Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism.

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

doi:10.1002/mds.28807

Abstract

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. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Highlights

PLA2G6 encodes the calcium-independent phospholipase A2β, which hydrolyzes membrane phospholipids and lysophospholipids, thereby regulating membrane homeostasis and generating lipid second messengers involved in cell proliferation, Ca2+ signaling, mitochondrial dynamics, and apoptosis.[1,2]
86 cases from 68 kindreds contributed to the phenogenotypic description of PLA2G6-related parkinsonism
We provided in-depth phenotypic and genotypic characterization of the largest cohort of PLA2G6related parkinsonism hitherto reported

Summary

Introduction

PLA2G6 encodes the calcium-independent phospholipase A2β (iPLA2β), which hydrolyzes membrane phospholipids and lysophospholipids, thereby regulating membrane homeostasis and generating lipid second messengers involved in cell proliferation, Ca2+ signaling, mitochondrial dynamics, and apoptosis.[1,2]. ANAD shows fairly slow progression during early childhood and rapid deterioration at the turn of the first decade of life.[4] Neuroradiological findings in INAD/ ANAD encompass cerebellar atrophy, cerebellar cortical magnetic resonance imaging (MRI)-T2 hyperintensity, iron deposition in the globus pallidus (GP) and/or substantia nigra (SN), white matter abnormalities, vertically oriented splenium of the corpus callosum, claval hypertrophy, and thinning of the optic pathway.[7] Axonal degeneration with distended axons (spheroid bodies) throughout the central and peripheral nervous systems is the pathological hallmark of INAD/ANAD.[3,4,6]. In 2009, PLA2G6 was linked to dystonia-parkinsonism with onset in the second to third decades of life.[8] Since additional phenotypes manifesting later than INAD/. Growing evidence suggests that PLA2G6-associated neurodegeneration (PLAN) is a phenotypic continuum.[12,15] For instance, childhood-onset phenotypes and PLA2G6-related parkinsonism share Lewy and tau pathology.[16] there are unsolved questions about. Controversies remain regarding why PLA2G6 mutations cause such a wide phenotypic spectrum, and why the same mutation leads to different phenotypes, even in the same pedigree

Objectives

Methods

Results

Conclusion