Cystinosis

This is part of Rare diseases.

Diagnosis: Cystinosis

Synonyms: --

Innehåll


Date of publication: 2014-03-24
Version: 2.0

ICD 10 code

E72.0A

The disease

Cystinosis belongs to the group of lysosomal diseases. It is an inherited disease found in three forms of varying degrees of severity. Nephropathic cystinosis is the most severe, and also the most common form, and is associated primarily with symptoms from the kidneys (nephros=kidney). This is also known as the infantile form as it presents during the first year of life. There is also an intermediate form with a slower progression, whose symptoms usually occur for the first time during the teenage years. In this form, as in nephropathic cystinosis, kidney problems are common. This variant is also known as the juvenile form, as it presents during adolescence. The third form, non-nephropathic cystinosis, is found exclusively in adults and is associated only with the eyes.

The disease was described for the first time in 1903 by the Swiss physiologist and biochemist Emil Aberhalden.

Currently (2013) we know of approximately seventy different lysosomal diseases. Lysosomes are small units found within all the cells of the body, apart from the red blood cells, and their role is to process and break down certain substances. Examples of other lysosomal diseases are Fabry disease and Gaucher disease. Separate information on these diseases is available in the rare disease database of the Swedish National Board of Health and Welfare.

Occurrence

Cystinosis occurs all over the world. Exactly how common it is in Sweden is unknown. It is estimated that one child becomes ill with the disease every second year, which corresponds to an incidence of one child per 200,000 births. In the rest of Europe and North America the figures are similar or a little higher.

Cause

Cystinosis is caused by a mutation in the CTNS gene. Gene CTNS is located on the short arm of chromosome 17 (17p13) and controls the production of the transport protein cystinosin. To date (2013), more than one hundred different mutations in the gene have been identified. These mutations often involve the loss of genetic material (deletions).

Lysosomes, with the help of enzymes (a type of protein), take care of and break down different materials. In this process the constituent parts of these materials are freed and become available for re-use. For example, this is the way different proteins are broken down into amino acids. These newly-released “building blocks” are transported out of the lysosomes and become available to cells for the production of new substances.

Normally, cystinosin transports cystine out through the walls of the lysosome. When cystinosis occurs, either cystinosin is not produced or it is produced in an altered and poorly functioning form. As a consequence, the amount of cystine increases successively within the lysosomes and hence in the tissues of the body, which can cause the formation of cystine crystals. This high concentration of cystine is harmful and causes cell function to deteriorate and/or causes cells to die.

Certain organs, such as the kidneys, the eyes and thyroid, are particularly sensitive to elevated levels of cystine. Symptoms develop in these parts of the body and function is often impaired, which usually occurs relatively early in the course of the disease.

The main functions of the kidneys are to remove potentially harmful soluble substances from the blood, to maintain normal water, salt and mineral levels, to maintain an acid-base balance and to produce different hormones. These hormones include erythropoetin, which stimulates the formation of red blood cells, and renin, which plays a part in regulating blood pressure and salt levels.

The production of urine starts when blood is filtered through narrow capillaries (glomeruli) in the kidneys. Each kidney contains approximately one million glomeruli. The resulting filtrate, primary urine, contains almost the same substances as blood, with the exception of proteins and blood cells. A normal healthy adult produces approximately 150 litres of primary urine every day. As primary urine is produced it is passed through a system of narrow tubes (tubuli). As the primary urine passes through the tubuli the kidneys reabsorb most of its content i.e. water, salts and minerals. A normal healthy adult with normal liquid intake excretes approximately one to two litres of urine per day. The re-absorption process in the tubuli is very tightly controlled; hence a balance can be maintained in the body even if, for example, the intake of salt and water varies.

In cystinosis the reabsorption capacity of the kidneys is impaired and important substances are excreted in the urine. This causes the various, sometimes life-threatening, deficiencies which make up Fanconi syndrome.

Heredity

The inheritance pattern of cystinosis is autosomal recessive. This means that both parents are healthy carriers of a mutated gene. In each pregnancy with the same parents there is a 25 per cent risk that the child will inherit double copies of the mutated gene (one from each parent). In this case the child will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Figure: Autosomal recessive inheritance

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.

Symptoms

There are three forms of cystinosis: nephropathic, intermediate and non-nephropathic. The most severe, and the most common, form is nephropathic cystinosis.

Symptoms of kidney disease

In nephropathic and intermediate cystinosis the proximal tubules, which make up the first part of the kidneys’ capillary system, are damaged. This results in the production of excessive amounts of urine. A neonate with nephropathic cystinosis can sometimes produce several litres every day. The production of excessive amounts of urine leads to severe thirst and a risk of dehydration. The risk of dehydration is particularly high when the individual is suffering from diarrhoea and fever. If the proximal tubules do not function normally the individual also loses large amounts of sodium and potassium, which has a negative effect on salt levels. The levels of simple sugars (such as glucose) amino acids, carnitine, phosphate, calcium and bicarbonate also fall. The loss of bicarbonate interferes with the acid-base balance in the body, often resulting in low pH levels, and in turn leading to increased acidity in the blood. This causes sickness and fatigue. The loss of phosphate and calcium leads to poor growth and a softening of the skeleton and without treatment, growth may be severely impaired. The kidney abnormalities associated with cystinosis are known as Fanconi syndrome.

As the child becomes older, symptoms from the kidneys gradually lessen. This is not a sign of improvement but is caused by successive damage to the glomeruli, which leads to a reduction in the production of primary urine. Damage to the glomeruli begins at around the age of five or six. If appropriate medication is not administered, kidney failure will result when the child is approximately ten years of age.

Symptoms from other organs

At the same time that the glomeruli begin to show sign of damage, the first symptoms present from other organs:

The function of the thyroid gland may be impaired (hypothyroidism). It is important that this is discovered, as deficiencies can lead to cognitive disability and organ damage.

Problems are caused as cystine accumulates in different parts of the eye, above all in the retina and cornea. Initially, symptoms include increased sensitivity to light, but from approximately the age of twelve, sight may be negatively affected. A few individuals become blind.

Puberty may be delayed and/or stop. The liver and the spleen become enlarged and function starts to fail. The pancreas too may be damaged and cause the individual to develop diabetes and to become dependent on insulin treatment.

Muscle deterioration also occurs in nephropathic cystinosis. This presents as weakness of the limbs, and as swallowing and breathing difficulties. The weakness is a result of carnitine deficiency and/or the accumulation of cystine in muscle cells.

Only a few studies have been carried out on symptoms of cystinosis in the nervous system. These symptoms occur in children but are more common after the age of twenty. Evidence indicating damage to the central nervous system includes deteriorating fine motor skills, walking difficulties and impaired visual memory (affecting the ability to store and retrieve visual memories). Intellectual development is also affected.

Nephropathic cystinosis

In nephropathic cystinosis symptoms from the kidneys can present from approximately six months of age and onwards. Symptoms from other organs often manifest later.

Intermediate cystinosis

In intermediate cystinosis the progress of the disease is usually much slower than in nephropathic cystinosis. Over time, kidney symptoms also present in this form of the disease, as well as problems with other organs such as the eyes. In the intermediate form of the disease kidney symptoms are usually less severe, and kidney failure does not usually occur until the ages of 15 to 30.

Non-nephropathic cystinosis

In non-nephropathic cystinosis only the eyes are affected, with increased light-sensitivity and a risk of impaired vision.

Diagnosis

Cystinosis should be suspected if the child produces large volumes of urine and does not gain weight. The diagnosis is made by measuring the level of cystine in the white blood cells (leukocytes). In cystinosis, the level is raised. A kidney biopsy is not essential.

DNA-based diagnosis is possible. At the time of diagnosis it is important that the family is offered genetic counselling. Carrier and prenatal diagnosis, as well as pre-implantation genetic diagnosis (PGD), in association with IVF (in vitro fertilization), are available in families where the mutation is known.

Treatment/interventions

There are four types of treatment of nephropathic and intermediate cystinosis: treatment of symptoms, cysteamine treatment, dialysis/kidney transplant, and other treatments. As the primary symptoms in this form of cystinosis are from the kidneys, and kidney failure may follow, treatment is often carried out at a renal unit.

Treating symptoms

The primary aim of treatment is to compensate for the loss of water, salts and other substances which occur as a result of impaired kidney function. It is often difficult to replace fluids over longer periods as the child may not manage, or wish, to drink the required amounts. To make this easier, a procedure whereby a thin feeding tube is inserted into the stomach through the abdominal wall (a percutaneous endoscopic gastrostomy, or PEG) may be considered. In this way the child can be provided with fluids, nourishment and medication. Another alternative is to prescribe indometacin, which reduces both the loss of fluids via the kidneys and the volume of urine.

Losses of sodium, potassium, phosphate, calcium, magnesium and bicarbonate need to be replaced. Vitamin D is also required, as a complement to supplements of calcium and phosphate. Sometimes carnitine is also necessary.

Hormone treatment may sometimes be required in the form of thyroid hormones, growth hormones and sex hormones. Growth hormones may be necessary if growth does not improve despite treatment with cysteamine, and (possibly) thyroxine. Deficiencies in nutrition, fluids and minerals may also require compensatory treatment.

In the case of low haemoglobin levels, treatment with erythropoetin will promote red blood cell production.

Preventive cysteamine treatment

Cysteamine is an effective treatment for cystinosis as it is able to enter the lysosome and alter cystine in such a way that it can be transported through the wall of the lysosome. Hence, the levels of cystine in the cells fall. To know how much cysteamine to administer, the levels of cystine in the white blood cells should be regularly measured.

The earlier the child starts cysteamine treatment the more effective it is, and for that reason treatment should start as soon as the diagnosis is made. For the treatment of cystinosis, cysteamine should be taken in tablet or capsule form, and most people also use eye drops. Treatment is life-long. In the case of pregnancy a temporary discontinuation should be seriously considered as it is not yet known whether cysteamine may harm the foetus.

Cysteamine is not judged to have any effect on previous kidney damage. However, it is clear that the medication postpones the development of kidney failure. There are also good grounds for believing that cysteamine has a positive effect on growth and reduces the risk of developing hypothyroidism. As those individuals who have received early treatment with cysteamine are still young, it is too early to say how many of these children will eventually develop kidney failure.

In nephropathic cystinosis eye symptoms are common and it is also common that cystine crystals form in the cornea and/or retina. As these crystals may impair vision, regular check-ups by an ophthalmologist are important. When the presence of crystals has been established at an eye examination, cysteamine eye drops should be considered as a complement to treatment with tablets or capsules, even if symptoms have not developed. If children are under five and their only eye symptom is the development of crystals in the eye, it is usual to postpone treatment with tablets or capsules. However, children should always be treated with eye drops even if they are under the age of five, if their symptoms include both the development of crystals in the eye and an increased sensitivity to light.

In non-nepropathic cystinosis, eye drops are the only form of treatment necessary.

Dialysis/kidney transplant

In the long term, dialysis or a kidney transplant is necessary. Often dialysis is a temporary solution before a kidney transplant is carried out. There are two types of dialysis, haemodialysis and peritoneal dialysis. In haemodialysis, blood is pumped out of the body then is passed through a machine which cleans it and removes impurities before returning it to the body. Treatment takes approximately four hours and most individuals require three treatments a week. In peritoneal dialysis, the blood never leaves the body, but it is cleaned by the dialysis fluid in the abdomen while it circulates through the patient’s own peritoneum. Peritoneal dialysis can be carried out during sleep, in the patient’s home.

Particularly for children, a kidney transplant is often desirable. It enables them to lead a more normal life than is possible with dialysis treatment. The accumulation of cystine continues after the transplant, so treatment with cysteamine should continue.

Other treatment

In addition to medication and a possible kidney transplant, contact with a physiotherapist is also desirable to train muscles and practice movements. The physiotherapist will also provide instruction in breathing and coughing techniques, so the individual can cough up phlegm more easily. When there are problems swallowing (dysphagia), contact with a speech/language pathologist and a dietician, or a dysphagia team, may be desirable. They are usually located at Sweden’s university hospitals. If vision is severely affected, a vision team can offer habilitation/rehabilitation training, which includes instruction in how to use various vision aids and techniques, including braille. Help from a specialist teacher may also be necessary.

Professional psychological and social support are important both for people with the condition and their families. Children and young people with the syndrome should be offered continuous psychological support adapted to their age and maturity.

Practical advice

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National and regional resources in Sweden

Specialist expertise in cystinosis can be found at Swedish university hospitals.

Kidney transplants are carried out in transplant clinics at Swedish university hospitals.

Measurement of cystine levels in leukocytes, for the purposes of diagnosis and optimizing cysteamine treatment, is carried out in Sweden at the Centre for Inherited Metabolic Diseases, Karolinska Hospital, Solna, Sweden.

Resource personnel

Paediatric kidney specialists

Associate Professor Gianni Celsi, Uppsala University Children’s Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 00 00, email: gianni.ennio.celsi@akademiska.se.

Associate Professor Sverker Hansson, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00.

Kidney specialists

Associate Professor Peter Barany, Renal Clinic, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00.

Centre for Inherited Metabolic Diseases

Associate Professor Ulrika von Döbeln, Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00.

Courses, exchanges of experience, recreation

Ågrenska is a national competence centre for rare diseases and its families’ programme arranges stays for children and young people with disabilities and their families. Ågrenska is open to families from the whole of Sweden and focuses particularly on the needs of children and young people with rare diseases. A number of programmes every year is also provided for adults with rare diseases. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

Organizations for the disabled/patient associations etc.

The Swedish Kidney Association, Sturegatan 4 A, Box 1386, SE-172 27 Sundbyberg, Sweden. Tel: +46 8 546 40 500, fax: +46 8 546 40 504, email: info@njurforbundet.se, www.njurforbundet.se.

SRF, The Swedish Association of the Visually Impaired, Sandsborgsvägen 52, SE-122 88 Enskede, Sweden. Tel: +46 8 39 90 00, fax: +46 8 39 93 22, email: info@srf.nu, www.srf.nu.

The Cystinosis Foundation in the US can be contacted at info@cystinosis.com, www.cystinosisfoundation.org/

Courses, exchanges of experience for personnel

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Research and development

International research is under way into the feasibility and value of screening all newborns for cystinosis, with the help of a blood test. Research is also under way into developing gene therapy and new medication, which would affect cystine levels in cells.

Information material

Short summaries of all the database texts are available as leaflets, in Swedish only. They can be printed out or ordered by selecting the Swedish version, and then clicking on the leaflet icon which will appear under, “Mer hos oss” in the column on the right-hand side.

Newsletter from Ågrenska, nr 197, 2002. Order from: Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se. The newsletter is also available on www.agrenska.se.

Literature

Besouw M, Masereeuw R, van den Heuvel, Levtchenko E. Cysteamine an old drug with new potential. Drug Discov Today 2013; 18: 785-792.

Cherqui S. Is genetic rescue of cystinosis an achievable treatment goal? Nephrol Dial Transplant 2013 Jul 16 Epub ahead of print.

Dohil R, Cabrera BL. Treatment of cystinosis with delayed-release cysteamine: 6-year follow-up. Pediatr Nephrol 2013; 28: 507-510.

Gahl WA, Balog JN, Kleta R. Nephropathic cystinosis in adults: natural history and effects of oral cysteamine therapy. Ann Intern Med 2007; 147: 242-250.

Kleta R, Gahl WA. Pharmacological treatment of nephropathic cystinosis with cysteamine. Expert Opin Pharmacother 2004; 5: 2255-2262. Review.

Nesterova G, Gahl WA. Cystinosis: the evolution of a treatable disease. Pediatr Nephrol 2013; 28: 51-59.

Stokes MB, Jernigan S, D’Agati VD. Infantile nephropathic cystinosis. Kidney Int 2008; 73, 782-786.

Ulmer FF, Landolt MA, Vinh RH, Huisman TA, Neuhaus TJ, Latal B et al. Intellectual and motor performance, quality of life and psychosocial adjustment in children with cystinosis. Pediatr Nephrol 2009; 24:1371-1378.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: cystinosis

Genetic Home Reference
www.ghr.nlm.nih.gov 
Search: cystinosis

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical experts who wrote the original material are Associate Professor Gianni Celsi, Uppsala University Children’s Hospital, and Dr Thomas Mårtensson, Karolinska University Hospital, Huddinge, Sweden.

The revision of the material was carried out by Associate Professor Gianni Celsi, Uppsala University Children’s Hospital.

The relevant organizations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2014-03-24
Version: 2.0
Publication date of the Swedish version: 2013-12-10

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.