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$Unique_ID{BRK03646}
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$Title{Cystinuria}
$Subject{Cystinuria Cistinuria Cystine-Lysine-Arginine-Ornithinuria Cystinuria
with Dibasic Aminoaciduria Type I Cystinuria Type II Cystinuria Type III
Cystinuria Hypercystinuria Dibasic Aminoaciduria Lysinuria Cystinosis}
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Copyright (C) 1986, 1987, 1988, 1990, 1991, 1993 National Organization
for Rare Disorders, Inc.

61:
Cystinuria

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

Synonyms

     Cistinuria
     Cystine-Lysine-Arginine-Ornithinuria
     Cystinuria with Dibasic Aminoaciduria

Disorder Subdivisions:

     Type I Cystinuria
     Type II Cystinuria
     Type III Cystinuria
     Hypercystinuria

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

     Dibasic Aminoaciduria
     Lysinuria
     Cystinosis

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.


Cystinuria is an inherited metabolic disorder characterized by the
abnormal movement (transport) in the intestines and kidneys, of certain
organic chemical compounds (amino acids).  These include cystine, lysine,
arginine, and ornithine.  Excessive amounts of undissolved cystine in the
urine (cystinuria) cause the formation of stones (calculi) in the kidney,
bladder, and/or ureter.

Four subtypes of Cystinuria are recognized.  In Type I Cystinuria, there
is a defect in the active transport of cystine and the amino acids (dibasic)
lysine, arginine, and ornithine in the kidneys and small intestine.  People
who are carriers of the gene for this type of the disorder generally have no
symptoms.  In Type II Cystinuria, cystine and lysine transport is severely
impaired in the kidneys and only somewhat impaired in the intestines.  In
Type III Cystinuria, kidney transport of cystine and lysine is defective;
intestinal transport is normal.  People who are carriers of the gene for this
variety of the disease typically have slightly elevated levels of cystine and
lysine in the urine.  In Hypercystinuria, there is generally a moderate
elevation of cystine in the urine; intestinal absorption of cystine and the
dibasic amino acids is normal.

Symptoms

People with Cystinuria excrete abnormally high levels of cystine in the
urine.  The level of cystine is so high that it remains undissolved in the
urine (insoluble).  The amino acids lysine, arginine, and ornithine are also
excreted in massive amounts by people with this disorder.  However, these
amino acids dissolve more readily in the urine (more soluble) and are not
associated with any particular symptoms.

The initial symptom of Cystinuria is usually sharp pain in the lower back
(renal colic).  Other symptoms may include blood in the urine (hematuria),
obstruction of the urinary track (ureters), and/or infections of the urinary
tract.  Frequent recurrences ultimately may lead to kidney damage.

People with Cystinuria typically produce stones (cystine calculi) that
are generally small, with a jagged crystalline surface.  These stones may be
accompanied by urinary "gravel," which consists of yellowish-brown hexagonal
crystals.  All patients with urinary stones should be screened for
Cystinuria.

Causes

Cystinuria is inherited as an autosomal recessive genetic 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.

The symptoms of Cystinuria develop due to the abnormal transport of
cystine and the dibasic amino acids.

Affected Population

Cystinuria is an inherited metabolic disorder that affects males and females
in equal numbers.  Symptoms of this disorder typically begin between 10 and
30 years of age, although elevated cystine excretion may be found in infancy.
The disorder occurs in approximately 1 in 7,000 to 1 in 10,000 people in the
United States.  The prevalence of Cystinuria varies in different countries.

Related Disorders

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

In Dibasic Aminoaciduria, the transport of lysine, arginine, and
ornithine is impaired, resulting in increased urinary levels of these amino
acids.  In Lysinuria, lysine transport alone is defective, with abnormally
excessive amounts of lysine in the urine.  Carriers of these diseases tend to
have increased levels of the relevant amino acids.

Cystinosis is a rare inherited disorder of cystine transport
characterized by the accumulation of cystine within the cells of the body,
especially in the kidneys and eyes.  Symptoms of this disorder include the
presence of cystine crystals in the urine, the excretion of abnormally large
volumes of urine (polyuria), abnormally low levels of circulating potassium
(hypokalemia), and/or renal tubular failure.  The accumulation of cystine in
the eyes may result in an increased sensitivity to light (photophobia),
headache, and/or itching and burning of the eyes.  Symptoms usually begin
during infancy.  (For more information on this disorder, choose "Cystinosis"
as your search term in the Rare Disease Database.)

Therapies:  Standard

The primary objective of treatment for Cystinuria is to reduce the cystine
concentration in the urine.  Consumption of large amounts of fluid both day
and night maintains a high volume of urine and reduces cystine concentration
in the urine.  Making the urine more alkaline (alkalization) helps cystine to
dissolve more readily in the urine and therefore may also prevent the
formation of stones.  Drugs that may be prescribed to make the urine more
alkaline include sodium bicarbonate, citrate, and acetazolamide.

Another approach to the treatment of Cystinuria is administration of d-
penicillamine, although there are some risks of side effects with this drug.
D-penicillamine promotes the formation of cystine in a different chemical
form (mixed disulfide), which is more soluble in the urine and is excreted.

The orphan drug alpha-mercaptopropionyl glycine, also known as tiopronin
(Thiola) has been approved as a treatment for Cystinuria.  This drug is
manufactured by Mission Pharmacal of San Antonio, Texas.  Thiola has been
shown to lower the level of cystine in the urine of patients with Cystinuria.

Kidney and/or bladder surgery sometimes becomes necessary, but stones
(calculi) commonly recur.  Small stones may be removed by a special
procedure; the surgeon views the stones through an illuminated optic
instrument and then removes them with special instruments (endoscopic basket
extraction).  Laser techniques and ultrasound have also been used to dissolve
stones in the bladder and/or kidneys that are caused by Cystinuria.

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

Therapies:  Investigational

The drug succimer (meso-2-3-dimercaptosuccinic acid) is being tested as a
treatment for Cystinuria.  This drug may be useful in preventing the
formation of cystine stones.  More study needs to be done to determine the
long-term effectiveness and safety of the drug.

The McNeil Consumer Products Co., Camp Hill Rd., Ft. Washington, PA,
19034, has received orphan drug designation for the drug 2,3-
Dimercaptosuccinic Acid (CHEMET).  It is being tested in some patients with
Cystinuria.  It is hoped that this drug may prevent damage to the kidney in
those patients with Cystinuria who are prone to recurring stones.

A solution of tromethamine-E solution or an acetylcysteine-bicarbo has
also been used experimentally to dissolve cystine stones.  Further studies
are required to determine the long term safety and effectiveness of these
medications in the treatment of Cystinuria.

This disease entry is based upon medical information available through
April 1993.  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 Cystinuria, please contact:

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

     The National Kidney Foundation
     2 Park Ave.
     New York, NY  10016
     [phone]
     [phone]

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

     Researcher:
     Charles Y.C. Pak, M.D.
     The University of Texas Health Science Center at Dallas
     5323 Harry Hines Blvd.
     Dallas, TX  75235

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
     301-652-5553

References

MENDELIAN INHERITANCE IN MAN, 10th Ed.:  Victor A. McKusick, Editor:  Johns
Hopkins University Press, 1992.  P. 1322.

THE METABOLIC BASIS OF INHERITED DISEASE, 6th Ed.:  Charles R. Scriver, et
al., Editors; McGraw Hill, 1989.  Pp. 2488-2493.

CECIL TEXTBOOK OF MEDICINE, 19th Ed.:  James B. Wyngaarden, and Lloyd H.
Smith, Jr., Editors; W.B. Saunders Co., 1990.  Pp. 603-608.

THE MERCK MANUAL, 16th Ed.:  Robert Berkow Ed.; Merck Research
Laboratories, 1992.  Pp. 2084.

BIRTH DEFECTS ENCYCLOPEDIA, Mary Louise Buyse, M.D., Editor-In-Chief;
Blackwell Scientific Publications, 1990.  Pp. 483-484.

THE KIDNEY, 4th Ed.; Barry M. Brenner, M.D. and Floyd C. Rector, Jr.,
M.D., Editors; W. B. Saunders Company, 1991.  Pp. 1602-1604.

CYSTINURIA.  D.S. Milliner; Endocrinol Metab Clin North Am (Dec 1990:
19(4)).  Pp. 889-907.

CYSTINURIA.  R.D. Feld; Crit Rev Lab Sci (1988:  26(3)).  Pp. 243-61.

PERCUTANEOUS CATHETER DISSOLUTION OF CYSTINE CALCULI:  S.P. Dretler, et
al.; Journal Urology (February 1984:  issue 131, 2).  Pp. 216-219.