Information on the following diseases can be found in the Related Disorders section of this report:

• Acidemias, Methylmalonic
• Isovaleric Acidemia
• Glutaricaciduria II
• Maple Syrup Urine Disease
• Propionic Acidemias

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.

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.

Isovaleric Acidemia is a metabolic disease which is characterized by a deficiency of the enzyme isovaleryl CoA dehydrogenase. The disorder may occur in an acute and a chronic intermittent form. In the acute form, vomiting, refusal to eat, and listlessness usually occur. With treatment and a diet low in protein the disorder becomes chronically intermittent and a nearly normal life is possible.

Methylmalonic Acidemias are another type of organic acidemia. All organic acidemias are inherited as autosomal recessive traits. Each is caused by an enzymatic defect in the metabolism of one amino acid. Without treatment, this may result in an abnormally high level of acid in the blood and body tissues (metabolic acidosis). In acute cases, drowsiness, coma, and/or seizures may occur. Mental retardation is a long-term consequence. The disorders may be caused either by a deficiency of the enzyme methylmalonyl CoA mutase, methylmalonyl racemase, or of adenosylcobalamin synthetic enzymes. Excretion of methylmalonate (a product of amino acid metabolism) in the urine is abnormally high. (For more information on this disorder, choose "Methylmalonic Acidemia" as your search term in the Rare Disease Database.)

Glutaricaciduria II (Glutaric Acidemia II) occurs in two forms during two different stages of life. Both are forms of organic acidemia, a group of metabolic disorders characterized by the presence of excess acid in the blood and urine.

Glutaricaciduria IIA (Glutaric Acidemia IIA)is the neonatal onset form of Glutaricaciduria. It is a very rare, sex-linked hereditary disorder characterized by large amounts of glutaric and other acids in blood and urine. Some researchers believe the disorder is caused by a defect in the breakdown of acyl-CoA compounds.

Glutaricaciduria IIB (Glutaric Acidemia IIB; Ethylmalonic Adipicaciduria)is the milder adult onset form of the disorder. It is inherited as an autosomal recessive trait. Symptoms may include acidity of the body tissues (metabolic acidosis) and a low blood sugar level (hypoglycemia) without an elevated level of ketones in body tissues (ketosis). Large amounts of glutaric acid in the blood and urine are caused by a deficiency of the enzyme "multiple acyl-CoA dehydrogenase". (For more information on this disorder, choose "Glutaricaciduria II" as your search term in the Rare Disease Database".)

Maple Syrup Urine Disease is a hereditary disorder resulting from abnormal metabolism of the four "branched chain" amino acids (protein building blocks), leucine, isoleucine, valine, and alloisoleucine. Without treatment, spasticity alternating with poor muscle tone, convulsions, and sometimes coma characterize the disorder. It derives its name from the odor of the patients' urine and sweat. (For more information on this disorder, choose "Maple Syrup Urine Disease" as your search term in the Rare Disease Database.)

Propionic Acidemia is a very rare genetic form of Ketotic Hyperglycinemia. The disorder is characterized by a deficiency of the coenzyme propionyl CoA carboxylase, one of the enzymes necessary in the process of breaking down amino acids. Propionic Acidemia occurs in two forms. One form begins at birth and the other is milder, occurring less frequently, with symptoms starting later during infancy. Without treatment, dehydration, drowsiness, lethargy, vomiting, and in some cases, coma may develop. (For more information on this disorder, choose "Propionic Acidemia as your search term in the Rare Disease Database.

Diagnosis
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.

Treatment
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.

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.

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.

TEXTBOOKS
Beers MH, Berkow R, eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:179-80.

Hamosh A, Johnston MV. Nonketotic hyperglycinemia. In: Scriver CR, Beaudet AL, Sly WS, et al., eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:2065-78.

REVIEW ARTICLES
Applegarth DA, Toone JR. Nonketotic hyperglycinemia (glycine encephalopathy): laboratory diagnosis. Mol Genet Metab. 2001;74:139-46.

Nissenkorn A, MichelsonM, Ben-Zeev B, et al. Inborn errors of metabolism: a cause of abnormal brain development. Neurology. 2001;56:1265-72.

JOURNAL ARTICLES
Viola A, Chabrol B, Nicoli F, et al. Magnetic resonance spectroscopy study of glycine pathways in nonketotic hyperglycinemia. Pediatr Res. 2002;52:292-300.

Huisman TA, Thiel T, Steinmann B, et al. Proton magnetic resonance spectroscopy of the brain of a neonate with nonketotic hyperglycinemia: in vivo-in vitro (ex vivo) correlation. Eur Radiol. 2002;12:858-61.

Siddiqi ZA, VanLandingham KE, Husain AM. Reflex seizures and non-ketotic hyperglycinemia: an unresolved issue. Seizure. 2002;11:63-66.

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.

Wiltshire EJ, Poplawski NK, Harrison JR, et al. Treatment of late-onset nonketotic hyperglycinemia: effectiveness of imipramine and benzoate. J Inherit Metab Dis. 2003;23:15-21.

Neuberger JM, Schweitzer S, Rolland MO, et al. Effect of sodium benzoate in the treatment of atypical nonketotic hyperglycinemia. J Inherit Metab Dis. 2003;23:22-26.

FROM THE INTERNET
Horizon Molecular Medicine. Nonketotic hyperglycinemia.
www.horizonmedicine.com/conditions.asp#Nonketotic

NKH Parent Network. About NKH. nd.
www.nkh-network.org/aboutnkh.html

Save babies Through Screening. Nonketotic Hyperglycinemia. nd. 2pp.
www.savebabies.orgdiseasedescriptions/nkh.htm