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NORD is very grateful to Uri S. Alon, MD, Professor of Pediatrics, Director, Bone and Mineral Disorders Clinic, Section of Pediatric Nephrology,The Children's Mercy Hospital and Clinics, for assistance in the preparation 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.
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.
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 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 of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
The symptoms of Cystinuria develop due to the abnormal transport of cystine
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.
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.)
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 potassium citrate, and acetazolamide. This treatment is accompanied by dietary salt restriction.
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. In case of a shortage of Thiola, physicians and pharmacists may contact Mission directly to obtain Thiola for cystinuria patients. To do so, they should call 1-800 531-3333 to request the patient and physician acknowledgement forms. Instructions for returning these forms to Mission have been posted on NORD's Web site. Another medicine that is used at times is captopril.
Kidney and/or bladder surgery sometimes becomes necessary, but stones (calculi) commonly recur. Small stones may pass spontaneously with high fluid intake and if needed pain medications. If unsucessful they 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.
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 National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
As of this writing (2008), there were three clinical trials for cystinuria listed on www.clinicalstrials.gov. One is investigating kidney stones and their cause. This study is sponsored by the Indiana Kidney Stone Institute, Indiana University School of Medicine, and University of Chicago. For information, contact Shelly Handa, RN, at (317) 962-0870 or firstname.lastname@example.org.
The second, sponsored by the Mayo Clinic, involves an herbal substance known as Cystone that is being studied for its effectiveness in dissolving kidney stones and preventing the formation of new ones. For information on this study, Ellen R. Olson at (507) 255-3984 or email@example.com.
The third, sponsored by Mario Negri Institute of Pharmaceutical Research, in Bergamo, Italy, studies the genetic aspects of the disease. Contact Erica Daina, MD daina@marionegri.
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Pediatric Nephrology. 5th Ed.; Ellis D. Avner, William E. Harmon, Patrick Niaudet, Editors, Lippincott Williams and Wilkins, 2004. Pp. 711-714 and 1097-1104.
FROM THE INTERNET
Online Mendelian Inheritance in Man (OMIM). Victor A. McKusick, Editor; Johns Hopkins University, Last Edit Date 11/17/98, Entry Number 220100; Last Edit Date 12/11/98, Entry Number 600918.
Report last updated: 2008/11/17 00:00:00 GMT+0