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$Unique_ID{BRK04035}
$Pretitle{}
$Title{N-Acetyl Glutamate Synthetase Deficiency}
$Subject{N-Acetyl Glutamate Synthetase Deficiency NAGS Deficiency Urea Cycle
Disorders Inborn Errors of Urea Synthesis }
$Volume{}
$Log{}

Copyright (C) 1986, 1987, 1990, 1992 National Organization for Rare
Disorders, Inc.

313:
N-Acetyl Glutamate Synthetase Deficiency

** IMPORTANT **
It is possible the main title of the article (N-Acetyl Glutamate
Synthetase Deficiency) is not the name you expected.  Please check the
SYNONYMS listing to find the alternate names and disorder subdivisions
covered by this article.

Synonyms

     NAGS Deficiency
     Urea Cycle Disorders
     Inborn Errors of Urea Synthesis

General Discussion

** REMINDER **
The information contained in the Rare Disease Database is provided for
educational purposes only.  It should not be used for diagnostic or treatment
purposes.  If you wish to obtain more information about this disorder, please
contact your personal physician and/or the agencies listed in the "Resources"
section of this report.


N-Acetyl Glutamate Synthetase (NAGS) Deficiency is one of several
hereditary urea cycle disorders.  These disorders are caused by a deficiency
of one of the enzymes needed for the breakdown of ammonia into urea, which is
normally excreted in the urine.  The deficiencies cause an excess of ammonia
in the blood (hyperammonemia).  (For more information on the other Urea Cycle
Disorders, choose "urea cycle disorder" as your search term in the Rare
Disease Database.)

In NAGS Deficiency the deficient enzyme is N-acetyl glutamate synthetase.
If left untreated, NAGS deficiency manifests itself by an elevated level of
toxic ammonia in the blood (hyperammonemia).  Untreated this imbalance may
lead to brain damage, coma, and eventually death.

Symptoms

NAGS Deficiency is characterized in infants by an excess of ammonia in the
blood (hyperammonemia).  Differential diagnosis is based on the absence of
citrulline and a low level of arginine in blood plasma and a low level of
orotic acid in the urine.  Immediate treatment after diagnosis in newborn
babies is imperative.  If left untreated, brain damage and coma usually
occur, which may lead to death.

Causes

NAGS Deficiency is an autosomal recessive hereditary disorder in which the
activity of the enzyme N-acetyl glutamate synthetase is deficient.  This
deficiency causes an accumulation of excess ammonia in blood and body
tissues.  (Human traits including the classic genetic diseases, are the
product of the interaction of two genes for that condition, one received from
the father and one from the mother.  In recessive disorders, the condition
does not appear unless a person inherits the same defective gene from each
parent.  If one receives one normal gene and one gene for the disease, the
person will be a carrier for the disease, but usually will show no symptoms.
The risk of transmitting the disease to the children of a couple, both of
whom are carriers for a recessive disorder, is twenty-five percent.  Fifty
percent of their children will be carriers, but healthy as described above.
Twenty-five percent of their children will receive both normal genes, one
from each parent and will be genetically normal.)

Affected Population

NAGS Deficiency is a very rare disorder affecting less than a thousand people
in the United States.  Males and females are affected equally.  Onset of the
symptoms occurs at birth.

Related Disorders

Organic Acidemias are characterized by hyperammonemia associated with
metabolic acidosis, with an anion gap, and sometimes ketonuria.  These
disorders are also of genetic origin and affect the Urea Cycle as a secondary
phenomenon.

Reye Syndrome is a combination of acute brain disease (encephalopathy),
and fatty degeneration of the abdominal organs (viscera), which tends to
follow some acute virus infections (such as flu and chickenpox) combined with
certain toxins (usually aspirin).  (For more information, choose "Reye" as
your search term in the Rare Disease Database.)

The following Urea Cycle Disorders can also be found in the Rare Disease
Database.  They are all characterized by deficiencies of enzymes that are
needed for different steps in the incorporation of ammonium into urea.  The
symptoms of all Urea Cycle Disorders result from hyperammonemia, in different
degrees of severity.

     Carbamyl Phosphate Synthetase (CPS) Deficiency
     Ornithine Transcarbamylase (OTC) Deficiency
     Citrullinemia
     Arginino Succinic Aciduria
     Arginase Deficiency

Therapies:  Standard

As soon as a urea cycle disorder is suspected, a number of diagnostic tests
should be performed, including measurement of pH to assess the acidity of
blood and body tissues, plasma levels of ammonia, amino acids, and
bicarbonate.  However, before the results of these tests are in, treatment of
hyperammonemia should be started to prevent coma and/or brain damage.

As soon as CPS Deficiency is diagnosed in a newborn baby, dialysis or
exchange transfusion should be started.  If hyperammoniac coma is present
shortly after birth, a combined treatment needs to be started as soon as
possible, which may include hemodialysis.

Genetic counseling is imperative for the family of children with CPS
Deficiency.

Enzyme replacement therapy shows potential promise for treatment of urea
cycle disorders including CPS Deficiency.  Research on this type of therapy
is in a preliminary stage.  A regimen consisting of acute hemodialysis
followed by a restricted intake of protein, plus sodium benzoate, sodium
phenylacetate, and orginine or citrulline is being used on an experimental
basis.

Two new investigational drugs, sodium (or calcium) benzoate, and sodium
(or calcium) phenylacetate, are used to enhance waste nitrogen excretion.
Thus they prevent toxic ammonia buildup in the blood.  These orphan drugs
have been developed by Dr. Saul Brusilow (see Resources section of this
entry) who is also developing sodium (or calcium) phenylbutyrate which does
not have an offensive smell.

The drug benzoate/phenylacetate (Ucephan) was approved in 1988 for use in
the prevention and treatment of hyperammonemia in patients with urea cycle
enzymopathy (UCE) due to enzyme deficiencies.  The drug is manufactured by:

     Kendall McGaw Laboratories, Inc.
     P.O. Box 25080
     Santa Ana, CA  92799-5080

For information on additional therapies that have been designated as
Orphan Drugs in the last few months, please return to the main menu of NORD
Services and access the Orphan Drug Database.

Therapies:  Investigational

Clinical trials are underway to study L-Carnitine in amino acid and fat
metabolism.  Interested persons may wish to contact:

     Charles R. Roe, M.D.
     Box 3028
     Duke University Medical Center
     Durham, NC 27710
     [phone]

to see if further patients are needed for this research.

This disease entry is based upon medical information available through
January 1992.  Since NORD's resources are limited, it is not possible to keep
every entry in the Rare Disease Database completely current and accurate.
Please check with the agencies listed in the Resources section for the most
current information about this disorder.

Resources

For more information on N-Acetyl Glutamate Synthetase Deficiency, please
contact:

     National Organization for Rare Disorders (NORD)
     P.O. Box 8923
     New Fairfield, CT  06812-1783
     [phone]

     National Urea Cycle Disorders Foundation
     4559 Vauxhall Rd.
     Richmond, VA  23234-3556

     National Digestive Diseases Information Clearinghouse
     Box NDDIC
     Bethesda, MD  20892
     [phone]

     Saul Brusilow, M.D.
     301 Children's Medical and Surgical Center
     Johns Hopkins Hospital
     600 N. Wolfe St.
     Baltimore, MD  21205
     [phone]

     The National Kidney Foundation
     2 Park Ave.
     New York, NY  10016
     (212) 8689-2210
     [phone]

     American Kidney Fund
     6110 Executive Blvd., Suite 1010
     Rockville, MD  20852
     [phone]
     [phone]
     [phone] (MD)

     Research Trust for Metabolic Diseases in Children
     Golden Gates Lodge, Weston Rd.
     Crewe CW1 1XN, England
     Telephone:  [phone]

For information on genetics and genetic counseling referrals, please
contact:

     March of Dimes Birth Defects Foundation
     1275 Mamaroneck Avenue
     White Plains, NY  10605
     [phone]

     Alliance of Genetic Support Groups
     35 Wisconsin Circle, Suite 440
     Chevy Chase, MD  20815
     (800) 336-GENE
     [phone]

References

DISORDERS OF THE UREA CYCLE:  Saul W. Brusilow; Hospital Practice (October
15, 1985; issue 305).  Pp.  65-72.

SYMPTOMATIC INBORN ERRORS OF METABOLISM IN THE NEONATE:  Saul W. Brusilow
and David L. Vallee; In:  Current Therapy in Neonatal-Perinatal Medicine.
Marcel Decker, 1985.  Pp. 207-212.