CD-ROM Today 1996 January/CD-ROM Today 1996 January.iso/dp/0409/04097.txt

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$Unique_ID{BRK04097}
$Pretitle{}
$Title{PEPCK Deficiency, Mitochondrial}
$Subject{PEPCK Deficiency Mitochondrial Phosphoenolpyruvate Carboxykinase
Deficiency Mitochondrial Korsakoff's Syndrome Leigh's Disease Pyruvate
Carboxylase Deficiency Pyruvate Dehydrogenase Deficiency}
$Volume{}
$Log{}

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

875:
PEPCK Deficiency, Mitochondrial

** IMPORTANT **
It is possible that the main title of the article (Mitochondrial PEPCK
Deficiency) is not the name you expected.  PLease check the SYNONYMS listing
to find the alternate name and disorder subdivisions covered by this article.

Synonyms

     Phosphoenolpyruvate Carboxykinase Deficiency, Mitochondrial

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

     Korsakoff's Syndrome
     Leigh's Disease
     Pyruvate Carboxylase Deficiency
     Pyruvate Dehydrogenase Deficiency

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.

Mitochondrial PEPCK Deficiency is an extremely rare disorder of
carbohydrate metabolism inherited as an autosomal recessive trait.  A
deficiency of the enzyme phosphoenolpyruvate carboxykinase, which is a key
enzyme in the conversion of proteins and fat to glucose (gluconeogenesis),
causes an excess of acid in the circulating blood (acidemia).
Characteristics of this disorder are low blood sugar (hypoglycemia), loss of
muscle tone, an abnormal enlargement of the liver and failure to gain weight
and grow normally.

Symptoms

Patients with Mitochondrial PEPCK Deficiency have an inherited deficiency in
the enzyme phosphoenolpyruvate carboxykinase.  This enzyme is key in the
process of converting proteins and fat to glucose (gluconeogenesis).  Major
symptoms of this disorder are:

Lactic acidemia - presence of excess acid in the circulating blood.

Hypoglycemia - an abnormally low blood sugar (glucose) level.  Glucose is
essential for the functioning of many organs and systems in the body,
especially the central nervous system.

Hypotonia - loss of muscle tone.

Hepatomegaly - abnormal enlargement of the liver.

Failure to thrive - inability to gain appropriate weight and grow
normally.

One patient with Mitochondrial PEPCK Deficiency was reported to have
swelling of the arms and legs (Peripheral edema), a disorder in liver
function and fever for no apparent reason.  It is not known whether these
symptoms are related to the disorder.

The course of this disorder can be very rapid.

Causes

Mitochondrial PEPCK Deficiency is a very rare disorder that is inherited as
an autosomal recessive trait.  Human traits, including the classic genetic
diseases, are the product of the interaction of two genes, 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 for the same
trait 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 not
show 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

Mitochondrial PEPCK Deficiency affects males and females in equal numbers.
This disorder is extremely rare and very few cases have been reported in the
medical literature.

Related Disorders

Symptoms of the following disorders can be similar to those of Mitochondrial
PEPCK Deficiency.  Comparisons may be useful for a differential diagnosis:

Korsakoff's Syndrome is a deficiency of vitamin B-1 (thiamine) which
causes cardiovascular, central and peripheral nervous system disturbances.
The disease results from either inadequate dietary intake of B-2 or from
impaired absorption or utilization of vitamin B-1.  It is common in the
orient where excessive milling of rice reduces its thiamine content.  (For
more information on this disorder, choose "Korsakoff" as your search term in
the Rare Disease Database).

Leigh's Disease is a rare genetic metabolic disorder characterized by
lesions of the brain, spinal chord, optic nerve and in some cases, an
enlarged heart.  Symptoms during infancy may include low body weight, slow
growth, tremors, skin changes and interrupted breathing patterns.
Progressive neurological disturbances, mental retardation, slurred speech and
loss of motor coordination (ataxia) may occur in cases beginning during or
after infancy.  Leigh's Disease is thought to be inherited through an
autosomal recessive trait.  (For more information on this disorder, choose
"Leigh" as your search term in the Rare Disease Database).

Pyruvate Carboxylase Deficiency is a rare metabolic disorder in which
there is a deficiency of the enzyme pyruvate carboxylase.  This disorder
causes an excess presence of acid in the circulating blood (lactic acidemia),
neurologic deterioration, vomiting, irritability, inactivity, loss of muscle
tone, abnormal eye movements, and seizures.  The course of this disorder is
progressive.  It is inherited through an autosomal recessive trait.  (For more
information on this disorder, choose "Pyruvate Carboxylase " as your search
term in the Rare Disease Database).

Pyruvate Dehydrogenase Deficiency is a rare disorder of carbohydrate
metabolism inherited through an autosomal recessive trait.  Symptoms are
caused by a deficiency of the enzyme pyruvate dehydrogenase resulting in
persistent or recurrent metabolic acidosis (acidemia).  The disorder is
manifested by mental retardation and other neurological symptoms.  (For more
information on this disorder, choose "Pyruvate Dehydrogenase" as your search
term in the Rare Disease Database).

Therapies:  Standard

Diagnosis of PEPCK Deficiency can be made shortly after birth by biochemical
analysis of fibroblast cells.

Genetic counseling may be of benefit for patients and their families.
Other treatment is symptomatic and supportive.

Therapies:  Investigational

Treatment of severe lactic acidosis with Dichloroacetate appears to improve
certain laboratory tests, but does not result in improvement of symptoms.  A
study published in the November 26, 1992 New England Journal of Medicine
indicated that only twelve percent of the Dichloroacetate-treated patients
survived and seventeen percent of the placebo-treated group survived.
Scientists do not understand why this appears to reduce arterial-blood
lactate concentrations and pH, but fails to alter the disease.

Research on inborn errors of metabolism, such as PEPCK Deficiency, is
ongoing.  Scientists are studying the causes of these disorders and trying to
design enzyme replacement therapies that will return a missing enzyme to the
body.  In PEPCK Deficiency patients are unable to metabolize the enzyme.
Scientists are investigating the reasons why the enzyme is not metabolized so
they can understand how to correct the metabolic defect.

The National Institutes of Health (NIH) is sponsoring the Human Genome
Project which is aimed at mapping every gene in the human body and learning
why they sometimes malfunction.  It is hoped that this new knowledge will
lead to prevention and treatment of birth defects in the future.

This disease entry is based upon medical information available through
December 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 Mitochondrial PEPCK Deficiency, please contact:

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

     Lactic Acidosis Support Group
     1620 Marie Ave.
     Denver, CO  80229
     [phone] or 287-4953

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

     Institute Digestive Diseases Information Clearinghouse
     P.O. Box NDDIC
     Bethesda, MD  20892
     [phone]

For Genetic Information and Genetic Counseling Referrals:

     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

MENDELIAN INHERITANCE IN MAN, 9th Ed.:  Victor A. McKusick, Editor:  Johns
Hopkins University Press, 1990.  Pp.  1421.

THE METABOLIC BASIS OF INHERITED DISEASE, 6th ed.:  Charles R. Schriver,
et al.; eds., McGraw Hill, 1989.  Pp.  878-9.

A CONTROLLED CLINICAL TRIAL OF DICHLOROACETATE FOR TREATMENT OF LACTIC
ACIDOSIS IN ADULTS:  P.W. Stacpoole, et al.; The New England Journal of
Medicine; (November 26, 1992, issue 327 (22)).  Pp. 1564-69.