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      Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations


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          The 2 major types of neurodegeneration with brain iron accumulation (NBIA) are the pantothenate kinase type 2 ( PANK2)-associated neurodegeneration (PKAN) and NBIA2 or infantile neuroaxonal dystrophy (INAD) due to mutations in the phospholipase A2, group VI ( PLA2G6) gene. We have recently demonstrated clinical heterogeneity in patients with mutations in the PLA2G6 gene by identifying a poorly defined subgroup of patients who present late with dystonia and parkinsonism. We report the clinical and genetic features of 7 cases with PLA2G6 mutations. Brain was available in 5 cases with an age of death ranging from 8 to 36 years and showed widespread alpha-synuclein-positive Lewy pathology, which was particularly severe in the neocortex, indicating that the Lewy pathology spread corresponded to Braak stage 6 and was that of the “diffuse neocortical type”. In 3 cases there was hyperphosphorylated tau accumulation in both cellular processes as threads and neuronal perikarya as pretangles and neurofibrillary tangles. Later onset cases tended to have less tau involvement but still severe alpha-synuclein pathology. The clinical and neuropathological features clearly represent a link between PLA2G6 and parkinsonian disorders.

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          PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron.

          Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis.
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            Characterization of PLA2G6 as a locus for dystonia-parkinsonism.

            Although many recessive loci causing parkinsonism dystonia have been identified, these do not explain all cases of the disorder. We used homozygosity mapping and mutational analysis in three individuals from two unrelated families who presented with adult-onset levodopa-responsive dystonia-parkinsonism, pyramidal signs and cognitive/psychiatric features, and cerebral and cerebellar atrophy on magnetic resonance imaging but absent iron in the basal ganglia. We identified areas of homozygosity on chromosome 22 and, subsequently, PLA2G6 mutations. PLA2G6 mutations are associated with infantile neuroaxonal dystrophy and have been reported previously to cause early cerebellar signs, and the syndrome was classified as neurodegeneration with brain iron accumulation (type 2). Our cases have neither of these previously pathognomic features. Thus, mutations in PLA2G6 should additionally be considered in patients with adult-onset dystonia-parkinsonism even with absent iron on brain imaging.
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              The progression of pathology in longitudinally followed patients with Parkinson's disease.

              The present study describes the pathological progression of longitudinally followed cases with levodopa-responsive Parkinson's disease who came to autopsy during the Sydney Multicenter Study of Parkinson's disease. Standardised clinical and neuropathological assessments over five epochs of time verified three different clinicopathological groups. A group of younger onset patients with a typical long duration clinical course of Parkinson's disease. This group of cases had Lewy body distributions consistent with the Braak staging of disease. In this group, brainstem Lewy bodies dominate in those surviving to 5 years; by 13 years, 50% of cases have a limbic distribution of Lewy bodies; and by 18 years, all will have at least this pathological phenotype. Approximately 25% of cases had an early malignant, dementia-dominant syndrome and severe neocortical disease consistent with dementia with Lewy bodies. The last group had an older onset, shorter survival, and a more complex disease course with higher Lewy body loads and a higher proportion with additional neuropathologies. These cases with higher loads of Lewy bodies and shorter survivals suggest that widespread Lewy body pathology either occurs at the onset of clinical disease or rapidly infiltrates the brain. In these cases with shorter survivals, there was more plaque pathology, supporting a more aggressive and linked phenotype. Our data suggest that the selection of similar study cohorts by pathology alone would not be able to differentiate the three different phenotypes identified. The data are also not consistent with a unitary concept of the pathogenesis of Lewy body disease.

                Author and article information

                Neurobiol Aging
                Neurobiol. Aging
                Neurobiology of Aging
                1 April 2012
                April 2012
                : 33
                : 4
                : 814-823
                [a ]Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
                [b ]Queen Square Brain Bank, UCL Institute of Neurology, London, UK
                [c ]Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK
                [d ]Rita Lila Weston Institute of Neurological Studies, London, UK
                [e ]Department of Pediatrics, University of Maryland, Baltimore, MD, UK
                [f ]Department of Clinical Neurosciences, Royal Free and University College Medical School, London, UK
                Author notes
                [* ]Corresponding author at: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom. Tel.: +44 2078373611 × 4391; fax: +44 2072785616 t.revesz@ 123456ion.ucl.ac.uk

                Equal contributions.

                © 2012 Elsevier Inc.

                This document may be redistributed and reused, subject to certain conditions.

                : 18 November 2009
                : 30 April 2010
                : 10 May 2010
                Regular Paper

                pla2g6,pank2,lewy bodies,parkinsonism,tau
                pla2g6, pank2, lewy bodies, parkinsonism, tau


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