Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism.

Anshita Arora, Kailash P Bhatia, Henry Houlden, Vivek Lal, Michele Tinazzi, John A Hardy, Nicholas W Wood, Sonia Gandhi, Tamas Revesz, Zane Jaunmuktane, Patrick A Lewis, Susanne A Schneider, Hrishikesh Kumar, Francesca Magrinelli, Carlos Estevez-Fraga, Eoin Mulroy, Anaita Hegde, Sergiu Groppa, Christopher Kobylecki, Purba Basu, Bettina Balint, Mark J Edwards, Anna Latorre, Giulia Di Lazzaro, Sahil Mehta

Journal: Movement disorders : official journal of the Movement Disorder Society 2022;37(1):148-161

PMID: 34622992

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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.

Address: Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.; Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.; Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.; Motor Control and Movement Disorders Group, Institute of Molecular and Clinical Sciences, St George's University of London, London, United Kingdom.; Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.; Department of Neurology, Institute of Neurosciences, Kolkata, India.; Department of Neurology, Salford Royal NHS Foundation Trust, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom.; Department of Neurology, University Medical Center of the Johannes-Gutenberg-University of Mainz, Mainz, Germany.; Department of Paediatric Neurology, Jaslok Hospital and Research Centre, Mumbai, India.; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.; Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany.; Royal Veterinary College, University of London, London, United Kingdom.; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.

DOI: 10.1002/mds.28807

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MeSH Terms: Age of Onset, Atrophy, Dystonia, Genotype, Group VI Phospholipases A2, Humans, Mutation, Parkinsonian Disorders, Pedigree, Phenotype