Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an inborn error of glycine metabolism in which large quantities of glycine accumulate in all body tissues, including the brain. The majority of glycine encephalopathy presents in the neonatal period (85% as the neonatal severe form and 15% as the neonatal mild form). Of those presenting in infancy, 50% have the infantile mild form and 50% have the infantile severe form. Overall, 20% of all children presenting as either neonates or infants have a less severe outcome, defined as developmental quotient greater than 20. A minority have atypical forms. The neonatal form manifests in the first hours to days of life with progressive lethargy, hypotonia, and myoclonic jerks leading to apnea and often death. Surviving infants have profound intellectual disability and intractable seizures. The infantile form is characterized by hypotonia, developmental delay, and seizures. The atypical forms range from milder disease, with onset from late infancy to adulthood, to rapidly progressing and severe disease with late onset.
Glycine encephalopathy is suspected in individuals with elevated glycine concentration in blood and CSF. An increase in CSF glycine concentration together with an increased CSF-to-plasma glycine ratio suggests the diagnosis. Enzymatic confirmation of the diagnosis relies on measurement of glycine cleavage (GCS) enzyme activity in liver obtained by open biopsy or autopsy. The vast majority of affected individuals have no detectable enzyme activity. The three genes known to be associated with glycine encephalopathy are: GLDC (encoding the P-protein component of the GCS complex and accounting for 70%-75% of disease), AMT (encoding the T-protein component of the GCS complex and accounting for ~20% of disease), and GCSH (encoding the H-protein component of the GCS complex and accounting for <1% of disease). Molecular genetic testing of all three genes is available on a clinical basis. About 5% of persons with-enzyme proven NKH do not have a mutation in any of these three genes.
Glycine encephalopathy is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3. Most individuals with glycine encephalopathy do not reproduce. Carrier testing and prenatal testing are possible if the disease-causing mutations in the family are known.