Overview of Inflammation in Neurometabolic Diseases

Neuroinflammation is an intrinsic component of the neurodegeneration of inborn errors of neurometabolic diseases. Diseases resulting in lysosomal, peroxisomal, and autophagocytic disruption lead to neuroinflammation by different mechanisms relating to accumulated substrates and/or downstream deficiencies that cause presymptomatic microglial activation, axonal instabilities and/or direct hyperactivation of intrinsic inflammatory mechanisms. Only in selected diseases is the blood-brain barrier (BBB) breached, thereby permitting peripheral adaptive immune mechanisms to amplify intrinsic immune reactions in the central nervous system. These result in evoking several different programmed cell death pathways, including apoptosis, necroptosis, and pyroptosis, with the subsequent neuronal death of specific types and in selected regions of the brain or spinal cord. In addition to correction of the primary genetic or metabolic defects, successful therapeutic interventions require greater molecular understanding of the specific neuroinflammatory components of neurometabolic diseases to permit identification of significant targets for intervention. (C) 2017 Elsevier Inc. All rights reserved.