Cystinosis is a hereditary disease belonging to the group of lysosomal accumulation diseases and characterized by impaired metabolism of the amino acid cystine, which leads to the formation of its crystals in the cells of various organs. The severity of the symptoms of this disease depends on the form of pathology, the main manifestations are signs of metabolic disorders (vomiting, polyuria), rickets resistant to the appointment of vitamin D, impaired kidney function, visual pathology. Diagnosis of cystinosis is based on the data of biochemical blood analysis, determination of the level of cystine in various tissues, ophthalmological examination, molecular genetic analyses. Treatment of cystinosis is performed by means that improve the metabolism of this amino acid, symptomatic measures are also used, in severe cases kidney transplantation is prescribed.
E72.0 Disorders of amino acid transport
Cystinosis is an autosomal recessive hereditary disease characterized by a violation of the metabolism of the amino acid cystine with the development of its accumulation and disruption of the work of many organs. For the first time such a disease was described back in 1903 by the Swiss physician and biochemist E. Abdergalden, who also pointed out its hereditary nature. For some time, cystinosis was identified with de Toni-Debre-Fanconi syndrome (or simply Fanconi syndrome), but further studies have shown that the etiology of these conditions is different. They are united by a lesion of the renal tubules, which entails similar disorders, but the cause of kidney damage in this case is different.
The incidence of cystinosis is approximately 1 case per 200,000 population, there are several clinical types of this disease, all of them are inherited by an autosomal recessive mechanism. The sexual distribution of this disease does not have any peculiarities. Cystinosis is one of the few genetic pathologies for which specific treatment is possible, however, timely diagnosis of this disease is important in order to avoid irreversible damage to internal organs (mainly kidneys).
According to recent studies, the main cause of cystinosis is mutations in the CTNS gene located on the 17th chromosome, in total, over a hundred different gene defects have been detected in this disease. The product of CTNS expression is the transmembrane protein cystinosine, located in the lysosomes of almost all cells of the body, its only function is the transport of cystine from lysosomes, where it is formed as a result of protein hydrolysis, into the cytoplasm of the cell.
Mutations of the CTNS gene lead to a change in the conformation or even the absence of this protein, resulting in a gradual accumulation of amino acids in lysosomes, which causes the development of cystinosis. Cystine is poorly soluble in water, so when its concentration increases, it forms crystals that are clearly visible under microscopy or even with the naked eye (for example, in the cornea).
The type of mutation of the CTNS gene has a great influence on the clinical course of cystinosis and the prognosis of this disease. Thus, with homozygous nonsense mutation, the formation of cystinosine in the body of patients does not occur at all, which leads to severe manifestations of the disease starting from early childhood (early infantile form).
Other types of cystinosis (childhood and adult types) are observed, as a rule, in patients who are compaud heterozygotes – one allele of the CTNS gene is affected by nonsense, and the other by a missense mutation that simply changes the conformation of cystinosine, reducing its activity. Many geneticists note that if there are missense mutations in both CTNS alleles, it does not lead to the development of cystinosis, but laboratory studies can reveal a slight increase in the concentration of cystine in tissues.
Currently , there are three main clinical forms of cystinosis:
- early infantile;
- juvenile (intermediate);
- adult (benign).
The reasons for the development of a particular type of disease lie in the molecular genetic aspects of this pathology – the type of mutation of the CTNS gene. Differences in the clinical course of various forms of cystinosis affect the age of development of the disease, the severity of symptoms, further prognosis and the choice of treatment tactics.
It is the most common type of pathology, causing up to 95% of all cases of the disease. Manifestations of metabolic disorders at the same time develop already at the age of 4-7 months – vomiting, dyspeptic disorders occur, the child often becomes restless, sleeps poorly, he has thirst and polyuria. Patients with this form of cystinosis lag behind their peers in physical development, they also have symptoms of rickets (violations of the overgrowth of fontanelles on the skull, deformities of limb bones, curvature of the spine).
The appointment of traditional doses of vitamin D and calcium and phosphorus preparations does not lead to a noticeable improvement in the condition of patients. Children also have photophobia, itching and itching of the eyes, the cornea may be edematous. As a rule, with this form of cystinosis, by the age of 7-10, patients develop chronic renal failure and diabetes mellitus, the complications of which are the cause of death. In some cases, blindness may develop due to corneal opacity and retinal degeneration.
It is characterized by a much more favorable course. In early childhood, no manifestations of this disease are noted, the first symptoms occur in children older than 10 years. The main manifestations of this type of cystinosis are identical to the infantile form, however, the lesion of the cornea, kidneys and pancreas develops much more slowly, which leads to less severity of symptoms and, sometimes, to a later diagnosis.
It is quite rare, but a number of experts attribute this circumstance to the low severity of symptoms and, as a result, frequent misdiagnosis of this condition. This type of disease is characterized by the accumulation of clinically significant amounts of cystine in the tissues of the cornea of the eye, which leads to photophobia, soreness and other ophthalmic symptoms. In laboratory studies, minor deposits of cystine crystals may be detected in other tissues, but this does not lead to a typical clinical picture of cystinosis with damage to the kidneys and other organs.
Deposits of cystine in various organs lead to the development of their dysfunction – most often this phenomenon is registered in the kidneys, cornea of the eyes, intestines, lymph nodes, pancreas, liver. In severe cystinosis, the deposition of amino acids in the epithelium of the tubules eventually causes a violation of the reabsorption of certain ions and low–molecular compounds – potassium, calcium, phosphate ions, glucose, carnitine and a number of others. This leads to the development of polyuria, dehydration of the body, rickets due to loss of calcium and phosphorus, violation of the acid-base balance of the blood.
With the further course of cystinosis, glomerular kidney failure and interstitial nephrosis develop, which entails uremia and other complications. Deposits of cystine in the tissues of the eye can lead to retinal degeneration, photophobia, inflammatory manifestations. As a rule, deposits of this amino acid in cystinosis in other organs are also detected by laboratory tests, but it does not lead to noticeable and pronounced clinical manifestations. The only exception is the pancreas – with a prolonged course of the disease, cystine deposits in it can cause the development of diabetes mellitus.
The diagnosis is made with the help of a general examination of the patient, based on the results of biochemical blood and urine tests, ophthalmological examination, molecular genetic studies:
- Histological and histochemical examination. Microscopic examination of some body tissues (liver, kidney, bone marrow biopsies) reveals flat hexagonal crystals with double refraction inside the cells of these organs. Biochemical tests confirm that the composition of these intracellular inclusions includes the amino acid cystine.
- Blood test. In infantile and manifesting childhood forms of cystinosis, a sharp decrease in the level of inorganic ions – potassium, calcium, chlorine, phosphorus – is observed in the blood. Hypoproteinemia is determined, compensatory hyperlipidemia is possible, anemia due to a lack of proteins and impaired kidney function.
- Biochemical urine samples. Urine tests reveal a significant increase in the concentration of low molecular weight compounds and proteins, which leads to glucosuria, hyperphosphaturia, hyperproteinuria. Daily diuresis increases sharply against the background of a decrease in urine density. Sometimes, against the background of ongoing treatment of cystinosis and a decrease in the main manifestations of the disease, polyuria and polydipsia occur quite sharply – often this indicates the addition of diabetes mellitus. An increase in the biochemical blood analysis of the level of nitrogenous compounds (for example, urea) indicates an increasing renal insufficiency and uremia.
- Ophthalmological examination. The fundus and cornea are examined using a slit lamp – oblong cystine crystals can be detected in the cornea.
- Molecular genetic diagnostics. Direct sequencing of the CTNS gene is performed in order to detect mutations. At the same time, it is also possible to identify the carrier of a pathological gene and determine the type of its mutation, which also affects the prognosis of the disease.
- Prenatal diagnosis. Prenatal diagnosis of cystinosis is possible through genetic or biochemical (determination of the level of cystine in chorionic villi cells) techniques.
Treatment of cystinosis is performed with both specific and supportive drugs. Almost the only remedy that can significantly improve the condition of patients is cysteamine, which facilitates the release of cystine from lysosomes into the cytoplasm of cells, where it is included in the overall metabolism. This reduces the degree of accumulation of this amino acid and helps to reduce the severity of manifestations of cystinosis.
So, with the timely appointment of cysteamine in the case of an infantile form of the disease, the development of uremia slows down by about two times, and the life of patients increases to 20-23 years. A much more pronounced effect of taking this remedy is observed with an intermediate form of cystinosis – patients with this disease can live to an advanced age. Cysteamine is also used for ophthalmic disorders accompanying a benign or adult form of the disease – in this case, there is no need for systemic administration of the drug, only instillation of its solution into the eyes is used.
Supportive and symptomatic treatment for infantile and intermediate types of cystinosis is reduced to taking large doses of vitamin D, strict observance of the correct drinking regime, compensation of electrolytes and proteins lost in the urine. A highly fortified diet is also prescribed, taking carnitine preparations, which is also excreted through the kidneys.
In case of uremia and renal insufficiency, traditional hemodialysis is used. Kidney transplantation is also possible, which significantly improves the patient’s condition and contributes to a noticeable increase in life expectancy with infantile cystinosis. In the case of diabetes mellitus, a special low-carbohydrate diet is developed and hypoglycemic drugs are prescribed.
Prognosis and prevention
The prognosis of cystinosis depends on the form and type of this condition – so with the infantile type of pathology, the prospects of the disease are often unfavorable. Patients without timely treatment die at the age of 7-12 years due to the phenomena of uremia and other concomitant disorders, the use of cystamine and hemodialysis can increase this figure to 20-23 years. Only kidney transplantation can significantly improve the prognosis of this form of cystinosis. The benign type of the disease is characterized by a favorable prognosis.
Prevention of cystinosis is possible only as a detection of the carriage of a mutant form of the CTNS gene and, if both parents have it, medical and genetic counseling before conception of a child. Prenatal diagnosis by amniocentesis with subsequent genetic and biochemical examination is also possible.