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.

Fig. 1

(A) Significant degree of pigment deposition in the globus pallidus in case 4. (B) Empty baskets highlighting significant Purkinje cell loss in the cerebellar cortex in case 1. (C) Large neuroaxonal swellings in the gracile nucleus in case 1, which were often immunoreactive for neurofilament (D). (A and C) Hematoxylin and eosin (H&E); (B and D) phospho-neurofilament immunohistochemistry (pNF) (RT97 antibody). The bar on (A) represents 40 μm.

Fig. 2

(A and B) Frequent Lewy bodies in substantia nigra neurons in case 1. Severe Lewy pathology is demonstrated in the entorhinal cortex (C), CA2 hippocampal subregion (D), and temporal neocortex (E) in case 1. The tau pathology was extensive in case 3 and demonstrated here in the temporal cortex. (A) Hematoxylin and eosin (H&E); (B–E) alpha-synuclein immunohistochemistry (αSyn); (F) tau immunohistochemistry (AT8 antibody). The bar on (A) represents 80 μm.