Niemann-Pick Type C Disease: At the Nexus of Neurodegenerative and Neurodevelopmental Disorders

Rare genetic diseases can provide valuable insights into more common disorders by linking specific genes and pathways to shared disease phenotypes.The rare Niemann-Pick Type C disease (NPC) is a neurological disorder that has often been compared to Alzheimer's Disease (AD) because both diseases are characterized by cognitive impairment in the presence of tau pathology and altered Amyloid Precursor Protein (APP) processing and Aβ metabolism.Here we review the molecular pathology of NPC and critically examine the similarities between NPC, AD and other neurological disorders.Besides the phenotypic overlap between AD and NPC, there is substantial evidence that cholesterol metabolism is altered in both diseases.Specifically, the epsilon 4 allele of the brain cholesterol transport protein Apolipoprotein E (ApoE4 ) is the strongest risk factor for late onset AD (LOAD) whereas NPC disease is caused by point mutations in the cholesterol transport proteins NPC1 and NPC2.In contrast to AD, NPC encompasses a broad neurovisceral disease phenotype having a diversity of penetrance, age of onset, and both central and peripheral manifestations.In addition to features that are in common with AD, NPC frequently exhibits close phenotypic overlap with neurodevelopmental disorders such as schizophrenia.Understanding the mechanistic links shared by NPC, AD, and neurodevelopmental disorders should enable a more holistic approach to therapeutic strategies to diseases which superficially appear very different.