Hyperglycinemia, Nonketotic

Key Features

• Severely affected newborns present with apnea, hypotonia, lethargy, myoclonic seizures, and hiccups and develop severe mental and motor retardation

• Mildly affected children have developmental delay, hyperactivity, mild chorea, and seizures

• Electroencephalography (EEG) shows burst suppression

• CSF glycine is elevated

• All forms of the condition are autosomal recessive

Clinical Findings

• Glycine accumulation in the brain may disturb neurotransmission of the glycinergic receptors and the N-methyl-D-aspartate type of glutamate receptor

• In its most severe form, newborn presents with hypotonia, lethargy proceeding to coma, myoclonic seizures, and hiccups, with a burst suppression pattern on EEG

• Respiratory depression may require ventilator assistance in the first 2 weeks followed by spontaneous recovery

• Severe mental retardation and therapy-resistant seizures develop

• Some patients have agenesis of the corpus callosum or posterior fossa malformations

• Some patients with an attenuated form present with seizures, varying developmental delay, and chorea, and half of these may present later in infancy or in childhood

Diagnosis

• Nonketotic hyperglycinemia should be suspected in any neonate or infant with seizures, particularly those with burst suppression pattern on EEG

• Diagnosis is confirmed by demonstrating a large increase in glycine in nonbloody CSF, with an abnormally high ratio of CSF glycine to plasma glycine

• Molecular analysis is diagnostic in more than 98% of cases

• Enzyme analysis on liver tissue can confirm the diagnosis

• Prenatal diagnosis is possible by molecular analysis if both mutations are known or by enzyme assay on uncultured chorionic villus sampling (CVS)

• All patients have restricted diffusion on MRI in the already myelinated long tracts at birth

Treatment

• In patients with mild disease sodium benzoate (to normalize plasma glycine levels) and dextromethorphan or ketamine (to block N-methyl-D-aspartate type of glutamate receptors) controls seizures and improves outcome

• High-dose benzoate therapy can aid in seizure control but does not prevent severe mental retardation

• Ketogenic diet reduces glycine levels, but the impact on outcome is very limited

• Treatment of severely affected patients is generally unsuccessful