glycine encephalopathy

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 de...