Non-ketotic hyperglycinemia (NKH), also termed glycine encephalopathy (MIM 605899), is an autosomal recessive inborn error of glycine degradation which leads to severe neurological symptoms and profound psychomotor disability. In NKH, glycine accumulates in all body fluids and tissues, including the CNS. The biochemical hallmark of NKH is increased glycine concentration in the plasma and to an even greater extent in the CSF, leading to an elevation of the CSF:plasma glycine ratio (C:PGR) to above 0.08 (normal <0.04). The fundamental defect is in the glycine cleavage system (GCS), a multienzyme complex located in the inner mitochondrial membrane of the liver, kidney, brain, and placenta. It consists of four individual protein components termed P (a pyridoxal phosphate-dependent glycine decarboxylase), H (a lipoic acid-containing hydrogen carrier protein), T (a tetrahydrofolate-dependent protein), and L (a lipoamide dehydrogenase). In more than 80% of patients the defect is in the P protein (MIM 238300), but defects in the T (MIM 238310) and H (MIM 238330) proteins have also been described. The pathogenesis of NKH is related to the properties of glycine as an excitatory neurotransmitter acting via the N-methyl-D-aspartate receptor in the cortex and an inhibitory neurotransmitter in the brainstem and spinal cord.