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Dissecting the Phenotype and Genotype of PLA2G6?Related Parkinsonism

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


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


Patrick Lewis



Complex parkinsonism is the commonest phenotype in late-onset PLA2G6-associated neurodegeneration.


The aim of this study was to deeply characterize phenogenotypically PLA2G6-related parkinsonism in the largest cohort ever reported.


We report 14 new cases of PLA2G6-related parkinsonism and perform a systematic literature review.


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.


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


Magrinelli, F., Mehta, S., Di Lazzaro, G., Latorre, A., Edwards, M. J., Balint, B., …Bhatia, K. P. (in press). Dissecting the Phenotype and Genotype of PLA2G6ÔÇÉRelated Parkinsonism. Movement Disorders,

Journal Article Type Article
Acceptance Date Sep 13, 2021
Online Publication Date Oct 8, 2021
Deposit Date Oct 11, 2021
Journal Movement Disorders
Print ISSN 0885-3185
Electronic ISSN 1531-8257
Publisher Wiley
Peer Reviewed Peer Reviewed
Keywords Clinical Neurology; Neurology
Public URL
Additional Information Received: 2021-07-06; Accepted: 2021-09-13; Published: 2021-10-08