Cystinuria
Encyclopedia
Cystinuria is an inherited autosomal
recessive disease
that is characterized by the formation of cystine
stones in the kidneys, ureter
, and bladder
.
Cystinuria is an autosomal recessive disease, which means that the defective gene responsible for the disease 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 disease. The parents of an individual with an autosomal recessive disease both carry
one copy of the defective gene, but usually do not experience any signs or symptoms of the disease.
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 disease 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.
in the urine. Cystine may precipitate out of the urine
, if the urine is neutral or acidic
, and form crystal
s or stones in the kidneys, ureters, or bladder. It is one of several inborn errors of metabolism included in the Garrod's tetrad
. The disease is attributed to deficiency in transport and metabolism of amino acids.
Cystinurics can also experience chronic pain in one, or both, kidneyshttp://cystinuria.com/symptoms/ due to the scars that the jagged edges of the stones can leave or damage from multiple stone removal surgerieshttp://www.ncbi.nlm.nih.gov/pubmed/18533622. This can leave a cystinuric in constant pain which often requires medical intervention, such as long term use of analgesics or surgical procedures, including T11, T12 or T13 nerve blocks (although, these procedures are often not successful, they can provide some relief). Aside from the chronic pain, a cystinuric will often have severe breakthrough pain from passing stones. This type of severe pain, if not properly treated, will force the cystinuric to seek help in an Emergency Department or Urgent Care facility. Since most cystinurics pass stones monthly, weekly, or daily, and need ongoing care, this usually causes medical staff to label these patients as drug seekers or hypochondriacs. Cystinurics have an increased risk for chronic kidney diseasehttp://www.ncbi.nlm.nih.gov/pubmed/21784825http://www.ncbi.nlm.nih.gov/pubmed/19339425 and since kidney damage or poor function is often present in cystinurics, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) or over the counter (OTC) medications should be used with caution. This leaves the patient with little choices regarding pain control and can lead to insufficient medical intervention by physicians.
Cystine stones are often not visible on most x-rays, CT's, and ultrasoundshttp://cystinuria.com/diagnosis/. This does not mean the cystinuric doesn't have a stone. It takes a trained eye and experience to spot a cystine stone. It is not unusual for a cystinuric to pass a stone, or stones, after being released from the hospital with a CT or x-ray result of no stones in the kidneys.
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 disease may be present. Currently genotyping is not available in the United States but might be available in Spain and Italy.
Regular x-rays often fail to show the cystine stones. Cystine stones seem to be 'invisible' with this method unless a dye is added to the blood stream (IVP). (Intravenous Pyelogram
)
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.
Videos of surgery are available on various websites that show stone removal by Percutaneous Nephrolithotomy.
ian species. These are: human
s, domestic dogs canine
s, 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
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
recessive disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
that is characterized by the formation of cystine
Cystine
Cystine is a dimeric amino acid formed by the oxidation of two cysteine residues that covalently link to make a disulfide bond. This organosulfur compound has the formula 2. It is a white solid, and melts at 247-249 °C...
stones in the kidneys, ureter
Ureter
In human anatomy, the ureters are muscular tubes that propel urine from the kidneys to the urinary bladder. In the adult, the ureters are usually long and ~3-4 mm in diameter....
, and bladder
Urinary bladder
The urinary bladder is the organ that collects urine excreted by the kidneys before disposal by urination. A hollow muscular, and distensible organ, the bladder sits on the pelvic floor...
.
Signs and symptoms
Cystinuria is a cause of persistent kidney stones. It is a disease 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 disease 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
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disease. The parents of an individual with an autosomal recessive disease both carry
Genetic carrier
A genetic carrier , is a person or other organism that has inherited a genetic trait or mutation, but who does not display that trait or show symptoms of the disease. They are, however, able to pass the gene onto their offspring, who may then express the gene...
one copy of the defective gene, but usually do not experience any signs or symptoms of the disease.
Cause
Cystinuria is caused by mutations in the SLC3A1SLC3A1
SLC3A1 is a protein associated with cystinuria.Neutral and basic amino acid transport protein rBAT is a protein that in humans is encoded by the SLC3A1 gene.-Further reading:...
and SLC7A9
SLC7A9
Solute carrier family 7 , member 9 also known as SLC7A9 is a protein which in humans is encoded by the SLC7A9 gene.- Function :...
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
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
, ornithine
Ornithine
Ornithine is an amino acid that plays a role in the urea cycle.-Role in urea cycle:L-Ornithine is one of the products of the action of the enzyme arginase on L-arginine, creating urea. Therefore, ornithine is a central part of the urea cycle, which allows for the disposal of excess nitrogen....
, arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
. 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 disease 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 acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
in the urine. Cystine may precipitate out of the urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
, if the urine is neutral or acidic
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
, and form crystal
Crystal
A crystal or crystalline solid is a solid material whose constituent atoms, molecules, or ions are arranged in an orderly repeating pattern extending in all three spatial dimensions. The scientific study of crystals and crystal formation is known as crystallography...
s or stones in the kidneys, ureters, or bladder. It is one of several inborn errors of metabolism included in the Garrod's tetrad
Garrod's tetrad
In medicine, Garrod's tetrad is a term named for British physician Archibald Garrod, who introduced the phrase "inborn errors of metabolism" in a lecture in 1908....
. The disease is attributed to deficiency in transport and metabolism of amino acids.
Clinical Features
Cystinuria is usually asymptomatic when no stone is formed. However, once a stone is formed, or if stone production is severe or frequent, the following symptoms may be present:- Nausea/Vomiting
- Dull ache or "colicColicColic is a form of pain which starts and stops abruptly. Types include:*Baby colic, a condition, usually in infants, characterized by incessant crying*Renal colic, a pain in the flank, characteristic of kidney stones...
ky" pain - Chronic pain
- HematuriaHematuriaIn medicine, hematuria, or haematuria, is the presence of red blood cells in the urine. It may be idiopathic and/or benign, or it can be a sign that there is a kidney stone or a tumor in the urinary tract , ranging from trivial to lethal...
- Obstructive syndromes like hydronephrosisHydronephrosisHydronephrosis is distension and dilation of the renal pelvis calyces, usually caused by obstruction of the free flow of urine from the kidney, leading to progressive atrophy of the kidney...
- Infective syndromes like pyelonephritisPyelonephritisPyelonephritis is an ascending urinary tract infection that has reached the pyelum or pelvis of the kidney. It is a form of nephritis that is also referred to as pyelitis...
- Blood in urine (blood in the urine is not always present in some cystinurics)
Cystinurics can also experience chronic pain in one, or both, kidneyshttp://cystinuria.com/symptoms/ due to the scars that the jagged edges of the stones can leave or damage from multiple stone removal surgerieshttp://www.ncbi.nlm.nih.gov/pubmed/18533622. This can leave a cystinuric in constant pain which often requires medical intervention, such as long term use of analgesics or surgical procedures, including T11, T12 or T13 nerve blocks (although, these procedures are often not successful, they can provide some relief). Aside from the chronic pain, a cystinuric will often have severe breakthrough pain from passing stones. This type of severe pain, if not properly treated, will force the cystinuric to seek help in an Emergency Department or Urgent Care facility. Since most cystinurics pass stones monthly, weekly, or daily, and need ongoing care, this usually causes medical staff to label these patients as drug seekers or hypochondriacs. Cystinurics have an increased risk for chronic kidney diseasehttp://www.ncbi.nlm.nih.gov/pubmed/21784825http://www.ncbi.nlm.nih.gov/pubmed/19339425 and since kidney damage or poor function is often present in cystinurics, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) or over the counter (OTC) medications should be used with caution. This leaves the patient with little choices regarding pain control and can lead to insufficient medical intervention by physicians.
Cystine stones are often not visible on most x-rays, CT's, and ultrasoundshttp://cystinuria.com/diagnosis/. This does not mean the cystinuric doesn't have a stone. It takes a trained eye and experience to spot a cystine stone. It is not unusual for a cystinuric to pass a stone, or stones, after being released from the hospital with a CT or x-ray result of no stones in the kidneys.
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 disease may be present. Currently genotyping is not available in the United States but might be available in Spain and Italy.
Regular x-rays often fail to show the cystine stones. Cystine stones seem to be 'invisible' with this method unless a dye is added to the blood stream (IVP). (Intravenous Pyelogram
Intravenous pyelogram
An intravenous pyelogram is a radiological procedure used to visualize abnormalities of the urinary system, including the kidneys, ureters, and bladder.-Procedure:...
)
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 therapyChelation therapy
Chelation therapy is the administration of chelating agents to remove heavy metals from the body. For the most common forms of heavy metal intoxication—those involving lead, arsenic or mercury—the standard of care in the United States dictates the use of dimercaptosuccinic acid...
with an agent such as penicillamine
Penicillamine
Penicillamine is a pharmaceutical of the chelator class. It is sold under the trade names of Cuprimine and Depen. The pharmaceutical form is D-penicillamine, as L-penicillamine is toxic...
.
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.
Videos of surgery are available on various websites that show stone removal by Percutaneous Nephrolithotomy.
Occurrence in animals
This disease is known to occur in at least three mammalMammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
ian species. These are: human
Human
Humans are the only living species in the Homo genus...
s, domestic dogs canine
Dog
The domestic dog is a domesticated form of the gray wolf, a member of the Canidae family of the order Carnivora. The term is used for both feral and pet varieties. The dog may have been the first animal to be domesticated, and has been the most widely kept working, hunting, and companion animal in...
s, and a wild canid, the Maned Wolf
Maned Wolf
The maned wolf is the largest canid of South America, resembling a large fox with reddish fur.This mammal is found in open and semi-open habitats, especially grasslands with scattered bushes and trees, in south, central-west and south-eastern Brazil The maned wolf (Chrysocyon brachyurus) is the...
of South America
South America
South America is a continent situated in the Western Hemisphere, mostly in the Southern Hemisphere, with a relatively small portion in the Northern Hemisphere. The continent is also considered a subcontinent of the Americas. It is bordered on the west by the Pacific Ocean and on the north and east...
.
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
See also
- CystineCystineCystine is a dimeric amino acid formed by the oxidation of two cysteine residues that covalently link to make a disulfide bond. This organosulfur compound has the formula 2. It is a white solid, and melts at 247-249 °C...
- CysteineCysteineCysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
- Thiola
- International Cystinuria FoundationInternational Cystinuria FoundationThe International Cystinuria Foundation is a Colorado based nonprofit organization that provides educational resources to individuals affected by cystinuria. Its mission is to strengthen, educate, and further the general well being of the cystinuric community...
- Hartnup diseaseHartnup diseaseHartnup disease is an autosomal recessive metabolic disorder affecting the absorption of nonpolar amino acids...
- CystinosisCystinosisCystinosis is a lysosomal storage disease characterized by the abnormal accumulation of the amino acid cystine. It is a genetic disorder that typically follows an autosomal recessive inheritance pattern. Cystinosis is the most common cause of Fanconi syndrome in the pediatric age group...
- HomocystinuriaHomocystinuriaHomocystinuria, also known as cystathionine beta synthase deficiency or CBS deficiency, is an inherited disorder of the metabolism of the amino acid methionine, often involving cystathionine beta synthase...