Inborn error of metabolism that leads to isolated
Glycine Encephalopathy; Glycinemia.
1:250,000 live births; most cases are from Finland
(1:12,000 live births).
Defect in enzymes of the hepatic glycine cleavage
system leads to accumulation of glycine. The system is composed of four
mitochondrial proteins known as P, H, T, and L, and catalyzes the
transformation of glycine in CO2, ammonia, and
hydroxymethyltetrahydrofolic acid. Elevation of glycine levels in the brain
is thought to be responsible for the clinical symptoms of the disease:
glycine is an inhibitory neurotransmitter at the level of the brainstem and
spinal cord but has excitatory effects on the cerebral cortex.
Elevated levels of glycine in plasma, cerebrospinal
fluid, and urine with no ketosis. Defect of enzyme system may be
demonstrated in liver biopsy specimen or prenatally in cultured chorionic
Three clinical presentations exist.
Neonatal Type: Most common presentation. After a few days (rarely more than 48 hours), the
neonate presents with rapidly progressing neurologic symptoms: hypotonia,
apneic attacks, seizures, lethargy, or coma. Seizures range from myoclonic
to grand mal convulsions and are often accompanied by hiccup. A
characteristic burst-suppression pattern is seen on electroencephalogram (EEG) during the first
month and is later replaced by hypsarrhythmia. Death frequently occurs
during infancy or childhood. Survivors have mental retardation, myoclonus,
seizures, and microcephaly.
Late-Inset Type: Nonspecific neurologic symptoms develop during infancy to adolescence.
Transient Neonatal Type: High neonatal plasma and cerebrospinal fluid (CSF) levels of glycine return to normal after a few
weeks. Immaturity of one of the components of the glycine cleavage system is
postulated to be the cause of this transient disease.
There is no effective treatment. Antagonists of N-methyl-d-aspartate
(NMDA) receptors, such as oral ketamine (8 mg/kg/day) or dextromethorphan,
have been used with some success. Oral benzoate (500-750 mg/kg/day)
complexes with glycine to form hippuric acid, which undergoes renal
elimination. Benzodiazepines are indicated for seizures.
Ensure adequate hydration and
calorific intake. Assess neurologic status.
Surgery may be associated with acute
deterioration. Adequate hydration and caloric input should be maintained
Ketamine appears to be a good choice
because of its NMDA receptor antagonist properties.
Ohtahara Syndrome: Congenital epileptiform encephalopathy
with typical EEG pattern of burst-break suppression awake and asleep. Onset in the
first month of life; frequent tonic seizures and severe developmental delay;
poor prognosis; usual evolution to infantile spasms.
Sami KA: Non-ketotic hyperglycinaemias. Can Anaesth Soc J
Tada K: Nonketotic hyperglycinemia, in Fernades J, Saudubray J-M, van den
Berghe G (eds): Inborn Metabolic Diseases. 3rd ed. Berlin, Springer, 2000, p 254.