-Graffenstaden, France.
⁶ Fondation Ophtalmologique A. de Rothschild, Paris, France.
⁷ Oxford University Hospitals NHS Trust and University of Oxford, Oxford, UK.
⁸ Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
⁹ Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France.
¹⁰ Laboratoire de diagnostic génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
¹¹ St. George's University Hospitals NHS Foundation Trust, London, UK.
¹² Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
¹³ Department of Pathology and Cell Biology, Columbia University Medical Center and the New York Presbyterian Hospital, New York, NY, USA.
¹⁴ Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵ Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
¹⁶ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.
¹⁷ Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.

^# Contributed equally.

Abstract

PPP2R5D-related neurodevelopmental disorder is characterized by a range of neurodevelopmental and behavioral manifestations. We report the association of early-onset parkinsonism with the PPP2R5D p.E200K mutation. Clinical characterization and exome sequencing were performed on three patients, with postmortem neuropathologic examination for one patient. All patients had mild developmental delay and developed levodopa-responsive parkinsonism between the ages of 25 and 40 years. The PPP2R5D c.598G>A (p.E200K) mutation was identified in all patients. Neuropathologic examination demonstrated uneven, focally severe neuronal loss and gliosis in the substantia nigra pars compacta, without Lewy bodies. Our findings suggest the PPP2R5D p.E200K mutation to be a possible new cause of early-onset parkinsonism. ANN NEUROL 2020;88:1028-1033.

Publication types

Case Reports
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Age of Onset
Autopsy
Brain / pathology
DNA / genetics
Exome
Female
Humans
Male
Middle Aged
Mutation / genetics
Parkinsonian Disorders / genetics*
Parkinsonian Disorders / pathology
Pedigree
Protein Phosphatase 2 / genetics*

Substances

PPP2R5D protein, human
DNA
Protein Phosphatase 2

Grants and funding

Z99 AG999999/ImNIH/Intramural NIH HHS/United States