Glycine Encephalopathy (Nonketotic Hyperglycinemia) - Pathophysiology

Pathophysiology

Glycine is the simplest amino acid, having no stereoisomers. It can act as a neurotransmitter in the brain, acting as an inhibitor in the spinal cord and brain stem, while having excitatory effects in the cortex of the brain. Glycine is metabolized to eventual end products of ammonia and carbon dioxide through the glycine cleavage system (GCS), an enzyme complex made up of four protein subunits. Defects in these subunits can cause glycine encephalopathy, although some causes of the disease are still unknown. The GCS has its highest activity levels in liver, brain and placental tissue. One of its main functions is to keep glycine levels low in the brain. Defects in GCS cause an increase of glycine concentration in blood plasma and cerebrospinal fluid. The exact pathophysiology of the disorder is not known, but it is considered likely that buildup of glycine in the brain is responsible for the symptoms.

All types on glycine encephalopathy show elevated levels of glycine in the plasma, and cerebral spinal fluid. Glycine concentrations in the cerebrospinal fluid are typically more markedly elevated than in plasma, leading to a corresponding elevation in the ratio of glycine concentrations in the cerebral spinal fluid to that in the plasma. The ratio can also be slightly elevated if the patient is receiving valproic acid.

Glycine encephalopathy (nonketotic hyperglycinemia) should not be confused with other metabolic disorders that can produce elevated glycine. For example, certain inherited 'organic acidurias' (aka 'organic acidemias') can produce elevated glycine in plasma and urine, although the disorders are not caused by defects in the glycine cleavage system. Glycine encephalopathy is unique in the fact that levels of glycine are disproportionately elevated in CSF (in addition to blood and urine), whereas CSF glycine levels are normal or near-normal in patients with inherited organic acidurias.