Fig. 1

Glycine reduction strategies. A In patients with nonketotic hyperglycinemia, in states where glucose is present, glycine clearance is largely dependent on its conjugation to benzoyl-CoA by glycine N-acyltransferase. In states of glucose deprivation, glycine is converted to serine which is used as a starting substrate for gluconeogenesis through its conversation to pyruvate by serine dehydratase. Both glycine-N-acyltransferase and serine dehydratase are expressed primarily in the liver. B When glycine levels are in the target range, then the amount of glycine provided reflects the sum of dietary glycine and endogenous glycine synthesis, whereas glycine use is determined by the combination of endogenous catabolism, the residual activity of the glycine cleavage enzyme and conjugation by benzoate. This balance is reflected in the glycine index which is an individualized parameter that is determined by the weight-based sodium benzoate dose required to achieve target glycine levels relative to the amount of dietary glycine. Ordinarily this index is constant and fixed over the course of an individual patient’s lifetime. The use of the ketogenic diet increases the endogenous use of glycine for gluconeogenesis and shifts the balance of the glycine index