CURRENT STATUS OF NMDA ANTAGONIST INTERVENTIONS IN THE TREATMENT OF NONKETOTIC HYPERGLYCINEMIA

Impairment of the catabolism of glycine caused by ''failure'' of the g lycine cleavage enzyme complex results in an inability to oxidatively decarboxylate this amino acid. As a result of this inability, the alph a carbon of glycine does not enter the one-carbon pool, leading to its reduction or depletion, and toxic accumulation of this amino acid neu rotransmitter occurs. Strategies for the treatment of the clinical con dition known as nonketotic hyperglycinemia, an autosomal recessive dis order associated with absent or diminished glycine cleavage enzyme act ivity, include reduction of the glycine burden, replenishment of the o ne-carbon pool, and antagonism of the neurotransmitter effects of glyc ine. Until recently, antagonism focused on interference with the glyci ne-associated chloride ionophore that is enriched in the brain stem an d spinal cord, using strychnine as a specific intervention. However, t he recent recognition of a ''strychnine-insensitive'' binding site for glycine on the N-methyl-D-aspartic acid (NMDA) receptor complex, a gl utamate-gated cationic channel, has led to some newer approaches. Also , the recognition of milder, atypical variants of classic nonketotic h yperglycinemia has stimulated efforts to evaluate the therapeutic effi cacy of these strategies to antagonize the NMDA receptor complex.