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Potentially life-threatening emergency
Nonketotic hyperglycinemia
Other Resources UpToDate PubMed
Potentially life-threatening emergency

Nonketotic hyperglycinemia

Contributors: Jennifer Vermilion MD, Richard L. Barbano MD, PhD
Other Resources UpToDate PubMed


Nonketotic hyperglycinemia (NKH, glycine encephalopathy) is a rare inborn error of metabolism due to impaired activity of the glycine cleavage system. NKH is an autosomal recessive disorder that can arise from mutations in GLDC, AMT, or GCSH, although rare cases of NKH without a known pathogenic mutation have been described. NKH is characterized by very low or absent enzyme levels resulting in elevated glycine levels in the blood and cerebrospinal fluid (CSF).

The classic form of NKH occurs in the vast majority of individuals, with symptom onset in the first hours to days of life. Initial symptoms include progressive lethargy, coma, hypotonia, myoclonus, and apnea. Children often require intubation and ventilatory support early on. Within 1-3 weeks, spontaneous respiration returns, and the level of alertness improves slightly. However, children develop intellectual disability and seizures with variable prognosis. NKH less commonly presents in infancy. Infantile onset is characterized by hypotonia, developmental delay, and seizures. Individuals may follow a severe or attenuated course, although an attenuated course is more commonly seen in children with infantile onset.

Individuals with a severe disease course make little to no developmental gains and develop refractory epilepsy and progressive spasticity. They may develop scoliosis and swallowing dysfunction. Individuals with an attenuated disease course make some developmental gains, and many learn to walk and talk or use sign language. They often have episodes of lethargy. Seizures are common but more amenable to treatment. Hyperactivity and chorea may develop.

Atypical forms of NKH have been described with onset ranging from late infancy to adulthood. The clinical phenotype in atypical forms varies and can be mild or severe and rapidly progressive.


E72.51 – Non-ketotic hyperglycinemia

237939006 – Non-ketotic hyperglycinemia

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Differential Diagnosis & Pitfalls

  • Transient glycine encephalopathy
  • Hyperglycinemia due to:
  • Hyperglycinuria due to:
    • Hyperprolinemia (type I or II)
    • Familial iminoglycinuria
    • Benign hyperglycinuria
  • Pyridoxamine 5'-phosphate oxidase (PNPO) deficiency
  • Zellweger syndrome
  • Sulfite oxidase deficiency
  • Molybdenum cofactor deficiency
  • Pyridoxine-dependent seizures
  • Pyridoxal 5'-phosphate-responsive encephalopathy
  • Phosphoglycerate dehydrogenase deficiency
  • Hypoxic ischemic encephalopathy

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Last Reviewed:07/28/2019
Last Updated:10/10/2022
Copyright © 2023 VisualDx®. All rights reserved.
Potentially life-threatening emergency
Nonketotic hyperglycinemia
A medical illustration showing key findings of Nonketotic hyperglycinemia : Seizures, Apnea, Coma, Hypotonia, Myoclonus, Developmental delay, Hiccups, Poor feeding
Copyright © 2023 VisualDx®. All rights reserved.