Cystinosis
Encyclopedia
Cystinosis 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. Fanconi syndrome occurs when the function of cells in renal tubules are impaired, leading to abnormal amounts of carbohydrate
s and amino acid
s in the urine
, excessive urination, and low blood levels of potassium
and phosphate
s.
cystine
within cells, forming crystals that can build up and damage the cells. These crystals negatively affect many systems in the body, especially the kidneys and eyes.
The accumulation is caused by abnormal transport of cystine from lysosome
s, resulting in a massive intra-lysosomal cystine accumulation in tissues. Via an as yet unknown mechanism, lysosomal cystine appears to amplify and alter apoptosis
in such a way that cells die inappropriately, leading to loss of renal epithelial cells[76. Park MA, Helip-Wooley A, Thoene J: Lysosomal Cystine Storage Augments Apoptosis in Cultured Human Fibroblasts and Renal Tubular Epithelial Cells. J Am Soc Nephrol. 2002; 13:2878-87; Park M, Pejovic V, Kerisit K, Junius S, Thoene J . Increased Apoptosis in Cystinotic Fibroblasts and Renal Proximal Tubule Epithelial Cells Results from Cysteinylation of PKCδ. J Am Soc Neph,17,3167-3175, 2006; Thoene J. Enhanced Apoptosis in the Pathophysiology of Cystinosis Current Pediatric Reviews, 7, 271-276, 2011]. This results in renal Fanconi syndrome
, and similar loss in other tissues can account for the short stature, retinopathy, and other features of the disease.
Definitive diagnosis and treatment monitoring are most often performed through measurement of white blood cell cystine level using tandem mass spectrometry.
problems (sometimes called renal Fanconi syndrome
). The kidney problems lead to the loss of important minerals, salts, fluids, and other nutrients. The loss of nutrients not only impairs growth, but may result in soft, bowed bones (hypophosphatemic rickets), especially in the legs. The nutrient imbalances in the body lead to increased urination, thirst, dehydration, and abnormally acidic blood (acidosis
).
By about age two, cystine crystals may also be present in the cornea
. The buildup of these crystals in the eye causes an increased sensitivity to light (photophobia
). Without treatment, children with cystinosis are likely to experience complete kidney failure by about age ten. Other signs and symptoms that may occur in untreated patients include muscle deterioration, blindness, inability to swallow, diabetes, and thyroid
and nervous system
problems.
The signs and symptoms of intermediate cystinosis are the same as nephropathic cystinosis, but they occur at a later age. Intermediate cystinosis typically begins to affect individuals around age twelve to fifteen. Malfunctioning kidneys and corneal crystals are the main initial features of this disorder. If intermediate cystinosis is left untreated, complete kidney failure will occur, but usually not until the late teens to mid twenties.
People with non-nephropathic or ocular cystinosis do not usually experience growth impairment or kidney malfunction. The only symptom is photophobia due to cystine crystals in the cornea.
It is currently being researched at UC San Diego, The University of Michigan, Tulane University School of Medicine, and at the National Institutes of Health
in Bethesda, Maryland
as well as at Robert Gordon University
in Aberdeen and in Sunderland, UK as well as the Necker Hospital in Paris.
Cystinosis occurs due to a mutation in the gene CTNS
, located on chromosome 17, which codes for cystinosin, the lysosomal cystine transporter. Symptoms are first seen at about 3 to 18 months of age with profound polyuria
(excessive urination), followed by poor growth, photophobia
, and ultimately kidney failure
by age 6 years in the nephropathic form.
All forms of cystinosis (nephropathic, juvenile and ocular) are autosomal recessive, which means that the trait is located on an autosomal gene, and an individual who inherits two copies of the gene - one from both parents - will have the disorder. There is a 25% risk of having a child with the disorder, when both parents are carriers of an autosomal recessive trait.
Cystinosis affects approximately 1 in 100,000 to 200,000 newborns. and there are only around 2,000 known individuals with cystinosis in the world. The incidence is higher in the province of Brittany
, France
, where the disorder affects 1 in 26,000 individuals.
to treat the blood acidosis, as well as potassium and phosphorus supplements. If the kidneys become significantly impaired or fail, then treatment must be begun to ensure continued survival, up to and including renal transplantation.
Lysosomal storage disease
Lysosomal storage diseases are a group of approximately 50 rare inherited metabolic disorders that result from defects in lysosomal function...
characterized by the abnormal accumulation of the amino acid
Amino 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...
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...
. It is a genetic disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
that typically follows an autosomal recessive
Dominance relationship
Dominance in genetics is a relationship between two variant forms of a single gene, in which one allele masks the effect of the other in influencing some trait. In the simplest case, if a gene exists in two allelic forms , three combinations of alleles are possible: AA, AB, and BB...
inheritance
Inheritance
Inheritance is the practice of passing on property, titles, debts, rights and obligations upon the death of an individual. It has long played an important role in human societies...
pattern. Cystinosis is the most common cause of Fanconi syndrome
Fanconi syndrome
Falconi syndrome is a disease of the proximal renal tubules of the kidney in which glucose, amino acids, uric acid, phosphate and bicarbonate are passed into the urine, instead of being reabsorbed. Fanconi syndrome affects the proximal tubule, which is the first part of the tubule to process fluid...
in the pediatric age group. Fanconi syndrome occurs when the function of cells in renal tubules are impaired, leading to abnormal amounts of carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
s and amino acid
Amino 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...
s in 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...
, excessive urination, and low blood levels of potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
and phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
s.
Diagnosis
Cystinosis is a rare genetic disorder that causes an accumulation of the 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...
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...
within cells, forming crystals that can build up and damage the cells. These crystals negatively affect many systems in the body, especially the kidneys and eyes.
The accumulation is caused by abnormal transport of cystine from lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
s, resulting in a massive intra-lysosomal cystine accumulation in tissues. Via an as yet unknown mechanism, lysosomal cystine appears to amplify and alter apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
in such a way that cells die inappropriately, leading to loss of renal epithelial cells[76. Park MA, Helip-Wooley A, Thoene J: Lysosomal Cystine Storage Augments Apoptosis in Cultured Human Fibroblasts and Renal Tubular Epithelial Cells. J Am Soc Nephrol. 2002; 13:2878-87; Park M, Pejovic V, Kerisit K, Junius S, Thoene J . Increased Apoptosis in Cystinotic Fibroblasts and Renal Proximal Tubule Epithelial Cells Results from Cysteinylation of PKCδ. J Am Soc Neph,17,3167-3175, 2006; Thoene J. Enhanced Apoptosis in the Pathophysiology of Cystinosis Current Pediatric Reviews, 7, 271-276, 2011]. This results in renal Fanconi syndrome
Fanconi syndrome
Falconi syndrome is a disease of the proximal renal tubules of the kidney in which glucose, amino acids, uric acid, phosphate and bicarbonate are passed into the urine, instead of being reabsorbed. Fanconi syndrome affects the proximal tubule, which is the first part of the tubule to process fluid...
, and similar loss in other tissues can account for the short stature, retinopathy, and other features of the disease.
Definitive diagnosis and treatment monitoring are most often performed through measurement of white blood cell cystine level using tandem mass spectrometry.
Symptoms
There are three distinct types of cystinosis each with slightly different symptoms: nephropathic cystinosis, intermediate cystinosis, and non-nephropathic or ocular cystinosis. Infants affected by nephropathic cystinosis initially exhibit poor growth and particular kidneyKidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
problems (sometimes called renal Fanconi syndrome
Fanconi syndrome
Falconi syndrome is a disease of the proximal renal tubules of the kidney in which glucose, amino acids, uric acid, phosphate and bicarbonate are passed into the urine, instead of being reabsorbed. Fanconi syndrome affects the proximal tubule, which is the first part of the tubule to process fluid...
). The kidney problems lead to the loss of important minerals, salts, fluids, and other nutrients. The loss of nutrients not only impairs growth, but may result in soft, bowed bones (hypophosphatemic rickets), especially in the legs. The nutrient imbalances in the body lead to increased urination, thirst, dehydration, and abnormally acidic blood (acidosis
Acidosis
Acidosis is an increased acidity in the blood and other body tissue . If not further qualified, it usually refers to acidity of the blood plasma....
).
By about age two, cystine crystals may also be present in the cornea
Cornea
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Together with the lens, the cornea refracts light, with the cornea accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is...
. The buildup of these crystals in the eye causes an increased sensitivity to light (photophobia
Photophobia
Photophobia is a symptom of abnormal intolerance to visual perception of light. As a medical symptom photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence of actual physical photosensitivity of the eyes, though the term...
). Without treatment, children with cystinosis are likely to experience complete kidney failure by about age ten. Other signs and symptoms that may occur in untreated patients include muscle deterioration, blindness, inability to swallow, diabetes, and thyroid
Thyroid
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
and nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
problems.
The signs and symptoms of intermediate cystinosis are the same as nephropathic cystinosis, but they occur at a later age. Intermediate cystinosis typically begins to affect individuals around age twelve to fifteen. Malfunctioning kidneys and corneal crystals are the main initial features of this disorder. If intermediate cystinosis is left untreated, complete kidney failure will occur, but usually not until the late teens to mid twenties.
People with non-nephropathic or ocular cystinosis do not usually experience growth impairment or kidney malfunction. The only symptom is photophobia due to cystine crystals in the cornea.
It is currently being researched at UC San Diego, The University of Michigan, Tulane University School of Medicine, and at the National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
in Bethesda, Maryland
Bethesda, Maryland
Bethesda is a census designated place in southern Montgomery County, Maryland, United States, just northwest of Washington, D.C. It takes its name from a local church, the Bethesda Meeting House , which in turn took its name from Jerusalem's Pool of Bethesda...
as well as at Robert Gordon University
Robert Gordon University
Robert Gordon University is located in Aberdeen, Scotland. Building on over 250 years involvement in education, it was granted university status in 1992. Robert Gordon University currently has approximately 16,407 students at its two campuses at Garthdee and the City Centre, studying on over 145...
in Aberdeen and in Sunderland, UK as well as the Necker Hospital in Paris.
Genetics
CTNS (gene)
Cystinosin is a protein that in humans is encoded by the CTNS gene.-External links:*...
, located on chromosome 17, which codes for cystinosin, the lysosomal cystine transporter. Symptoms are first seen at about 3 to 18 months of age with profound polyuria
Polyuria
Polyuria is a condition usually defined as excessive or abnormally large production or passage of urine . Frequent urination is sometimes included by definition, but is nonetheless usually an accompanying symptom...
(excessive urination), followed by poor growth, photophobia
Photophobia
Photophobia is a symptom of abnormal intolerance to visual perception of light. As a medical symptom photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence of actual physical photosensitivity of the eyes, though the term...
, and ultimately kidney failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
by age 6 years in the nephropathic form.
All forms of cystinosis (nephropathic, juvenile and ocular) are autosomal recessive, which means that the trait is located on an autosomal gene, and an individual who inherits two copies of the gene - one from both parents - will have the disorder. There is a 25% risk of having a child with the disorder, when both parents are carriers of an autosomal recessive trait.
Cystinosis affects approximately 1 in 100,000 to 200,000 newborns. and there are only around 2,000 known individuals with cystinosis in the world. The incidence is higher in the province of Brittany
Brittany
Brittany is a cultural and administrative region in the north-west of France. Previously a kingdom and then a duchy, Brittany was united to the Kingdom of France in 1532 as a province. Brittany has also been referred to as Less, Lesser or Little Britain...
, France
France
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...
, where the disorder affects 1 in 26,000 individuals.
Treatment
Cystinosis is normally treated with a drug called cysteamine (brand name Cystagon). The administration of cysteamine can reduce the intracellular cystine content. Cysteamine concentrates inside the lysosomes and reacts with cystine to form both cysteine and a cysteine-cysteamine complex, which are able to leave the lysosomes. When administered regularly, cysteamine decreases the amount of cystine stored in lysosomes and correlates with conservation of renal function and improved growth. Cysteamine eyedrops remove the cystine crystals in the cornea that can cause photophobia if left unchecked. Patients with cystinosis are also often given sodium citrateSodium citrate
Trisodium citrate has the chemical formula of Na3C6H5O7. It is sometimes referred to simply as sodium citrate, though sodium citrate can refer to any of the three sodium salts of citric acid. It possesses a saline, mildly tart flavor. For this reason, citrates of certain alkaline and alkaline earth...
to treat the blood acidosis, as well as potassium and phosphorus supplements. If the kidneys become significantly impaired or fail, then treatment must be begun to ensure continued survival, up to and including renal transplantation.
External links
- Cystinosis Research Network - a non-profit organization advocating research, providing family assistance, and educating the public about cystinosis.
- Cystinosis Patient Registry - contribute to research and be informed of available clinical trials and studies
- GeneReviews/NCBI/NIH/UW entry on Cystinosis
- Cystinosis - Cystinosis Research Foundation- an international research support and education foundation
- BC Health Guide
- Cystinosis Foundation UK - a UK Charity Supporting Families & Research
- Hide and Seek Foundation For Lysosomal Disease Research