Neuropathological features of genetically confirmed DYT1 dystonia: Investigating disease-specific inclusions

• Type of Material: Article
• Authors: Reema Paudel, UCL Institute of Neurology; Aoife Kiely, UCL Institute of Neurology; Abi Li, UCL Institute of Neurology; Tammaryn Lashley, UCL Institute of Neurology; Rina Bandopadhyay, UCL Institute of Neurology; John Hardy, UCL Institute of Neurology; Hyder Jinnah, Emory University; Kailash Bhatia, UCL Institute of Neurology; Henry Houlden, UCL Institute of Neurology; Janice L. Holton, UCL Institute of Neurology
• Language: English
• Date: 2014-01-27
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2014 Paudel et al.; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s40478-014-0159-x
• Title of Journal or Parent Work: Acta Neuropathologica Communications
• ISSN: 2051-5960
• Volume: 2
• Issue: 1
• Start Page: 159
• End Page: 159
• Grant/Funding Information: Prof Jinnah is supported by grants from the NIH (NS 065701), private research foundations (Bachmann-Strauss Dystonia Parkinson’s Foundation and the Benign Essential Blepharospasm Research Foundation) and clinical studies grants from industry (Ipsen Pharmaceuticals, Merz Pharmaceuticals, Psyadon Pharmaceuticals).; Prof Holton is supported by the Reta Lila Weston Institute for Neurological Studies, the Multiple System Atrophy Trust and Parkinson’s UK.; This research was funded by grant NS 065701 to the Dystonia Coalition by the American National Institute of Neurological Disorders and Stroke and the Office of Rare Diseases Research at the National Center for Advancing Translational Sciences, Impact Studentship UCL and supported by researchers at the National Institute for Health Research University College London Hospitals Biomedical Research Centre.; Prof Bhatia is supported by Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL.; Dr Kiely is supported by the Multiple System Atrophy Trust. Dr Lashley is supported by Alzheimer’s Research UK. Prof Hardy reports no financial disclosure.; Dr Bandopadhyay and Dr Li are supported by Reta Lila Weston Institute for Neurological Studies.
• Keywords: Inclusion Bodies; Neurons; Brain; Immunohistochemistry; Male; Molecular Chaperones; Female; Dystonic Disorders; Humans; Aged, 80 and over; Aged
• Research Categories: Biology, Genetics; Biology, Neuroscience

Abstract

Introduction: Early onset isolated dystonia (DYT1) is linked to a three base pair deletion ((increment)GAG) mutation in the TOR1A gene. Clinical manifestation includes intermittent muscle contraction leading to twisting movements or abnormal postures. Neuropathological studies on DYT1 cases are limited, most showing no significant abnormalities. In one study, brainstem intraneuronal inclusions immunoreactive for ubiquitin, torsinA and lamin A/C were described. Using the largest series reported to date comprising 7 DYT1 cases, we aimed to identify consistent neuropathological features in the disease and determine whether we would find the same intraneuronal inclusions as previously reported. Result: The pathological changes of brainstem inclusions reported in DYT1 dystonia were not replicated in our case series. Other anatomical regions implicated in dystonia showed no disease-specific pathological intracellular inclusions or evidence of more than mild neuronal loss. Conclusion: Our findings suggest that the intracellular inclusions described previously in DYT1 dystonia may not be a hallmark feature of the disorder. In isolated dystonia, DYT1 in particular, biochemical changes may be more relevant than the morphological changes.