Cystinuria

Cystinuria is an inherited autosomal recessive metabolic disorder that is characterized by the formation of cystine stones in the kidneys, ureter, and bladder.

Signs and symptoms
Cystinuria is a cause of persistent kidney stones. It is a disorder involving the defective transepithelial transport of cystine and dibasic amino acids in the kidney and intestine, and is one of many causes of kidney stones. If not treated properly, the disorder could cause serious damage to the kidneys and surrounding organs, and in some rare cases death. The stones may be identified by a positive nitroprusside cyanide test. The crystals are usually hexagonal, translucent, white. Upon removal, the stones may be pink or yellow in color, but later they turn to greenish due to exposure to air.

Genetics
Cystinuria is an autosomal recessive disorder, which means that the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.

Cause
Cystinuria is caused by mutations in the SLC3A1 and SLC7A9 genes. These genes encode two parts of a transporter protein that is made primarily in the kidneys. These defects prevent proper reabsorption of basic, or positively charged, amino acids: lysine, ornithine, arginine. Under normal circumstances, this protein allows certain amino acids, including cysteine, to be reabsorbed into the blood from the filtered fluid that will become urine. Mutations in either of these genes disrupt the ability of this transporter protein to reabsorb these amino acids, allowing them to become concentrated in the urine. As the levels of cystine in the urine increase, the crystals typical of cystinuria are able to form, resulting in kidney stones. Cystine crystals form hexagonal-shaped crystals that can be viewed upon microscopic analysis of the urine. The other amino acids that are not reabsorbed do not create crystals in urine. The disorder affects 1 in 10,000 people, making it the most common genetic error of amino acid transport. Cystinuria is inherited in an autosomal recessive pattern.

Pathophysiology
Cystinuria is characterized by the inadequate reabsorption of cystine in the proximal convoluted tubules after the filtering of the amino acids by the kidney's glomeruli, thus resulting in an excessive concentration of this amino acid in the urine. Cystine may precipitate out of the urine, if the urine is neutral or acidic, and form crystals or stones in the kidneys, ureters, or bladder. It is one of several inborn errors of metabolism included in the Garrod's tetrad. The disorder is attributed to deficiency in transport and metabolism of amino acids.

Clinical Features
Cystinuria is usually asymptomatic when no stone is formed. Once a stone is formed, however, the following symptoms may be present:


 * Dull ache or "colicky" pain
 * Hematuria
 * Obstructive syndromes like hydronephrosis
 * Infective syndromes like pyelonephritis

Investigations
1. Blood: Routine hemogram along with blood sugar, urea, and creatinine.

2. Urine: For cystine crystals, and casts.

3. USG/CT scan to reveal if a stone is present.

4. Genetic analysis to determine which mutation associated with the disorder may be present. Currently genotyping is not available in the United States but might be available in Spain and Italy.

Treatment
Initial treatment is with adequate hydration, alkalinization of the urine with citrate supplementation, and dietary modification to reduce salt and protein intake. If this fails then patients are usually started on chelation therapy with an agent such as penicillamine. Once renal stones have formed, however, the first-line treatment is surgery. Both endoscopic surgery and conventional open-abdominal surgery have proven to be effective treatment modalities for patients with more advanced disease.

Jeffrey Rimer of the University of Houston suggested in October 2010 that treatment with L-cystine dimethylester could prevent the formation of these kidney stones.

Occurrence in animals
This disease is known to occur in at least three mammalian species. These are: humans, domestic dogs canines, and a wild canid, the Maned Wolf of South America. Cystine uroliths have been demonstrated, most usually in male dogs, from approximately 70 breeds including the Australian cattle dog, Australian shepherd, Basenji, Basset, Bullmastiff, Chihuahua, Scottish deerhound, Scottish terrier, Staffordshire terrier and Welsh corgi; and in both male and female Newfoundland dogs