Disorders of intermediary metabolism: Toxic leukoencephalopathies

Abstract

Myelination starts in the latter half of gestation. It is initiated by oligodendrocyte progenitor cells. Three sequential steps can be distinguished: (1) initial ensheathment of axons by premyelin sheaths generated by oligodendrocyte progenitor cells; (2) initial insertion of myelin basic protein (MBP) into transitional sheaths; and (3) generation of mature MBP-rich myelin. Different inborn errors of metabolism can interfere with different stages of these physiological processes, causing white-matter diseases, i.e. toxic leukoencephalopathies. Some inborn errors of metabolism disturb the formation of myelin by being toxic to oligodendrocytes or by interference with the biosynthesis of cholesterol and lipids, e.g. globoid cell leukodystrophy and phenylketonuria. Remethylation defects, e.g. methylenetetrahydrofolate reductase deficiency, cobalamin C, D, E, F and G defects, interfere with the expression, processing and insertion of MBP. The concept of excitotoxicity, which has been developed in neurons, has recently been modified and has been extended to the oligodendroglial lineage. Mitochondriopathies and cerebral organic acid disorders may cause secondary excitotoxicity resulting in toxic encephalopathies, which may affect both neurons and oligodendrocytes. This review aims to present relevant diseases, summarizing recent knowledge on mechanisms and formulating testable hypotheses of pathophysiology leading to new and improved treatment strategies.