Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism

Francesca Magrinelli^{1

2}, Sahil Mehta³, Giulia Di Lazzaro^{1

4}, Anna Latorre¹, Mark J Edwards⁵, Bettina Balint^{1

6}, Purba Basu⁷, Christopher Kobylecki⁸, Sergiu Groppa⁹, Anaita Hegde¹⁰, Eoin Mulroy¹, Carlos Estevez-Fraga¹¹, Anshita Arora¹⁰, Hrishikesh Kumar⁷, Susanne A Schneider¹², Patrick A Lewis^{11

13}, Zane Jaunmuktane¹, Tamas Revesz¹⁴, Sonia Gandhi¹, Nicholas W Wood¹, John A Hardy¹¹, Michele Tinazzi², Vivek Lal³, Henry Houlden¹⁴, Kailash P Bhatia¹

Affiliations

¹ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
² Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
³ Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
⁴ Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
⁵ Motor Control and Movement Disorders Group, Institute of Molecular and Clinical Sciences, St George's University of London, London, United Kingdom.
⁶ Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.
⁷ Department of Neurology, Institute of Neurosciences, Kolkata, India.
⁸ Department of Neurology, Salford Royal NHS Foundation Trust, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom.
⁹ Department of Neurology, University Medical Center of the Johannes-Gutenberg-University of Mainz, Mainz, Germany.
¹⁰ Department of Paediatric Neurology, Jaslok Hospital and Research Centre, Mumbai, India.
¹¹ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
¹² Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany.
¹³ Royal Veterinary College, University of London, London, United Kingdom.
¹⁴ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.

PMID: 34622992
DOI: 10.1002/mds.28807

Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism

Francesca Magrinelli et al. Mov Disord. 2022 Jan.

. 2022 Jan;37(1):148-161.

doi: 10.1002/mds.28807. Epub 2021 Oct 8.

Authors

Affiliations

¹ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
² Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
³ Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
⁴ Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
⁵ Motor Control and Movement Disorders Group, Institute of Molecular and Clinical Sciences, St George's University of London, London, United Kingdom.
⁶ Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.
⁷ Department of Neurology, Institute of Neurosciences, Kolkata, India.
⁸ Department of Neurology, Salford Royal NHS Foundation Trust, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom.
⁹ Department of Neurology, University Medical Center of the Johannes-Gutenberg-University of Mainz, Mainz, Germany.
¹⁰ Department of Paediatric Neurology, Jaslok Hospital and Research Centre, Mumbai, India.
¹¹ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
¹² Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany.
¹³ Royal Veterinary College, University of London, London, United Kingdom.
¹⁴ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.

PMID: 34622992
DOI: 10.1002/mds.28807

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.

Keywords: NBIA; PLA2G6; PLAN; parkinsonism; systematic review.

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Comment in

Juvenile PLA2G6-Parkinsonism Due to Indian 'Asian' p.R741Q Mutation, and Response to STN DBS.
Ravat P, Shinde S, Shinde SR, Bangar S, Nayak N, Agarwal PA. Ravat P, et al. Mov Disord. 2022 Mar;37(3):657-658. doi: 10.1002/mds.28950. Epub 2022 Feb 3. Mov Disord. 2022. PMID: 35113461 No abstract available.
Reply to: Juvenile PLA2G6-parkinsonism due to Indian 'Asian' p.R741Q mutation, and response to STN DBS.
Magrinelli F, Rajapaksha I, Kobylecki C, Latorre A, Mulroy E, Estevez-Fraga C, Houlden H, Tinazzi M, Bhatia KP. Magrinelli F, et al. Mov Disord. 2022 Mar;37(3):658-662. doi: 10.1002/mds.28955. Epub 2022 Feb 13. Mov Disord. 2022. PMID: 35152491 No abstract available.

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Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism

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Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism

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