NORD gratefully acknowledges David J. Sas, DO, Pediatric Nephrologist, Mayo Clinic, Rochester, MN, 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. (A “carrier” is someone who only has one gene mutation for cystinuria, rather than two.) 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 or side of the abdomen (renal colic). Other symptoms may include blood in the urine (hematuria), obstruction of the urinary tract (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.
The symptoms of cystinuria develop due to the abnormal transport of cystine.
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. Recessive genetic disorders occur when an individual inherits two copies of an altered gene for the same trait, one from each parent. If an individual inherits 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 altered gene and 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 is 25%. The risk is the same for males and females.
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.
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 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. Thiola has been shown to lower the level of cystine in the urine of patients with cystinuria. 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 on their own with high fluid intake and, if needed, pain medications. If spontaneous stone passage is unsuccessful, stones may be removed by a special procedure. The surgeon can view the stones through an illuminated optic instrument inserted in the urethra and passed up into the upper urinary tract.The stones are then removed 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 is recommended for patients and their families. Other treatment is symptomatic and supportive.
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Online Mendelian Inheritance in Man (OMIM). Victor A. McKusick, Editor; Johns Hopkins University, Entry Number 220100 Last Update 09/15/2016. https://www.omim.org/entry/220100. Accessed February 15, 2017.
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