The neuropathological mechanisms underlying the inborn errors of lysine metabolism

Optimal lysine catabolism is essential for the proper growth and development of mammals. Lysine is degraded through either the saccharopine or pipecolate pathway, processes characterized by distinct tissue specificity and subcellular compartmentalization. Although controversy persists, accumulating evidence suggests that the saccharopine pathway serves as the predominant route for lysine degradation in the mammalian brain. Pathogenic variants of genes encoding the enzymes involved in lysine catabolism lead to severe inborn errors of metabolism, including hyperlysinemia-II, pyridoxine-dependent epilepsy- ALDH7A1 , and glutaric aciduria type I, which are biochemically characterized by the systemic accumulation of neurotoxic metabolites. Patients with the aforementioned disorders exhibit apparent neurological symptoms, ranging from cognitive impairment to severe encephalopathy, indicating that the dysregulation of lysine metabolism has deteriorative impacts on brain development and function. It is worth noting that a subset of patients still suffers from developmental delay and chronic neurological dysfunction, despite the amelioration of acute seizures or encephalopathic crises resulting from a combination of a lysine-restricted diet and pharmacotherapy. This elusive neuropathology has prompted increasing research aimed at identifying the pivotal regulatory roles of enzymes in neural functions and the neurotoxic effects of lysine metabolites in the brain. Here, we summarize current insights into the pathogenic mechanisms underlying the neurological manifestations of lysine metabolism disorders. A comprehensive understanding of the association between biochemical abnormalities and neurometabolic deficiencies has profound implications for refining therapeutic strategies to improve neurodevelopmental outcomes in affected patients. • The saccharopine pathway serves as the major route of lysine catabolism in mammalian brains. • Accumulation of toxic lysine metabolites impairs neuronal function via cell-dependent and cell-independent mechanisms. • LKR represents a promising therapeutic target for lysine catabolism-related disorders. • Neuropathological profiling of lysine catabolism-related disorders is essential for improving diagnosis and treatment.