title: Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations.
abstract: 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.
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Coro
authors.initials: C
authors.lastname: Paisán-Ruiz
authors.forename: Abi
authors.initials: A
authors.lastname: Li
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Schneider
authors.forename: Janice L
authors.initials: JL
authors.lastname: Holton
authors.forename: Robert
authors.initials: R
authors.lastname: Johnson
authors.forename: Desmond
authors.initials: D
authors.lastname: Kidd
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chataway
authors.forename: Kailash P
authors.initials: KP
authors.lastname: Bhatia
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lees
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Tamas
authors.initials: T
authors.lastname: Revesz
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000473:pathology*; D002648:Child; D004252:DNA Mutational Analysis; D020821:Dystonic Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D054522:Group VI Phospholipases A2 / Q000235:genetics*; D006801:Humans; D016631:Lewy Bodies / Q000235:genetics / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D016875:tau Proteins; D054522:Group VI Phospholipases A2; C516475:PLA2G6 protein, human