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Cystinosis is a rare, multisystem genetic disorder characterized by the accumulation of an amino acid called cystine in different tissues and organs of the body including the kidneys, eyes, muscles, liver, pancreas and brain. Generally, cystinosis is broken down into three different forms known as nephropathic cystinosis, intermediate cystinosis and non-nephropathic (or ocular) cystinosis. The age of onset, symptoms, and severity of cystinosis can vary greatly from one person to another. Nephropathic cystinosis presents in infancy and is the most common and severe form. Early detection and prompt treatment are critical in slowing the development and progression of symptoms associated with cystinosis. The kidneys and eyes are the two organs most often affected. Individuals with nephropathic or intermediate cystinosis ultimately require a kidney transplant. Non-nephropathic cystinosis only affects the corneas of the eyes. Cystinosis is caused by mutations of the CTNS gene and is inherited as an autosomal recessive disease.
Cystinosis was first described in the medical literature in 1903 by Abderhalden. Cystinosis is classified as a lysosomal storage disorder. Lysosomes are membrane bound compartments within cells that break down certain nutrients such as fats, proteins and carbohydrates. Lysosomes are the primary digestive unit within cells. Some enzymes within lysosomes break down (metabolize) these nutrients, while other enzymes transport the leftover metabolic products (such as cystine) out of the lysosome. The lack of such a specific transporter causes cystine to accumulate in lysosomes in cells throughout the body. Cystine forms crystals (crystallizes) in many types of cells and slowly damages affected organs.
At one time, nephropathic cystinosis was fatal at a very young age. However, the development of a medication known as cysteamine (which lowers the levels of cystine in the body) and improvements in kidney transplants have transformed cystinosis from a fatal kidney disorder to a chronic, multisystem disorder with a life expectancy well into adulthood and even beyond 50 years of age.
The specific symptoms and severity of cystinosis vary greatly from one person to another based upon several factors including age of onset and whether the disorder is promptly diagnosed and treated. The progression of the disorder can be slowed by early diagnosis and treatment. Eventually, cystinosis can affect all tissues of the body. The age of onset for different symptoms varies greatly.
It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals and parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
Nephropathic cystinosis is the most frequent and most severe form of cystinosis. The symptoms of nephropathic cystinosis usually become apparent within the second half of the first year of life. Specific symptoms can be mild or severe based upon each individual case and the age when treatment is started.
Growth failure and renal Fanconi syndrome are usually the first noticeable complications of the disorder. Although infants appear normal at birth, by the age of one they often fall into the third percentile for height and weight. In addition, affected infants may have episodes of vomiting, poor appetite, and feeding difficulties that contribute (along with kidney dysfunction) to nutritional deficiency and the failure to gain weight and grow at the expected rate (failure to thrive). Ultimately, growth in untreated children with cystinosis occurs at 60 percent the expected rate.
Infants with nephropathic cystinosis develop renal Fanconi syndrome, a rare disorder characterized by kidney dysfunction. The kidneys are two bean-shaped organs located just under the ribcage. The kidneys have several functions including filtering and excreting waste products from the blood and body, creating certain hormones and helping maintain the balance of certain chemicals in the body such as potassium, sodium, chloride, calcium, magnesium, and other minerals and electrolytes. In nephropathic cystinosis, the kidney tubules fail to reabsorb a variety of needed substances, including the compounds mentioned above as well as amino acids, phosphate, calcium, glucose, carnitine, certain proteins and electrolytes. Consequently, affected individuals have abnormally low levels of many of these substances in the body.
Symptoms of renal Fanconi syndrome usually become apparent between 6 and 12 months of age and may include excessive thirst (polydipsia), excessive production and passage of urine (polyuria), electrolyte imbalances, vomiting, and dehydration with or without fever. Dehydration can be severe in some cases.
Kidney dysfunction can also cause hypophosphatemic rickets, a condition in which the kidneys are unable to reabsorb phosphorous from the urine, resulting in progressive softening and weakening of the bone (rickets). Rickets can cause bone deformity and can delay walking, because it is painful. Affected children may walk gingerly. Kidney dysfunction can also cause excessive amounts of calcium to be lost from the body through the urine (hypercalciuric hypocalcemia). Low levels of calcium can cause intermittent muscle spasms (tetany) and seizures.
If left untreated, kidney function will continue to deteriorate, eventually progressing to kidney failure at 10 years of age. Treatment with medications that lower cystine levels can slow or stop the progression of kidney disease and eliminate or delay the need for a kidney transplant into the teen-age years, the 20s or later. Any existing kidney damage that occurs before diagnosis (and therefore before treatment) is irreversible.
Children with nephropathic cystinosis may also develop symptoms unrelated to the kidneys (extrarenal symptoms). Again, these findings are highly variable and affected children will not develop all of the symptoms discussed below. Specific extrarenal symptoms will vary greatly depending upon the age that treatment is begun and the specific organs that become involved; those organs can include the eyes, bone marrow, liver, pancreas, spleen, intestine, brain, thyroid, muscles and testes.
At any age, children may develop an abnormal sensitivity to light (photophobia) and irritation due to the formation of cystine crystals in the cornea. The severity of photophobia can vary. In some untreated individuals, pain and recurrent corneal erosions may develop.
Around the age of 10, affected children may also develop deficiency of thyroid hormone production (hypothyroidism) due to cystine crystals accumulating in the thyroid. The thyroid is a butterfly-shaped gland located at the base of the neck. The thyroid secretes hormones into the bloodstream that influence certain activities of the body such as growth, maturation and the rate of metabolism. Symptoms of hypothyroidism are highly variable, but may include fatigue, feeling cold, dry skin, constipation and depression.
Children with nephropathic cystinosis do not produce tears, sweat or salivate normally. Tear production may be diminished causing the eyes to dry out. An impaired ability to sweat can potentially cause total exhaustion or collapse due to heat (heat prostration).
Puberty may be delayed by one or two years. Untreated males experience hypogonadism, in which the testes produce reduced amounts of testosterone. Testosterone plays a key role in growth and the development of male secondary sexual characteristics during puberty.
Intelligence is usually normal, although many children often experience learning disabilities. Some children may have problems with processing visual information, short-term visual memory, difficulties identifying common objects by touch (tactile recognition) and an inability to visually recognize the spatial relationship among objects (poor visuospatial skills). An example of visuospatial skills is distance and depth perception. Issues with motor speed and sustained attention have also been reported. Some affected children display behavioral and psychosocial issues, which are common in children dealing with chronic illnesses. IQ levels, while in the normal range, may be lower than would be expected based upon the IQ levels of parents and siblings.
Children with nephropathic cystinosis may have mildly altered facial features (craniofacial dysmorphology). Delayed dental development and delayed eruption of permanent teeth can also occur. Some affected individuals may develop increased pressure of cerebrospinal fluid within the brain (intracranial hypertension), which can cause headaches and swelling of the optic disc (papilledema).
The increased longevity of individuals with nephropathic cystinosis has revealed that additional complications affecting organs other than the kidneys can occur later during life. These complications develop due to the chronic accumulation of cystine crystals in individuals who have not been adequately treated by cysteamine, although they have undergone a kidney transplant. These additional complications generally develop between 20 and 40 years of age.
Accumulation of cystine in muscle tissue can cause muscle disease (myopathy) leading to progressive weakness and wasting of affected muscles. Impairment of muscles in the throat can lead to swallowing and feeding difficulties. Involvement of chest muscles can result in pulmonary insufficiency.
A wide variety of gastrointestinal symptoms can develop including enlargement of the liver (hepatomegaly) causing high blood pressure of the main vein of the liver (portal hypertension), enlargement of the spleen (splenomegaly), gastroesophageal reflux, ulcers, inflammation of the esophagus (esophagitis), and dysfunction of the muscles of the gastrointestinal tract (dysmotility). Additional symptoms include inflammatory bowel disease, tearing of the bowel causing the contents of the intestines to flow into the abdominal cavity (bowel perforation), and inflammation of the peritoneum (peritonitis), which is the membrane that lines the abdominal wall and organs.
High blood pressure (hypertension), coronary artery atherosclerosis, and blood clotting abnormalities are complications of the renal disease associated with cystinosis.
Additional findings include metabolic bone disease and an inability to properly digest food due to a lack of digestive enzymes normally produced by the pancreas (pancreatic exocrine insufficiency). Adults with cystinosis may also develop abnormalities affecting the eyes including spasms of the eyelids (blepharospasm), band keratopathy and pigmentary retinopathy. Band keratopathy refers to the accumulation of calcium deposits in a band across the central surface of the cornea, which can cause pain and decreased clarity of vision (visual acuity). Pigmentary retinopathy is characterized by progressive degeneration of the retina, the thin layer of nerve cells that line the inner surface of the back of the eyes. The retina senses light and converts it to nerve signals, which are then relayed to the brain through the optic nerve. Pigmentary retinopathy can impair night and color vision and, eventually, can contribute to overall reduced clarity of vision.
Although uncommon, some older adults with cystinosis eventually develop progressive brain dysfunction. The exact reason this occurs is unknown. Specific symptoms will vary, but some affected individuals may experience a decline in both motor and mental capabilities. In some cases, neurological dysfunction can progress to dementia.
Individuals with nephropathic cystinosis appear to have a higher rate of diabetes than the general population because of destruction of the pancreas by cystine accumulation.
Also known as nephropathic juvenile cystinosis or adolescent cystinosis, this form of cystinosis is characterized by all of the signs and symptoms of nephropathic cystinosis described above. However, onset of these symptoms does not occur until later perhaps around 8 years of age. Generally, the symptoms are less severe than in the classical infantile nephropathic form and have a slower progression. If untreated, end-stage renal failure in intermediate cystinosis usually develops at some point between 15 and 25 years of age. There is a spectrum of disease severity in cystinosis, with overlap of the infantile and intermediate forms.
Also known as ocular or "benign" cystinosis, this form usually affects adults during middle age; it was once called adult cystinosis. Kidney disease does not occur in these individuals. The disorder appears to only affect the eyes. Untreated individuals with non-nephropathic cystinosis eventually develop photophobia due to cystine crystal accumulation in the eyes.
All types of cystinosis are caused by mutations of the CTNS gene. The disease is inherited in an autosomal recessive fashion. Recessive genetic disorders occur when an individual inherits a mutation in the same gene 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 for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.
Investigators have determined that the CTNS gene is located on the short arm (p) of chromosome 17 (17p13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 17p13" refers to band 13 on the short arm of chromosome 17. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The CTNS gene contains instructions for producing (encoding) a protein called cystinosin that is required to transport the amino acid cystine from inside lysosomes. Lysosomes break down (degrade) certain proteins into their component amino acids such as cystine. Cystine is then transported out of the lysosome by cystinosin. Deficient levels of functional cystinosin result in the accumulation (storage) of cystine in the lysosomes of various tissues and organs of the body. The accumulated cystine forms crystals, which eventually damage the affected organs.
Cystinosis affects males and females in equal numbers. The disorder is estimated to occur in 1 in 100,000-200,000 people in the general population. Cystinosis has been reported worldwide, in all ethnic groups. Cystinosis is the most common cause of renal Fanconi syndrome in children and accounts for approximately 5 percent of all childhood cases of kidney failure.
Symptoms of the following disorders can be similar to those of cystinosis. Comparisons may be useful for a differential diagnosis.
Many different disorders can cause renal Fanconi syndrome in children including Lowe syndrome, Wilson disease, tyrosinemia type I, galactosemia, and glycogen storage diseases. Additional disorders that may have symptoms similar to those found in cystinosis include Bartter's syndrome and diabetes insipidus. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
There are several types of metabolic disorders in which secondary accumulation of certain substances such as fats and carbohydrates occurs in the body. These disorders include galactosemia, sialidosis, Gaucher disease, galactosialidosis, Wolman disease, cholesteryl ester storage deficiency, the mucopolysaccharidoses and other lysosomal storage disorders. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
A diagnosis of cystinosis is based upon identification of characteristic symptoms (e.g., symptoms of renal Fanconi syndrome), a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A prompt diagnosis of cystinosis is critical to maximize the preventive and therapeutic benefits of cystine depleting medications.
Clinical Testing and Work-Up
A diagnosis of cystinosis can be confirmed by measuring cystine levels in certain white blood cells ("polymorphonuclear leukocytes").
Urinary examination may reveal excess loss of nutrients including minerals, electrolytes, amino acids, carnitine and water, which is indicative of renal Fanconi syndrome.
A physician may use a special microscope called a slit lamp to view the eyes through high magnification, which can reveal cystine crystals in the cornea. This is diagnostic if performed by an experienced ophthalmologist.
A diagnosis of cystinosis can be confirmed by molecular genetic testing, which can identify the characteristic CTNS gene mutation that causes the disorder. Molecular genetic testing is available through a commercial laboratory.
Prenatal diagnosis is available for families with a known risk for having a baby with cystinosis. Cystine levels can be measured in cells obtained from the fluid that surrounds the developing fetus (amniotic fluid). A test known as chorionic villi sampling can also be used to obtain a prenatal diagnosis of cystinosis. Chorionic villi are thin, hair-like structures found on the placenta. These cells can be examined to detect elevated levels of cystine.
The treatment of cystinosis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, kidney specialists (nephrologists), eye specialists (ophthalmologists), digestive disorder specialists (gastroenterologists), psychologists and other healthcare professionals may need to systematically and comprehensively plan an affected child's treatment.
Nephropathic and intermediate cystinosis were once progressively fatal disorders, with a lifespan for the infantile form of less than 10 years. However, the development of cystine depleting therapies along with improvements in kidney transplantation have extended the lifespan well into adulthood.
Cystine Depleting Therapy
In 1994, the Food and Drug Administration (FDA) approved cysteamine bitartrate (Cystagon®) for the treatment of individuals with cystinosis. In 2013, the FDA approved Procysbi®, an extended release form of cysteamine. Cysteamine is a cystine-depleting agent that can greatly lower cystine levels within cells. Therapy with cysteamine slows the development and progression of kidney damage and enhances growth in children. Cysteamine can significantly delay the need for a kidney transplant. Some individuals who underwent early, diligent treatment with cysteamine were able to delay a kidney transplant into their 20s or longer.
Therapy with cysteamine should be begun immediately after diagnosis to prevent or slow kidney damage. Cysteamine should be continued throughout life because studies have shown that long-standing treatment with cysteamine and can prevent many of the non-renal, late onset complications of cystinosis.
Cysteamine is taken orally, but oral cysteamine does not reach the cornea effectively and, therefore, fails to eliminate cystine crystals from the cornea. Cystaran® (Sigma-Tau Pharmaceuticals) was approved by the FDA in 2012 as a treatment for corneal cystine crystal accumulation associated with cystinosis. This eye-drop solution containing cysteamine is the only FDA approved treatment for the eye complications of this disorder.
Therapy with cysteamine can cause nausea, vomiting and gastrointestinal discomfort. Cysteamine also causes excess secretion of stomach acids. Some individuals taking cysteamine may need to take proton pump inhibitors such as omeprazole to reduce the production of stomach acid, helping to improve gastrointestinal symptoms.
Cysteamine smells and tastes foul, which sometimes leads to compliance issues with affected individuals.
Renal Fanconi syndrome is treated with a high intake of fluids and electrolytes to prevent excessive reduction of body water (dehydration). Sodium bicarbonate, sodium citrate, magnesium and potassium may be administered to help to maintain normal electrolyte balance. Acetylcholinesterase (ACE) inhibitors are sometimes used with the hope of slowing the progression of the renal disease.
Indomethacin is an anti-inflammatory medication that is sometimes used to reduce urinary losses of water and electrolytes; sometimes it also helps to improve growth rate. If affected individuals take indomethacin, they must be closely monitored with respect to their renal function.
Phosphates and vitamin D are often given to correct impaired uptake of phosphate into the kidneys and prevent rickets. Carnitine may be prescribed for some affected individuals in order to improve muscle strength.
Proper nutrition is vitally important to ensure affected infants and children can maximize their growth potential. Growth hormone therapy has significantly improved growth in many cases. L-thyroxine is used to treat hypothyroidism, insulin is used to treat insulin-dependent diabetes and testosterone is used to treat males with underactive testicular function (hypogonadism) so that secondary sexual characteristics will develop.
Ocular symptoms of cystinosis can be treated with avoidance of bright light, sunglasses and lubrication. In extremely rare cases, a corneal transplant may be necessary. This is usually required only for individuals with large band keratopathies or those suffering from pain due to repeated corneal erosions.
Some infants and children with cystinosis (e.g., those with dysphagia, poor nutrition and increased risk of aspiration) may require the implantation of a gastronomy tube. With this procedure, a thin tube is placed into the stomach via a small incision in the abdomen, allowing for the direct intake of food and/or medicine.
Speech and language therapy may be beneficial in some cases. Genetic counseling may be of benefit for affected individuals and their families.
Despite early and prompt treatment, individuals with infantile and intermediate cystinosis eventually develop end stage renal disease (ESRD), requiring a kidney transplant. Initially, an affected individual may undergo dialysis. Dialysis is a procedure in which a machine is used to perform some of the functions of the kidney - filtering waste products from the bloodstream and helping to maintain proper levels of essential chemicals such as potassium. ESRD is not reversible so individuals will eventually require a kidney transplant. The rate of progressive of kidney dysfunction to ESRD can vary greatly from one individual to another. Individuals with cystinosis generally respond very well to a kidney transplant, which can cure renal Fanconi syndrome because cystine does not accumulate in the donated kidney. However, cystine still accumulates in other tissues and organs of the body.
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Trauner DA. Neurological and Cognitive Consequences of Nephropathic Cystinosis. In: Cognitive and Behavioral Abnormalities of Pediatric Diseases, Nass RD, Frank Y, eds. 2010 Oxford University Press, New York, NY. pp. 333-341.
Gahl WA. Cystinosis. In: Pediatric Nephrology, 6th ed, Avner ED, Harmon WE, Niaudet P, Yoshikawa N, eds. 2009 Springer-Verlag, Berlin, Germany. Pp. 1019-1038.
Chadha V, Warady BA. Cystinosis. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:683.
Brodin-Sartorius A, Tete MJ, Niaudet P, et al. Cysteamine therapy delays the progression of nephropathic cystinosis in late adolescents and adults. Kidney Int. 2011; [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/21900880
Wilmer MJ, Schoeber JP, Lambertus P, van den Heuvel, Levtchenko EN. Cystinosis: practical tools for diagnosis and treatment. Pediatr Nephrol. 2011;26:205-215. http://www.ncbi.nlm.nih.gov/pubmed/20734088
Besouw MT, Hulstijn-Dirkmaat GM, van der Rijken RE, et al. Neurocognitive functioning in school-aged cystinosis patients. J Inherit Metab Dis. 2010;33:787-793. http://www.ncbi.nlm.nih.gov/pubmed/20814825
Nesterova G, Gahl W. Nephropathic cystinosis: late complications of a multisystemic disease. Pediatr Nephrol. 2008;23:863-878. http://www.ncbi.nlm.nih.gov/pubmed/18008091
Gahl WA, Balog JZ, Kleta R. Nephropathic cystinosis in adults: natural history and effects of oral cysteamine therapy. Ann Intern Med. 2007;147:242-250. http://www.ncbi.nlm.nih.gov/pubmed/17709758
Ueda M, O'Brien K, Rosing DR, et al. Coronary artery and other vascular calcifications in patients with cystinosis after kidney transplantation. Clin J Am Soc Nephrol. 2006;1:555-562. http://www.ncbi.nlm.nih.gov/pubmed/17699259
Gahl WA, Thoene JG, Schneider JA. Cystinosis. N Engl J Med. 2002;347:111-121. http://www.ncbi.nlm.nih.gov/pubmed/12110740
Nesterova G, Gahl WA. Cystinosis. 2001 Mar 22 [Updated 2012 May 17]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1400/ Accessed Dec 26, 2013.
Elenberg E, Langman CB. Cystinosis. Emedicine Journal, Updated: May 13, 2013. Available at: http://emedicine.medscape.com/article/981650-overview Accessed Dec 26, 2013.
Niaduet P. Cystinosis. Orphanet encyclopedia, March 2004. Available at: http://www.orpha.net/data/patho/Pro/en/Cystinosis-FRenPro11.pdf Accessed Dec 26, 2013.
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