Glycine encephalopathy

Glycine encephalopathy (GE), also known as non-ketotic hyperglycinemia or simply NKH, is a rare, inherited, autosomal recessive disorder of glycine metabolism. The condition arises from defects in the glycine cleavage system, an essential enzyme complex for glycine breakdown. This results in toxic accumulation, particularly in the brain, causing seizures, lethargy, muscle weakness, respiratory problems, and a high risk of early mortality. The condition typically manifests within the first couple months of life presenting as progressive lethargy and muscle weakness that can quickly lead to respiratory failure. The diagnosis of GE or NKH is often suspected based on abnormally high levels of the amino acid, glycine, in bodily fluids and tissues, especially the cerebrospinal fluid. Severity of symptoms and outcomes correlate with age at onset, with those presenting symptoms in the first few days having worse outcomes than those in the first few weeks to months. Among individuals that survive, they often have mild to severe intellectual disabilities, motor difficulties, and intractable seizures. Some individuals develop cortical blindness, scoliosis, and hip dysplasia.

NKH is primarily caused by mutations in the GLDC gene and, less frequently the AMT gene. These mutations result in defective P-protein and T-protein subunits of the glycine cleavage system, which are key components of glycine metabolism in mitochondria. Excess glycine results in disrupted glycine signaling in the brain especially NMDA receptors. Additionally, without glycine metabolism the body and brain are depleted of glycine-derived one carbon donors which are important for early brain development.

There is currently no cure for NKH; treatment focuses on reducing plasma glycine levels and symptom management. Sodium benzoate is used to reduce plasma glycine levels and NMDA receptor antagonists, like dextromethorphan or ketamine, are used to decrease NMDA receptor stimulation which can improve seizures, though many individuals require multiple anti-seizure drugs. Ongoing research continues to explore replacing the faulty gene through gene therapy, evaluating alternative glycine lowering agents especially that may do so in the brain, and providing alternative one carbon units including both dietary interventions and drugs. NKH is a life-limiting disorder and while life-expectancy is reduced advancements in care and treatment have improved outcomes for those with the disorder, especially the attenuated form.

NKH is an ultra-rare disease with an estimated 1 in every 76,000 globally or around 500 people worldwide. After phenylketonuria, glycine encephalopathy is the second most common disorder of amino acid metabolism. NKH was first described in 1965 and referred to as 'a new type of idiopathic hyperglycinemia' and later 'non-ketotic hyperglycinemia', a reference to the biochemical findings seen in patients with the disorder, and to distinguish it from the disorders that cause "ketotic hyperglycinemia" (as seen in propionic acidemia and several other inherited metabolic disorders). To avoid confusion, the term "glycine encephalopathy" is sometimes used, to better describe the clinical underpinnings of the disorder.