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Key Features

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  • 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

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Clinical Findings

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  • 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

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Diagnosis

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  • 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

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Treatment

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  • 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

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