Nonketotic Hyperglycinemia

At a glance

Isolated hyperglycinemia due to deficiency of the glycine cleavage enzyme system. Most patients present in the first week of life with lethargy, hypotonia, and myoclonic jerks, and often progress to apnea requiring ventilator support.

Synonyms

Glycine Encephalopathy; Glycinemia Disease.

Incidence

1:76,000 live births; most cases are from Finland (1:12,000 live births).

Genetic inheritance

Autosomal recessive.

Pathophysiology

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. The P, T, and H proteins are encoded by GLDC (9p24.1), AMT (3p21.31), and GCSH (16q23.2) genes, respectively. 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 brain stem and spinal cord, but has excitatory effects on the cerebral cortex.

Diagnosis

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 villi.

Clinical aspects

Three clinical presentations exist.

• Neonatal Type: Most common presentation. After a few days (rarely >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.

Precautions before anesthesia

Ensure adequate hydration and calorific intake. Assess neurologic status.

Anesthetic considerations

Surgery may be associated with acute deterioration. Prolonged sedation and delayed recovery have been reported. Adequate hydration and caloric input should be maintained perioperatively.

Pharmacological implications

Ketamine appears to ...