Glycine encephalopathy

Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is a rare inborn error of glycine metabolism caused by a defect in the glycine cleavage system. This enzymatic complex, located in the mitochondria, is responsible for breaking down the amino acid glycine. When this system malfunctions, glycine accumulates to toxic levels in body fluids and tissues, particularly in the brain and cerebrospinal fluid. The condition primarily affects the central nervous system, as excess glycine acts as an excitatory neurotransmitter at NMDA receptors, leading to severe neurological dysfunction. The most common and severe form is the neonatal type, which presents in the first days of life with progressive lethargy, hypotonia (poor muscle tone), myoclonic seizures, and apnea (episodes of stopped breathing), often progressing to coma. Surviving infants typically develop profound intellectual disability, intractable seizures, and spasticity. An attenuated (mild) form exists, presenting later in infancy or childhood with variable intellectual disability, seizures, and behavioral problems. A transient form has also been described in neonates who show biochemical abnormalities that resolve over time. Glycine encephalopathy is caused by pathogenic variants in genes encoding components of the glycine cleavage system, most commonly GLDC (accounting for approximately 70-75% of cases), AMT (approximately 20% of cases), and rarely GCSH. Treatment remains largely supportive and symptomatic. Sodium benzoate is used to reduce plasma glycine levels, and dextromethorphan or ketamine (NMDA receptor antagonists) may be used to counteract the excitatory effects of glycine at NMDA receptors. Despite treatment, outcomes for the severe neonatal form remain poor, with most affected individuals experiencing significant neurological impairment. Individuals with the attenuated form may have a better prognosis with early and aggressive management, though intellectual disability and seizures often persist.

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