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Nonketotic Hyperglycinemia
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Copyright 1988, 1989, 1990, 1994, 2004
Synonyms of Nonketotic Hyperglycinemia


Glycinemia, Nonketotic
Hyperglycinemia, Nonketotic
Disorder Subdivisions

No subdivisions found.
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 lateonset form.
Symptoms
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.
Causes
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 Hproteins 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.
Related Disorders
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.
Standard Therapies
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.
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
www.clinicaltrials.gov. 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
Email: [email protected]
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
Organizations related to Nonketotic Hyperglycinemia

CLIMB (Children Living with Inherited Metabolic Diseases)
Climb Building
176 Nantwich Road
Crewe, CW2 6BG United Kingdom
Phone #: 440-845-2412173
800 #: N/A
e-mail: [email protected]
Home page: http://www.CLIMB.org.uk

Genetic and Rare Diseases (GARD) Information Center
PO Box 8126
Gaithersburg, MD 20898-8126
Phone #: 301-251-4925
800 #: 888-205-2311
e-mail: N/A
Home page: http://rarediseases.info.nih.gov/GARD/

MUMS National Parent-to-Parent Network
150 Custer Court
Green Bay, WI 54301-1243 USA
Phone #: N/A
800 #: N/A
e-mail: [email protected]
Home page: http://www.netnet.net/mums/

NIH/National Institute of Diabetes, Digestive & Kidney Diseases
Office of Communications & Public Liaison
Bldg 31, Rm 9A06
31 Center Drive, MSC 2560
Bethesda, MD 20892-2560
Phone #: 301-496-3583
800 #: -e-mail: [email protected]
Home page: http://www2.niddk.nih.gov/

NKH International Family Network
1401 Ridgefield Avenue
Ocoee, FL 34761 USA
Phone #: 407-484-8479
800 #: -e-mail: [email protected]
Home page: http://www.nkh-network.org

Organic Acidaemias UK
5, Saxon Road
Ashford
Middlesex, TW15 1QL United Kingdom
Phone #: 440-178-4245989
800 #: -e-mail: [email protected]
Home page: http://myweb.tiscali.co.uk/priddy/

The Arc
1825 K Street NW, Suite 1200
Washington, DC 20006
Phone #: 202-534-3700
800 #: 800-433-5255
e-mail: [email protected]
Home page: http://www.thearc.org

Vaincre Les Maladies Lysosomales
2 Ter Avenue
Massy, 91300 France
Phone #: 016-975-4030
800 #: -e-mail: [email protected]
Home page: http://www.vml-asso.org
References
TEXTBOOKS
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.
Beers MH, Berkow R, eds. The Merck Manual, 17th ed. Whitehouse Station, NJ:
Merck Research Laboratories; 1999:179-80.
JOURNAL ARTICLES
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;23:2226.
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.
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.
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.
FROM THE INTERNET
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.
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