Year: 2021
Type: review
Study design: Observational Study
Abstract: BACKGROUND: Complex parkinsonism is the commonest phenotype in late-onset PLA2G6-associated neurodegeneration. OBJECTIVES: The aim of this study was to deeply characterize phenogenotypically PLA2G6-related parkinsonism in the largest cohort ever reported. METHODS: We report 14 new cases of PLA2G6-related parkinsonism and perform a systematic literature review. RESULTS: PLA2G6-related parkinsonism shows a fairly distinct phenotype based on 86 cases from 68 pedigrees. Young onset (median age, 23.0 years) with parkinsonism/dystonia, gait/balance, and/or psychiatric/cognitive symptoms were common presenting features. Dystonia occurred in 69.4%, pyramidal signs in 77.2%, myoclonus in 65.2%, and cerebellar signs in 44.6% of cases. Early bladder overactivity was present in 71.9% of cases. Cognitive impairment affected 76.1% of cases and psychiatric features 87.1%, the latter being an isolated presenting feature in 20.1%. Parkinsonism was levodopa responsive but complicated by early, often severe dyskinesias. Five patients benefited from deep brain stimulation. Brain magnetic resonance imaging findings included cerebral (49.3%) and/or cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%. Presynaptic dopaminergic terminal imaging was abnormal in all where performed. Fifty-four PLA2G6 mutations have hitherto been associated with parkinsonism, including four new variants reported in this article. These are mainly nontruncating, which may explain the phenotypic heterogeneity of childhood- and late-onset PLA2G6-associated neurodegeneration. In five deceased patients, median disease duration was 13.0 years. Brain pathology in three cases showed mixed Lewy and tau pathology. CONCLUSIONS: Biallelic PLA2G6 mutations cause early-onset parkinsonism associated with dystonia, pyramidal and cerebellar signs, myoclonus, and cognitive impairment. Early psychiatric manifestations and bladder overactivity are common. Cerebro/cerebellar atrophy are frequent magnetic resonance imaging features, whereas brain iron deposition is not. Early, severe dyskinesias are a tell-tale sign. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Source: Movement Disorders
DOI: 10.1002/mds.28807
Authors: Francesca Magrinelli, Sahil Mehta, Giulia Di Lazzaro, Anna Latorre, Mark J. Edwards, Bettina Balint, Purba Basu, Christopher Kobylecki, Sergiu Groppa, Anaita Hegde, Eoin Mulroy, Carlos Estevez‐Fraga, Anshita Arora, Hrishikesh Kumar, Susanne A. Schneider, Patrick A. Lewis, Zane Jaunmuktane, Tamas Revesz, Sonia Gandhi, Nicholas W. Wood, John A. Hardy, Michele Tinazzi, Vivek Lal, Henry Houlden, Kailash P. Bhatia
Institutions: University of Verona, UCL Queen Square Institute of Neurology, University College London, Post Graduate Institute of Medical Education and Research, University of Rome Tor Vergata, St George's, University of London, University Hospital Heidelberg, Institute of Neurosciences Kolkata, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, University of Manchester, Johannes Gutenberg University Mainz, University Medical Center of the Johannes Gutenberg University Mainz, Jaslok Hospital, Ludwig-Maximilians-Universität München, University of London, Royal Veterinary College
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,300
Funders: Muscular Dystrophy Association, Stiftung VERUM, Wellcome Trust, Muscular Dystrophy UK, Università degli Studi di Milano, Brain Research UK, National Institute for Health and Care Research, Parkinson's UK, Ataxia UK, University of Cambridge, University College London, University of Oxford, Rosetrees Trust, Great Ormond Street Hospital Charity, Università degli Studi di Verona, European Academy of Neurology, National Institutes of Health, University of California, San Francisco, Medical Research Council, National Institute of General Medical Sciences
Awards: Using genetic variability in whole transcriptome expression in cells and tissues to understand the pathogenesis of Parkinson's and Alzheimer's disease, G3327757157, Resource for Biocomputing Visualization and Informatics, G374229005, G4815039349, G4957603983, Understanding the genes for Parkinson's disease, Risk and Modifying factors in Fronto Temporal Dementia, G6140582619, MRC Strategic Award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases, G7433172200, G755868891, G7612322874, G7979393549, Dissecting molecular mechanisms of Parkinson's disease, Using Next Generation Sequencing to Unravel the Pathogenesis of Sporadic Inclusion Body Myositis - The International IBM Consortium Genetic Study, Leveraging the power of genomics and transcriptomics to revolutionise the diagnosis and understanding of neurological disorders, NIHR Senior Investigator Award
OpenAlex ID: W3202496055