The History and Nosology of the Glycine Disorders: A Framework for Clinicians

Despite its simple chemical structure, glycine plays a complex role in the body. The glycine cleavage system regulates brain glycine levels and is a key one-carbon donor to folate. Its metabolism is tightly integrated with that of serine. In addition to its biochemical role, glycine functions as a neurotransmitter and neuromodulator. Primary defects in the glycine cleavage system have long been known to cause human disease with a primarily neurological phenotype, and this was labelled as 'nonketotic hyperglycinaemia' in 1968. With increasing availability of molecular testing, many additional genetic conditions became apparent, as well as non-genetic factors that cause hyperglycinaemia. There is now a much greater appreciation of the marked clinical impact of this heterogeneity. The previous terminology of 'classical' and 'atypical' nonketotic hyperglycinaemia does not adequately address these numerous genetic aetiologies, nor does it account for the phenotypic spectrum within individual genetic disorders. We provide here a clinically relevant classification of the glycine encephalopathies, based on the underlying genetic aetiology and its relation to the glycine cleavage system. Characteristic clinical and biochemical features of each condition, as well as non-genetic phenocopies that cause hyperglycinaemia, are discussed in detail. This provides a readily usable framework for clinicians when faced with a patient with elevated glycine levels.