Insights into Lewy body disease from rare neurometabolic disorders

Professor Kurt Jellinger is well known for his seminal work on the neuropathology of age-associated neurodegenerative disorders, particularly Lewy body diseases. However, it is less well known that he also contributed important insights into the neuropathological features of several paediatric neurometabolic diseases, including Alpers-Huttenlocher syndrome, a syndrome of mitochondrial disease caused by POLG mutations, and infantile neuroaxonal dystrophy, a phenotype resulting from PLA2G6 mutations. Despite these rare diseases occurring in early life, they share many important pathological overlaps with age-associated Lewy body disease, particularly dysregulation of α-synuclein. In this review, we describe several neurometabolic diseases linked to Lewy body disease mechanisms, and discuss the wider context to pathological overlaps between neurometabolic and Lewy body diseases. In particular, we will focus on how understanding disease mechanisms in neurometabolic disorders with dysregulated α-synuclein may generate insights into predisposing factors for α-synuclein aggregation in idiopathic Lewy body diseases.