Mechanisms of malformation of the central nervous system in inborn errors of metabolism.
| Energy deprivation and defective cell respiration |
| Aerobic metabolism in the brain tends to increase during periods of rapid neuronal proliferation, differentiation, and migration. Examples: Pyruvate dehydrogenase deficiency, respiratory chain deficiencies |
| Accumulation of neurotoxic metabolites |
| Intracellular accumulation of metabolites, such as glycine, lactic acid, or sulfites can produce direct neurotoxic effects. Examples: nonketotic hyperglycinemia, sulfite oxidase deficiency |
| Defects within cellular signaling pathways |
| Inborn errors of metabolism may have regulatory effects on the molecules involved in cell-to-cell signaling, an essential phenomena for organogenesis. Example: Smith-Lemli-Opitz syndrome |
| Alterations in the biophysical properties of cell membranes |
| The biophysical properties of cell membranes has a key role in the regulation of the cell physiology. Membrane clustering of receptors and ligands allows the formation of concentration gradients that are critical for axonal guidance. Cholesterol deficiency within membranes affects fluidity, potentially interfering with efficient anchoring of tyrosine kinase receptors and diffusibility of signaling molecules, resulting in disruption of signaling gradients. Example : Glu-1 deficiency syndrome, Smith-Lemli-Opitz syndrome |
| Interrelationships of subcellular organelle functions |
| Several subcellular organelles participate in the cholesterol biosynthetic pathway: the cytosol, mitochondria, and peroxisomes. Sequential steps in the pathway are compartmentalized and distributed among these organelles. Disturbance in peroxisomal function affects cholesterol biosynthesis. Example: Zellweger syndrome |