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.

Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA)

“…In line with early clinical and imaging signs of cerebellar involvement, variable depletion of cerebellar cortical neurons (granular cells more than Purkinje cells) accompanied by marked astrocytosis was present [99]. Accumulation of hyperphosphorylated tau in both cellular processes as threads and neuronal perikarya as pretangles and neurofibrillary tangles, corresponding to Braak and Braak stage 5, has also been observed, again in contrast to PKAN [99]. Milder phenotypes in late-onset disease tended to show less tau involvement [106,107].…”

“…Notably, the signal abnormality differs from the "eye of the tiger" sign of PKAN in that there is no central hyperintensity. Iron deposits in the SN are present in some atypical cases [98,99]. Contrary to PKAN, iron accumulation is not a universal feature of PLAN.…”

“…Changes were particularly severe in the neocortex, corresponding to Braak stage 6 of the "diffuse neocortical type" of idiopathic PD [99]. In line with early clinical and imaging signs of cerebellar involvement, variable depletion of cerebellar cortical neurons (granular cells more than Purkinje cells) accompanied by marked astrocytosis was present [99]. Accumulation of hyperphosphorylated tau in both cellular processes as threads and neuronal perikarya as pretangles and neurofibrillary tangles, corresponding to Braak and Braak stage 5, has also been observed, again in contrast to PKAN [99].…”

“…the pyramidal, spinocerebellar, spinothalamic, and the gracile and cuneate fasciculi. In recent studies in both gene-proven mouse models [100] and human brains [99,105] widespread alpha-synuclein-positive Lewy pathology has been identified strengthening the link of PLA2G6 to idiopathic PD. Changes were particularly severe in the neocortex, corresponding to Braak stage 6 of the "diffuse neocortical type" of idiopathic PD [99].…”

“…In recent studies in both gene-proven mouse models [100] and human brains [99,105] widespread alpha-synuclein-positive Lewy pathology has been identified strengthening the link of PLA2G6 to idiopathic PD. Changes were particularly severe in the neocortex, corresponding to Braak stage 6 of the "diffuse neocortical type" of idiopathic PD [99]. In line with early clinical and imaging signs of cerebellar involvement, variable depletion of cerebellar cortical neurons (granular cells more than Purkinje cells) accompanied by marked astrocytosis was present [99].…”