Nonketotic hyperglycinemia is a disorder characterized by abnormally high levels of a molecule called glycine in the body (hyperglycinemia). The excess glycine builds up in tissues and organs, particularly the brain. Affected individuals have serious neurological problems.

Nonketotic hyperglycinemia has two forms, the severe form and the attenuated form. Both forms usually begin shortly after birth, although in some cases, signs and symptoms can begin in the first few months of life. Only the attenuated form begins later in infancy. The forms are distinguished by the seriousness of the signs and symptoms. Severe nonketotic hyperglycinemia is more common. Affected babies experience extreme sleepiness (lethargy) that worsens over time and can lead to coma. They can also have weak muscle tone (hypotonia) and life-threatening breathing problems in the first days or weeks of life. Most children who survive these early signs and symptoms develop feeding difficulties, abnormal muscle stiffness (spasticity), profound intellectual disability and seizures that are difficult to control. Most affected children do not achieve normal developmental milestones, such as drinking from a bottle, sitting up, or grabbing objects, and they may lose any acquired skills over time.

The signs and symptoms of the attenuated form of nonketotic hyperglycinemia are similar to, but milder than, those of the severe form of the condition. Children with attenuated nonketotic hyperglycinemia typically reach developmental milestones, although the skills they achieve vary widely. Despite delayed development, many affected children eventually learn to walk and are able to interact with others, often using sign language. Some affected children develop seizures; if present, seizures are usually mild and can be treated. Other features can include spasticity, involuntary jerking movements (chorea), or hyperactivity.

Individuals with nonketotic hyperglycinemia can also have certain changes in the brain, which can be seen using magnetic resonance imaging (MRI). For example, in children with the severe form of the condition, the tissue that connects the left and right halves of the brain (the corpus callosum) is smaller than average.

Nonketotic hyperglycinemia is estimated to affect at least 1 in 76,000 people worldwide. In Finland, the condition occurs in about 1 in 55,000 newborns, and in British Columbia, Canada, it occurs in about 1 in 63,000 newborns.

Mutations in the GLDC or AMT gene cause nonketotic hyperglycinemia. About 80 percent of cases result from mutations in the GLDC gene, while AMT gene mutations cause about 20 percent of all cases.

The GLDC and AMT genes provide instructions for making enzymes that work together as a group. This group, known as the glycine cleavage system, is responsible for breaking down glycine into smaller pieces when it is no longer needed. Glycine is an amino acid, which is a building block of proteins. Glycine also acts as a neurotransmitter, which is a chemical messenger that transmits signals in the brain. Too much glycine can disrupt brain function.

In addition, the breakdown of glycine by the glycine cleavage system produces a molecule called a methyl group. This molecule is added to and used by a vitamin called folate. Folate is required for many functions in the cell and is important for brain development.

Mutations in either the GLDC or AMT gene impair the system's ability to break down glycine. Some mutations reduce the activity of the glycine cleavage system, while others completely eliminate its activity. When the function of the glycine cleavage system is disrupted, excess glycine can build up in the body's organs and tissues. In addition, the production of methyl groups for use by folate is reduced. It is unclear how these abnormalities contribute to the developmental disability, seizures, breathing difficulties, and other features characteristic of nonketotic hyperglycinemia.

The activity level of the glycine cleavage system helps determine the severity of the disorder: GLDC or AMT gene mutations that completely eliminate the system's activity result in severe nonketotic hyperglycinemia, while mutations that preserve some activity cause attenuated nonketotic hyperglycinemia.

Genetic Testing Information

• Genetic Testing Registry: Non-ketotic hyperglycinemia

Genetic and Rare Diseases Information Center

• Glycine encephalopathy

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• GLYCINE ENCEPHALOPATHY 1; GCE1

Scientific Articles on PubMed

• PubMed

• Aliefendioglu D, Tana Aslan Ay, Coskun T, Dursun A, Cakmak FN, Kesimer M. Transient nonketotic hyperglycinemia: two case reports and literature review. Pediatr Neurol. 2003 Feb;28(2):151-5. doi: 10.1016/s0887-8994(02)00501-5. Citation on PubMed
• Applegarth DA, Toone JR. Glycine encephalopathy (nonketotic hyperglycinaemia) : review and update. J Inherit Metab Dis. 2004;27(3):417-22. doi: 10.1023/b:boli.0000031222.38328.59. Citation on PubMed
• Applegarth DA, Toone JR. Glycine encephalopathy (nonketotic hyperglycinemia): comments and speculations. Am J Med Genet A. 2006 Jan 15;140(2):186-8. doi: 10.1002/ajmg.a.31030. No abstract available. Citation on PubMed
• Coughlin CR 2nd, Swanson MA, Kronquist K, Acquaviva C, Hutchin T, Rodriguez-Pombo P, Vaisanen ML, Spector E, Creadon-Swindell G, Bras-Goldberg AM, Rahikkala E, Moilanen JS, Mahieu V, Matthijs G, Bravo-Alonso I, Perez-Cerda C, Ugarte M, Vianey-Saban C, Scharer GH, Van Hove JL. The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT. Genet Med. 2017 Jan;19(1):104-111. doi: 10.1038/gim.2016.74. Epub 2016 Jun 30. Erratum In: Genet Med. 2018 Sep;20(9):1098. doi: 10.1038/gim.2017.232. Citation on PubMed
• Dinopoulos A, Matsubara Y, Kure S. Atypical variants of nonketotic hyperglycinemia. Mol Genet Metab. 2005 Sep-Oct;86(1-2):61-9. doi: 10.1016/j.ymgme.2005.07.016. Citation on PubMed
• Hoover-Fong JE, Shah S, Van Hove JL, Applegarth D, Toone J, Hamosh A. Natural history of nonketotic hyperglycinemia in 65 patients. Neurology. 2004 Nov 23;63(10):1847-53. doi: 10.1212/01.wnl.0000144270.83080.29. Citation on PubMed
• Kikuchi G, Motokawa Y, Yoshida T, Hiraga K. Glycine cleavage system: reaction mechanism, physiological significance, and hyperglycinemia. Proc Jpn Acad Ser B Phys Biol Sci. 2008;84(7):246-63. doi: 10.2183/pjab.84.246. Citation on PubMed or Free article on PubMed Central
• Stence NV, Fenton LZ, Levek C, Tong S, Coughlin CR 2nd, Hennermann JB, Wortmann SB, Van Hove JLK. Brain imaging in classic nonketotic hyperglycinemia: Quantitative analysis and relation to phenotype. J Inherit Metab Dis. 2019 May;42(3):438-450. doi: 10.1002/jimd.12072. Epub 2019 Mar 20. Citation on PubMed
• Swanson MA, Coughlin CR Jr, Scharer GH, Szerlong HJ, Bjoraker KJ, Spector EB, Creadon-Swindell G, Mahieu V, Matthijs G, Hennermann JB, Applegarth DA, Toone JR, Tong S, Williams K, Van Hove JL. Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia. Ann Neurol. 2015 Oct;78(4):606-18. doi: 10.1002/ana.24485. Epub 2015 Aug 10. Erratum In: Ann Neurol. 2016 Mar;79(3):505. doi: 10.1002/ana.24600. Citation on PubMed or Free article on PubMed Central
• Van Hove JLK, Coughlin C II, Swanson M, Hennermann JB. Nonketotic Hyperglycinemia. 2002 Nov 14 [updated 2019 May 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK1357/ Citation on PubMed