Journal
PARKINSONISM & RELATED DISORDERS
Volume 15, Issue 4, Pages 281-286Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.parkreldis.2008.07.005
Keywords
Autosomal dominant; Axonal dystrophy; Neuronal cytoplasmic inclusions; Pallidonigral; Parkinsonism; Perry syndrome; TARDBP; TDP-43
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Funding
- Swiss National Science Foundation, Parkinson Switzerland
- Robert H. and Clarice Smith and the M.L Simpson Foundation Trust
- Morris K. Udall Center of Excellence for Parkinson Disease Research [P50-NS40256]
- Mayo Clinic ADRC grant [P50-AG16574]
- Pacific Alzheimer Research Foundation (PARF) [C06-01]
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Objective: Autosomal dominant parkinsonism, hypoventilation, depression and severe weight loss (Perry syndrome) is an early-onset rapidly progressive disease. At autopsy, previous studies have found severe neuronal loss in the substantia nigra without Lewy bodies. Transactive response DNA-binding protein of 43 kDa (TDP-43) has recently been identified as a major ubiquitinated constituent of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis. This study reports clinical, genetic and neuropathologic investigations of Perry syndrome. Methods: Clinical data and autopsy brain tissue samples were collected from eight patients from four genealogically unrelated kindreds with Perry syndrome. Brain tissue was studied with immunohistochemistry and biochemistry for TDP-43. Patients were screened for mutations in the progranulin (GRN) and TDP-43 (TARDBP) genes. Results: The mean age at onset was 47 years (range 40-56), and the mean age at death was 52 years (range 44-64). In all patients, we identified TDP-43-positive neuronal inclusions, dystrophic neurites and axonal spheroids in a predominantly pallidonigral distribution, and we demonstrated changes in solubility and electrophoretic mobility of TDP-43 in brain tissue. The inclusions were highly pleomorphic and predominated in the extrapyramidal system, sparing the cortex, hippocampus and motor neurons. There were no mutations in GRN or TARDBP. Interpretation: Perry syndrome displays unique TDP-43 pathology that is selective for the extrapyramidal system and spares the neocortex and motor neurons. (C) 2008 Elsevier Ltd. All rights reserved.
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