Cystinosis is an inherited condition in which the body accumulates the amino acid cystine within the cells. Excess cystine forms crystals that can build up and damage cells. These crystals can negatively affect many systems in the body, especially the kidneys and eyes. There are three distinct types of cystinosis: nephropathic cystinosis, intermediate cystinosis, and non-nephropathic or ocular cystinosis. All three types of cystinosis are caused by mutations in the CTNS gene and inherited in an autosomal recessive pattern.
Cystinosis is classified into 2 general phenotypes: nephropathic and nonnephropathic cystinosis (benign variant).
Nephropathic cystinosis is further subdivided into infantile (early-onset form) and intermediate cystinosis (late-onset), based on the age at presentation. A typical cystinotic patient has pale blond hair and blue eyes, although the disease also occurs among dark-haired individuals.
Nephropathic Infantile cystinosis (early-onset form) is the most frequent (95% of cases) and most severe variant. Symptoms of multiorgan involvement may be mild to severe, depending on the patient's age at diagnosis, the age when treatment was instituted and genetic factors. The initial symptoms of infantile nephropathic cystinosis include:
- Lost of appetite
- Failure to thrive
- Severe dehydration
- Electrolyte imbalance
- Metabolic acidosis during a mild illness
Some children may have recurrent bouts of fever and manifestations of heat intolerance (becoming red like beets) caused by a defect in sweat production. Patients typically have short stature and renal Fanconi syndrome. They have poor appetite, crave salty and hot and spicy foods, and prefer specific food textures. In children younger than 1 year the progressive disease usually cause growth retardation, rickets, metabolic acidosis, and other chemical evidence of renal tubular abnormalities, such as increased renal excretion of glucose, amino acids, phosphate, and potassium. They may require frequent hospital admissions because of dehydration. As children age, failure to thrive is prominent. Corneal crystals are apparent by age 1-2 years. The untreated cornea is packed with crystals by age 3-4 years, leading to photophobia in early childhood. By age 7-10 years, previously noted symptoms become more severe, and patients develop increased proteinuria, progressive renal failure, increased photophobia, and thyroid insufficiency. ESRD develops in adolescence, usually at age 10-13 years. The good adherence to therapy may slow down the progression of renal failure by several more years. Sexual maturation is almost always delayed. Retinal damage does not occur until the second or third decade of life. Cerebral calcifications and muscular and swallowing difficulties cluster around the third decade of life. The major complication of cystinosis in patients older than 20 years is legal blindness, distal vacuolar myopathy, cerebral calcifications or atrophy, swallowing dysfunction, diabetes mellitus, and liver disease (eg, hepatomegaly, nodular degenerative hyperplasia).
Late-onset Nephropathic (intermediate) cystinosis is a more indolent form of the disease. Most cases are diagnosed in early adolescence. Symptoms are usually restricted to kidneys (eg, less severe form of Fanconi syndrome, proteinuria) and eyes (eg, photophobia). Progression of the disease is slower and end-stage renal disease (ESRD) occurs after age 15 years.
Non-nephropathic cystinosis is considered a benign variant and is usually diagnosed by an ophthalmologist treating patients for photophobia. Photophobia may not begin until middle age and is not usually as debilitating as in the nephropathic form of the disease. Slit-lamp examination reveals corneal crystal deposits. In addition to the eye, cystine crystals are present in the bone marrow and leukocytes but are absent in the kidney and the retina.
All forms of cystinosis have autosomal recessive patterns of inheritance. Cystinosis is caused by a defect in transport of cystine across the lysosomal membrane due to defective function of the lysosomal membrane protein cystinosin, resulting from mutations of the cystinosis gene (CTNS). CTNS resides on chromosome 17p13. The CTNS gene has 12 exons, the last 10 of which code for cystinosin.
Cystinosin (an integral lysosomal membrane protein) has 367 amino acids and 7 transmembrane domains. In nephropathic cystinosis patients, CTNS mutations can cause either an absence of cystinosin or a disruption of transmembrane domains and loss of protein function, leading to inhibition of cystine transport through the lysosomal membrane (which is carrier-dependent). More than 80 different CTNS mutations (missense, nonsense, splice-site, deletion, and promoter mutations) are described in patients with nephropathic cystinosis; the most common are 57 kilobases (kb) (approximately 60% of the mutations in US patients).
Patients with a mild form of cystinosis that is diagnosed when patients are younger than 7 years or patients with late-onset (intermediate) cystinosis have mutations of CTNS that affect functionally unimportant regions of cystinosin, accounting for a milder clinical course. The various CTNS mutations can explain why patients have a wide spectrum of clinical symptomatology.
The parents of patients with cystinosis are obligate heterozygotes for cystinosis; they each carry a single gene for the disease. Individuals heterozygous for cystinosis have never been reported to have cystine crystals in any tissue or cell. Despite the clinically normal appearance of individuals who are heterozygous for cystinosis, their polymorphonuclear cells contain an increased amount of cystine.
Late-onset (intermediate) cystinosis appears to be due to the inheritance of a mutation known to cause infantile disease in one allele and a relatively less clinically severe mutation in the other or due to the inheritance of a relatively less severe mutation in both alleles.
Nephropathic cystinosis is an inherited disorder and little can be done to prevent the disease. Families with this condition should have genetic counseling to better understand their risk.
The diagnosis of cystinosis is established by documenting:
- Renal tubular Fanconi syndrome, i.e., increased urinary losses of essential nutrients including electrolytes (sodium, potassium, bicarbonate), minerals (calcium, phosphate, magnesium), glucose, amino acids, carnitine, and water
- Typical cystine crystals in the cornea on slit lamp examination;
- Increased cystine content of leukocytes.
Identification of two mutations in CTNS, the only gene known to be associated with cystinosis, is confirmatory.
Newborn screening diagnosis: For pregnancies at increased risk for nephropathic cystinosis, prenatal testing is also available biochemically, based upon elevated cystine concentration in both chorionic villi obtained at approximately ten to 12 weeks' gestation by chorionic villus sampling (CVS), and amniocytes, obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation. Molecular-based prenatal diagnosis is possible by analysis of DNA extracted from fetal cells obtained either by CVS or by amniocentesis. Both disease-causing alleles of an affected family member must be identified before prenatal testing using molecular genetic testing methods can be performed. Requests for prenatal testing for conditions such as cystinosis that do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate. Preimplantation genetic diagnosis may be available for families in which the disease-causing mutations have been identified.
In the early 1960s, nephropathic cystinosis was considered a fatal renal disease of childhood; patients died of progressive renal failure before age 10 years. The natural history of the disease has changed dramatically since the introduction of cysteamine and renal transplantation. Patients with infantile cystinosis now survive into even the fifth decade of life. Cysteamine markedly slows the progression of renal failure.
It is recommended that a multidisciplinary team that includes nephrologists, metabolic disease specialists, ophthalmologists, neurologists, gastroenterologists, nutritionists and psychologists manage individuals with cystinosis.
Cystine depletion therapy with cysteamine bitartrate (Cystagon) has revolutionized the management and prognosis of nephropathic cystinosis. Cysteamine is now the treatment of choice for cystinosis throughout the world. This free thiol can deplete cystinotic cells of more than 90% of their cystine content. Cysteamine therapy should be considered for all affected individuals, regardless of age and transplantation status. With early, diligent treatment many individuals with cystinosis have survived into their twenties without the need for renal transplantation.
- Chronic and diligent cysteamine therapy prevents or delays end stage renal disease (ESRD) and hypothyroidism, enhances growth, and depletes muscle parenchyma of cystine.
- It is critical to initiate cysteamine therapy immediately after diagnosis to allow for kidney growth and acquisition, rather than loss, of renal function.
- Side effects of cysteamine treatment include nausea and vomiting, in part because of its repulsive odor and taste. Cysteamine increases gastrin synthesis and gastric acid production. Omeprazole may be of benefit for oral cysteamine treatment.
- With long-term cystine-depleting therapy most late complications of cystinosis can be avoided.
- Despite diligent oral cysteamine therapy, cysteamine hydrochloride eyedrops are required to achieve sufficient tissue concentration to dissolve corneal crystals. With good compliance photophobia is relieved within weeks. Systemic cysteamine treatment ameliorates or postpones retinal deterioration. Cysteamine eyedrops remain investigational.
Refer to Research Publications.