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Glycine encephalopathy

Synonym(s) NKA
Non-ketotic hyperglycinemia
Prevalence 1-9 / 1 000 000
Inheritance Autosomal recessive
Age of onset Infancy
  • E72.5
MeSH -
MedDRA -


Disease definition

Glycine encephalopathy (GE) is an inborn error of glycine metabolism characterized by accumulation of glycine in body fluids and tissues, including the brain, resulting in neurometabolic symptoms of variable severity.


In Finland, an incidence at birth of 1/55,000 is reported and in British Columbia, Canada, 1/63,000, with a calculated carrier rate of 1/125.

Clinical description

Three forms of GE have been recognized based on the age of onset: neonatal, infantile and atypical glycine encephalopathy (see these terms). Most patients have the life-threatening neonatal form and present mild to severe disease manifestations starting within a few days of birth including lethargy or even coma, hypotonia, hiccups, myoclonic jerks, and breathing/swallowing disorders, with subsequent intellectual deficit, spasticity and intractable seizures. A smaller proportion of patients show developmental delay and generally mild seizures in the infantile period, while others do not develop symptoms until late infancy or adulthood. Although patients usually have either a mild or severe course, there is a continuous clinical spectrum. Some patients develop choreic movements. Atypical glycine encephalopathy indicates hyperglycinemic patients whose clinical presentations are different from those of neonatal or infantile form, for example, transient or late-onset hyperglycinemia and patients with spastic paraparesis.


Mutations in two genes are known to cause glycine encephalopathy: GLDC (9p22) and AMT (3p21.2-p21.1). These genes encode the P-protein and T-protein components of the enzymatic glycine cleavage system (GCS), respectively. Although GCSH is another GCS gene, no mutations have been identified in neonatal or infantile forms. Deficient GCS activity results in defective glycine metabolism and accumulation of the amino acid in body tissues. In some patients with deficient GCS enzyme activity no mutation could be identified by exon sequencing analysis of any GCS gene. The vast majority of patients have no detectable enzyme activity. Etiology of atypical forms remains largely unknown.

Diagnostic methods

GE should be suspected in cases of elevated glycine levels in blood and cerebrospinal fluid (CSF). Increased CSF-to-plasma glycine ratios also suggest the diagnosis. Measurement of GCS activity of biopsied liver sample or by 13C-glycine breath test and genetic testing may confirm diagnosis. Brain MRI may reveal hypogenesis of corpus callosum, abnormal gyrus, and hypogenesis of cerebellum in the neonatal form. Suppression burst and hypsarrhythmia are common in EEG. Subsequently, delayed myelination and atrophy may be observed.

Differential diagnosis

Differential diagnosis includes organic acidemias that may present hyperglycinemia such as D-glyceric acidemia, propionic acidemia, methylmalonic acidemia, isovaleric acidemia, and ketoacidosis due to beta-ketothiolase deficiency (see these terms). Conditions characterized by neonatal seizures should also be considered. Valproate treatment may cause hyperglycinemia.

Antenatal diagnosis

Prenatal diagnosis for at-risk pregnancies can be performed either by molecular genetic testing of the causative genes or by GCS enzyme analysis of chorionic villi sample.

Genetic counseling

Glycine encephalopathy is inherited in an autosomal recessive manner.

Management and treatment

The following tests should be used to guide treatment: brain MRI, EEG, and developmental and neurological assessment. There are only supportive and symptomatic measures for GE including antiepileptics for seizure control, placement of a gastrostomy tube for swallowing disorders, and treatment for gastroesophageal reflux. Sodium benzoate is used to reduce plasma glycine levels. NMDA receptor antagonists may ameliorate neurological symptoms although it remains to be established whether they improve long term outcome.


Prognosis depends on disease severity. Most patients with neonatal or infantile forms have a severe outcome. In the neonatal form, early death sometimes occurs due to apnea. Prognosis in atypical cases is variable.

Expert reviewer(s)

  • Shigeo KURE

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