Nonketotic Hyperglycinemia

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  • Glycinemia, Nonketotic
  • Hyperglycinemia, Nonketotic

Disorder Subdivisions

  • None

General Discussion

Nonketotic hyperglycinemia is an inborn error of metabolism characterized by the accumulation of large amounts of the amino acid glycine in blood, urine and, particularly, the cerebrospinal fluid (CSF). The metabolic block occurs in the conversion of glycine into smaller molecules. There are four forms of this disorder: a relatively common neonatal form, an infantile form, a mild-episodic form, and a late-onset form.


The presence of the neonatal form of nonketotic hyperglycinemia becomes apparent in the first few days after birth. This form is characterized by severe illness, failure to thrive, low muscle tone (hypotonia), and drowsiness or lethargy. Intractable seizures are not uncommon and profound mental retardation will almost invariably develop.

The infantile form of is usually recognized after about six months of seemingly normal development, when seizures begin and the signs of varying degrees of mental retardation become evident.

The mild-episodic form appears during childhood in the form of episodes of delirium; involuntary, jerky movements (chorea); inability to look upward (vertical gaze palsy); fever and mild mental retardation.

The late-onset form presents in childhood as well, with progressive stiffness in both legs (spastic diplegia) and degeneration of the optic nerve (optic atrophy), leading to loss of sight. Neither seizures nor mental retardation are associated with this form.

In all forms, the amount of glycine in blood, urine and cerebrospinal fluid is very high.


Nonketotic hyperglycinemia is an autosomal recessive hereditary disorder caused by mutations affecting the breakdown of the amino acid glycine. These mutations occur in the "Glycine Cleavage System", which involves four different protein components known as P-protein, T-protein, H-protein, and L-protein. Mutations in P-, T-, and H-proteins are responsible for nonketotic hyperglycinemia. Most affected individuals have a defect in the P-protein. A few have a defect in the T-protein and, in at least one case, a defect in the H-protein has been identified as the cause. No cases of a defect in the L-protein have been reported.

The gene responsible for encoding the P-protein has been traced to the short arm of chromosome 9 (9p22).

The gene responsible for encoding the T-protein has been traced to the short arm of chromosome 3 (3p21.2-p21.1).

The gene responsible for encoding the H-protein has been traced to the long arm of chromosome 16 (16q24).

The gene responsible for encoding the L-protein has not yet been mapped.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22, and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further subdivided into many bands that are numbered. For example, "chromosome 9p22" refers to band 22 on the short arm of chromosome 9. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Affected Populations

Nonketotic hyperglycinemia is a rare metabolic disorder that usually affects infants soon after birth. Males and females appear to be affected in equal proportions.

In many countries the incidence of this disorder is estimated to be about 1 in 250,000 births. However, in northern Finland the incidence rises to about 1 in 6,000 births.

Standard Therapies


Laboratory tests for the level of glycine in blood serum and in cerebrospinal fluid are key to the diagnosis. In some instances, the diagnosis is made or confirmed by proton magnetic resonance spectroscopy.

Prenatal diagnosis is available but some false negatives have been reported.


Strychnine treatment for seizures has been a moderate success in a few cases of nonketotic hyperglycinemia. The tranquilizer diazepam and sodium benzoate, with or without choline and folic acid (vitamins of the B complex) can sometimes also be beneficial to treat the seizures occurring in this disorder. Other treatment is symptomatic and supportive.

Genetic counseling is recommended for families of children with nonketotic hyperglycinemia.

Investigational Therapies

Research on enzyme replacement therapy is ongoing. It is possible that treatment of Non-Ketotic Hyperglycinemia will be enhanced when scientists learn how to replace or increase enzymes in children affected by enzyme deficiencies.

Information on current clinical trials is posted on the Internet at All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222

TTY: (866) 411-1010


For information about clinical trials sponsored by private sources, contact:



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Toone JR, Applegarth DA, Coulter-Mackie MB, et al. Biochemical and molecular investigations of patients with nonketotic hyperglycinemia. Mol Genet Metab. 2000;70:116-20.

Applegarth DA, Toone JR, Rolland MO, et al. Non-concordance of CVS and liver glycine cleavage enzyme in three families with non-ketotic hyperglycinemia (NKH) leading to false negative prenatal diagnoses. Prenat Diagn. 2000;20:367-70.


McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Glycine Encephalopathy; GCE. Entry Number; 605899: Last Edit Date; 1/10/2003.

McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Glycine Decarboxylase [P-protein]. Entry Number; 238300: Last Edit Date; 1/10/2003.

McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Aminomethyltransferase [T-protein]. Entry Number; 238310: Last Edit Date; 3/11/2002.

McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Glycine Cleavage System L Protein. Entry Number; 238331: Last Edit Date; 6/22/2001.

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