Index
It is a rare multisystemic genetic disorder.
It is 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 divided 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 person to person. Nephropathic cystinosis occurs in childhood and is the most common and severe form.
Early detection and prompt treatment are critical to reduce the development and progression of symptoms associated with cystinosis. The kidneys and eyes are the two most affected organs.
People 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 in 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 excess metabolic products (such as cystine) out of the lysosome.
In the case of cystinosis, the lack of such a specific transporter causes cystine to accumulate in the lysosomes of cells throughout the body. Cystine forms crystals (crystallizes) in many types of cells and slowly damages affected organs.
Signs and symptoms
At one point, nephropathic cystinosis was fatal at a very young age.
However, the development of a drug known as cysteamine (which lowers cystine levels in the body) and improvements in kidney transplants have transformed cystinosis from a fatal kidney disorder to a chronic multisystemic disorder with a life expectancy that it reaches into adulthood and even beyond.
The specific symptoms and severity of cystinosis vary greatly from person to person based on several factors, including age of onset and whether the disorder is diagnosed and treated promptly.
Progression of the disorder can be slowed by early diagnosis and treatment. Eventually, cystinosis can affect all tissues in 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 discuss their specific case, associated symptoms, and general prognosis with their doctor and medical team.
Cistinosis nefropática
Nephropathic or infantile cystinosis is the most common and severe form of cystinosis. The symptoms of nephropathic cystinosis usually appear in the second half of the first year of life.
Specific symptoms can be mild or severe depending on the individual case and the age at which treatment is started.
Growth failure and renal Fanconi syndrome are often the first notable complications of the disorder. Although babies appear normal at birth, by the age of one they often fall in the third percentile for height and weight.
Additionally, affected babies may have bouts of vomiting, poor appetite, and feeding difficulties that contribute (along with kidney dysfunction) to nutritional deficiency and lack of weight gain and growth at the expected rate (lack of growth). .
On average, growth in children not treated with cystinosis occurs at 60 percent of the expected rate.
Babies with nephropathic cystinosis develop Fanconi renal syndrome, a rare disorder characterized by kidney dysfunction. The kidneys are two bean-shaped organs located just below the rib cage.
The kidneys have several functions, such as filtering and excreting waste products from the blood and body, creating certain hormones, and helping to 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 are unable to reabsorb a variety of necessary 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 manifest between 6 and 12 months of age and may include excessive thirst (polydipsia), excessive urine production and passage (polyuria), electrolyte imbalances, vomiting, and dehydration with or without fever.
Dehydration can be serious in some affected people.
Fanconi’s renal syndrome can also cause hypophosphatemic rickets. In this disorder, because the kidneys cannot reabsorb phosphorus from the urine, the body filters phosphate from the bones to maintain phosphorus levels in the blood; This results in progressive softening and weakening of the bone (rickets).
Rickets can cause bone deformity and delay walking because it is painful. Affected children can walk cautiously. Kidney dysfunction can also cause excessive amounts of calcium to be lost from the body through the urine (hypercalciuric hypocalcemia).
Low calcium levels can cause intermittent muscle spasms (tetany) and, rarely in cystinosis, seizures.
If left untreated, the kidney’s filtering function will continue to deteriorate, eventually progressing to kidney failure by age 10.
Treatment with drugs that lower cystine levels can slow or stop the progression of kidney disease and delay the need for a kidney transplant in the teenage years, to age 20 or older.
Any existing kidney damage that occurs before diagnosis (and therefore before treatment) is irreversible.
Extrarenal symptoms
Children with nephropathic cystinosis may also develop non-kidney related symptoms (extrarenal symptoms). Again, these findings are highly variable, and an affected child will not develop all of the symptoms discussed below.
Specific extrarenal symptoms vary greatly depending on the age at which treatment is started and the specific organs involved; Those organs may include:
- The eyes.
- The bone marrow.
- The liver.
- The pancreas.
- Spleen
- The intestine.
- Brain.
- Thyroid
- The muscles.
- The testicles.
At any age, children can develop abnormal sensitivity to light (photophobia) and irritation due to the formation of cystine crystals on the cornea. The severity of photophobia can vary. In some untreated individuals, recurrent corneal erosions and pain may develop.
Around the age of 10, affected children may also develop a deficiency in thyroid hormone production (hypothyroidism) due to the accumulation of cystine crystals 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 in the body, such as growth, maturation, and the rate of metabolism. The symptoms of hypothyroidism are highly variable, but can include fatigue, feeling cold, dry skin, constipation, and depression.
As a group, children with nephropathic cystinosis do not produce normal amounts of tears, sweat, or saliva. Tear production can decrease and the eyes become dry.
A decreased ability to sweat can potentially cause total exhaustion or collapse due to heat (heat prostration).
Puberty can take a year or two. Untreated males experience hypogonadism, in which the testes produce reduced amounts of testosterone.
Testosterone plays a key role in the growth and development of male secondary sexual characteristics during puberty.
Intelligence is usually normal, although many children experience learning disabilities.
Some children may have problems with visual information processing, short-term visual memory, difficulties identifying common objects through touch (tactile recognition), and an inability to visually recognize the spatial relationship between objects (poor visuospatial skills) .
An example of visuospatial skills is the perception of distance and depth. Problems with engine speed and sustained attention have also been reported.
Some affected children have behavioral and psychosocial problems, which are common in children with chronic illnesses.
IQ levels, while in the normal range, may be lower than would be expected based on the IQ levels of parents and siblings.
Children with nephropathic cystinosis may have slightly 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 the cerebrospinal fluid within the brain (intracranial hypertension), which can cause headaches and swelling of the optic disc (papilledema).
Late onset abnormalities
The increased longevity of people with nephropathic cystinosis has revealed that additional complications affecting organs other than the kidneys can occur during life.
These complications develop due to the chronic accumulation of cystine crystals in individuals who have not been adequately treated with cysteamine, although they have undergone a kidney transplant. These additional complications usually develop between the ages of 20 and 40.
Cystine build-up in muscle tissue can cause muscle disease (myopathy) leading to progressive weakness and wasting of the affected muscles.
Deterioration of the throat muscles can lead to swallowing and feeding difficulties. Involvement of the chest muscles can lead to lung failure.
A wide variety of gastrointestinal symptoms can develop, such as:
- Enlargement of the liver (hepatomegaly), high blood pressure in the main vein of the liver (portal hypertension).
- Enlarged spleen (splenomegaly).
- Gastroesophageal reflux.
- Ulcers, inflammation of the esophagus (esophagitis).
- Dysfunction of the muscles of the gastrointestinal tract (dysmotility).
Additional unusual symptoms include:
- Inflammatory bowel disease
- Tear of the intestine that causes the contents of the intestine to flow into the abdominal cavity (intestinal perforation).
- Inflammation of the peritoneum (peritonitis), which is the membrane that lines the abdominal wall and organs.
High blood pressure (hypertension), atherosclerosis of the coronary arteries, and abnormalities of blood clotting are complications of kidney disease associated with cystinosis.
Additional findings include metabolic bone disease and the inability to properly digest food due to a lack of digestive enzymes normally produced by the pancreas (exocrine pancreatic insufficiency).
Adults with cystinosis can also develop eye abnormalities, such as eyelid spasms (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 perceives light and converts it into nerve signals, which are then transmitted to the brain through the optic nerve.
Although rare, brain dysfunction occurs in some older adults with cystinosis. The exact reason why this occurs is unknown.
Specific symptoms will vary, but some affected individuals may experience a decline in motor and mental abilities. In very rare cases, neurological dysfunction can progress to dementia.
People with nephropathic cystinosis appear to have a higher rate of diabetes than the general population due to the destruction of the pancreas by the accumulation of cystine.
Cistinosis intermedia
Also known as juvenile nephropathic cystinosis or adolescent cystinosis, this form of cystinosis is characterized by all of the signs and symptoms of nephropathic cystinosis described above.
However, the onset of these symptoms does not occur until later, perhaps at 8-20 years of age.
In general, the symptoms are less severe than in the classic childhood nephropathic form and have a slower progression. If left untreated, end-stage kidney failure in intermediate cystinosis usually develops sometime between 15 and 25 years of age.
There is a spectrum of disease severity in cystinosis, with overlap between infantile and intermediate forms.
Cistinosis no nefropática
Also known as ocular or “benign” cystinosis, this form generally affects adults during middle age; It was once called adult cystinosis. Kidney disease does not occur in these individuals.
The disorder appears to affect only the eyes. Untreated individuals with non-nephropathic cystinosis eventually develop photophobia due to the accumulation of cystine crystals in the eyes.
Causes
All types of cystinosis are caused by CTNS.gene mutations. The disease is inherited in an autosomal recessive manner.
Recessive genetic disorders occur when an individual inherits a mutation in the same gene from each parent. If an individual receives a normal gene and a gene for the disease, the person will be a carrier of the disease, but usually will not show symptoms.
Carriers of cystinosis (eg, parents of affected people) never have symptoms of the disease. The risk of two carrier parents passing on the defective gene and thus having an affected child is 25 percent with each pregnancy.
The risk of having a child who is a carrier like the parents is 50 percent with each pregnancy. The chance that a child will receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for men and women.
Researchers have determined that the CTNS gene is located on the short (p) arm of chromosome 17 (17p13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information of each individual. Human cells normally have 46 chromosomes.
Human chromosome pairs are numbered 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 as “p” and a long arm designated as “q”.
Chromosomes are subdivided 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 approximate location of the thousands of genes that are present on each chromosome.
The CTNS gene contains instructions for making (encoding) a protein called cystinosine that is required to transport the amino acid cystine out of lysosomes and into the rest of a cell.
Lysosomes break down (break down) certain proteins into amino acids from their components, such as cystine.
Cystine is transported out of the lysosome by cystinosine. Deficient levels of functional cystinosine result in the accumulation (storage) of cystine in the lysosomes of various tissues and organs in the body.
The accumulated cystine forms crystals, which eventually damage the affected organs.
Affected populations
Cystinosis affects men and women 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, accounting for about 5 percent of all childhood cases of kidney failure.
Related disorders
The symptoms of the following disorders may be similar to those of cystinosis. Comparisons can be useful for a differential diagnosis.
Many different disorders can cause renal Fanconi syndrome in children such as Lowe’s syndrome, Wilson’s disease, type I tyrosinemia, galactosemia, and glycogen storage diseases.
Additional disorders that may have symptoms similar to those found in cystinosis include Bartter syndrome and diabetes insipidus.
There are several types of metabolic disorders in which the secondary accumulation of certain substances such as fats and carbohydrates occurs in the body.
These disorders include:
- Galactosemia.
- Sialidosis.
- Gaucher disease.
- Galactosialidosis.
- Wolman’s disease.
- Cholesteryl ester storage disease.
- Mucopolisacaridosis.
- Other lysosomal storage disorders.
Diagnosis
A diagnosis of cystinosis is based on the identification of characteristic symptoms (eg, symptoms of renal Fanconi syndrome), a detailed history of the patient, a complete clinical evaluation, and a variety of specialized tests.
A rapid diagnosis of cystinosis is essential to maximize the preventive and therapeutic benefits of cystine-depleting medications.
Clinical tests and exams
The diagnosis of cystinosis can be confirmed by measuring cystine levels in certain white blood cells (“polymorphonuclear leukocytes”).
Urinary examination may reveal an excessive loss of nutrients, including minerals, electrolytes, amino acids, carnitine, and water, which is indicative of Fanconi renal syndrome.
A doctor can use a special microscope called a slit lamp to view the eyes at high magnification, which can reveal cystine crystals on 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 mutation in the CTNS gene that causes the disorder. Molecular genetic testing is available through a commercial laboratory.
Prenatal diagnosis is available for families with a known risk of 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 villus sampling can also be used to obtain a prenatal diagnosis of cystinosis. Chorionic villi are thin, hair-like structures found in the placenta.
These cells can be tested for elevated levels of cystine.
Treatment
The treatment of cystinosis is directed towards the specific symptoms that are evident in each individual. Treatment may require the coordinated efforts of a team of specialists.
Pediatricians, kidney specialists (nephrologists), vision specialists (ophthalmologists), specialists in digestive disorders (gastroenterologists), psychologists and other health professionals may need a systematic and comprehensive plan for the treatment of the affected child. .
Nephropathic and intermediate cystinosis was 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 lifespan into adulthood.
Cystine depletion therapy
In 1994, the Food and Drug Administration (FDA) approved cysteamine bitartrate (Cystagon®) for the treatment of people with cystinosis. In 2013, the FDA approved Procysbi®, an extended-release form of cysteamine.
Cysteamine is a cystine reducing agent that can greatly decrease cystine levels within cells. Cysteamine therapy slows the development and progression of kidney damage and improves growth in children.
Cysteamine can significantly delay the need for a kidney transplant. Some people who underwent early and diligent cysteamine treatment were able to delay a kidney transplant to 20 years or more.
Cysteamine therapy should be started immediately after diagnosis to prevent or delay kidney damage. Cysteamine must be continued throughout life because studies have shown that prolonged treatment with cysteamine and can prevent many of the nonrenal and late complications of cystinosis.
Cysteamine is taken orally, but oral cysteamine does not reach the cornea effectively and therefore fails to remove cystine crystals from the cornea.
Cystaran® (Sigma-Tau Pharmaceuticals) was approved by the FDA in 2012 as a treatment for the accumulation of cystine crystals in the cornea associated with cystinosis.
This cysteamine-containing eye drop solution is the only FDA-approved treatment for eye complications of this disorder.
Cysteamine therapy can cause nausea, vomiting, and gastrointestinal upset. Cysteamine also causes excessive secretion of stomach acids.
Some people taking cysteamine may need to take proton pump inhibitors, such as omeprazole, to reduce stomach acid production, which helps improve gastrointestinal symptoms.
Cysteamine smells and tastes bad, sometimes leading to compliance issues with affected individuals.
Symptomatic therapy
Renal Fanconi syndrome is treated with a high fluid and electrolyte intake to prevent excessive reduction in body water (dehydration).
Sodium bicarbonate, sodium, magnesium, and potassium citrate may be given to help maintain normal electrolyte balance. Acetylcholinesterase (ACE) inhibitors are sometimes used in the hope of slowing the progression of kidney disease.
Indomethacin is an anti-inflammatory drug that is sometimes used to reduce urinary losses of water and electrolytes; Sometimes it also helps to improve the growth rate. If affected individuals take indomethacin, they should be closely monitored regarding their kidney function.
Phosphates and vitamin D are often given to correct impaired phosphate reabsorption from the blood and prevent rickets. Carnitine may be prescribed for some people before transplantation to improve muscle strength.
Proper nutrition is vitally important to ensure that affected infants and children maximize their growth potential. Growth hormone therapy has significantly improved growth in many patients.
L-thyroxine is used to treat hypothyroidism, insulin to treat insulin-dependent diabetes, and testosterone to treat men with underactive testicular function ( hypogonadism ) so that secondary sexual characteristics develop.
Infertility will not respond to testosterone treatment.
Eye symptoms of cystinosis can be treated by avoiding bright light, sunglasses, and lubrication. In extremely rare cases, a corneal transplant may be necessary.
This is generally only required for people with large band keratopathies or those suffering from pain due to repeated corneal erosion.
Some infants and children with cystinosis (for example, those with dysphagia, poor nutrition, and an increased risk of aspiration) may require a gastronomy tube implantation.
With this procedure, a thin tube is placed into the stomach through a small incision in the abdomen, allowing the direct intake of food and / or medicine.
Speech and language therapy can be beneficial in some cases. Genetic counseling can be beneficial to affected individuals and their families.
Kidney transplant
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 person can undergo dialysis.
Dialysis is a procedure in which a machine is used to perform some of the functions of the kidneys: filtering waste products from the bloodstream and helping maintain adequate levels of essential chemicals, such as potassium.
ESRD is not reversible, so people will eventually require a kidney transplant. The rate of progression from kidney dysfunction to ESRD can vary greatly from one individual to another.
People 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.
