Glutamatergic Neurotransmission Disruption as a Pathomechanism of Brain Damage in Disorders of Amino Acid and Organic Acid Metabolism: Insights from Animal and Cellular Studies.

Inborn errors of metabolism (IEMs) are inherited disorders biochemically characterized by the accumulation of potentially toxic metabolites in tissues and body fluids of the affected patients. Although clinical findings are heterogeneous, neurological symptoms, including coma and seizures associated with brain abnormalities, are very frequent. The mechanisms of neurotoxicity of the accumulated metabolites and their effects on cellular functions are still poorly established in many of these disorders. However, animal and cellular studies have shown that disturbances in glutamatergic neurotransmission, potentially leading to excitotoxicity, may represent a relevant mechanism of brain damage in some of these disorders. In agreement with this, treatments for some IEMs aim to mitigate overstimulation of N-methyl-D-aspartate (NMDA) receptors by NMDA receptor antagonists and to reduce the levels of the accumulated metabolites that activate these receptors. This review will focus on pre-clinical data showing disturbed glutamatergic neurotransmission in cells and animal models of IEMs that may offer perspectives for the development of novel adjuvant treatments for these diseases.