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Cystinosis is a multisystemic, autosomal recessive disorder of lysosomal transport that results in intracellular accumulation of the amino acid cystine, which leads to cellular dysfunction and death. The incidence of this disease is estimated at 1 per 100,000 to 200,000 live births, and it occurs in all ethnic groups.

There are three forms of cystinosis. The most severe is nephropathic (infantile) cystinosis (NC), which accounts for 95% of cases. Intermediate (juvenile) cystinosis has a later onset of renal complications, whereas ocular (non-nephropathic) cystinosis generally causes only corneal crystals.
NC first presents in early infancy with generalized renal proximal tubular dysfunction. Untreated, it progresses to chronic kidney disease in the first decade of life. In the past, an affected child’s lifespan was limited to 10 years; however, with the emergence of kidney transplantation and effective medical treatment (including cystine-depleting agents), patients can now expect a reasonably normal quality of life for several decades.


Patients with cystinosis have mutations in the CTNS gene, located on chromosome 17p13. This gene encodes cystinosin, a lysosomal membrane transport protein that contains 367 amino acids and 7 transmembrane domains. CTNS mutations account for all types of cystinosis, and more severe mutations are associated with the NC form. Approximately 100 different CTNS mutations have been identified; the most common is a 57,257 base pair deletion, which is present in the homozygous or heterozygous state in about 76% of NC patients of northern European origin.
Functional cystinosin deficiency causes impaired efflux of cystine from lysosomes to the cytoplasm, where it is normally further processed and then reused. As a result, cystine accumulates in lysosomes, forming crystals that are poorly soluble and hexagonal, rectangular, or needle-shaped. Cystine crystals are thought to induce cellular apoptosis, which leads to dysfunction in multiple organ systems.
The most prominent defect occurs in the kidneys, where proximal tubular dysfunction leads to impaired reabsorption of electrolytes, water, amino acids, glucose, bicarbonate, and other molecules, a phenomenon known as the renal Fanconi syndrome (FS). The cellular mechanism of renal FS in this instance, however, is not well understood. Tubular and interstitial cystine accumulation may impede the normal transport and cotransport of small molecules in tubular cells; however, recent studies indicate that lysosomal cystine accumulation disrupts the interaction of lysosomes and mitochondria needed for normal apoptotic and autophagic processes. The result is adenosine triphosphate (ATP) deficiency, which leads to intracellular energy depletion, oxidative stress, and inexorable deterioration of renal cell function.

The typical child with cystinosis appears normal at birth and then presents between 6 and 12 months of age as a small, listless infant. Early diagnosis is critical so that life-saving treatment may be rapidly instituted. The most striking features are usually referable to the presence of renal FS, which causes polyuria, proximal renal tubular acidosis (see Plate 3-25), and wasting of electrolytes, glucose, amino acids, carnitine, and tubular proteins. The profound homeostatic abnormalities that result can cause failure to thrive, cardiac dysfunction, muscle hypotonia, and hypophosphatemic rickets. In some patients who present later in infancy, one of these sequelae may be the presenting complaint.
Any patient found to have renal FS should undergo slit lamp examination because corneal cystine crystal accumulation occurs in all patients by 16 months of age. The presence of both renal FS and corneal crystals is diagnostic of NC. The clinical diagnosis can be confirmed by measuring cystine concentrations in polymorphonuclear leukocytes using mass spectroscopy or the cystine binding protein assay. Targeted testing for a panel of CTNS mutations, including the most common 57-kb deletion, is also available.
If corneal crystals are not seen, other inherited or acquired causes of renal FS should be investigated, such as heavy metal poisoning, adverse medication effect, multiple myeloma, hereditary fructose intolerance, galactosemia, Dent disease, and Lowe disease.
Prenatal diagnosis can be performed if there is a family history of cystinosis. Elevated cystine concentrations may be noted in the placenta, cultured skin fibroblasts, amniocytes, and chorionic villus cells.
Because of dramatic improvements in the average lifespan of an affected patient, several additional sequelae of this disorder are becoming better appreciated. Some of the many manifestations, grouped by organ system, include:
Renal Disease. In addition to renal FS, patients develop medullary nephrocalcinosis (secondary to phosphaturia and calciuria) and renal insufficiency that eventually leads to end-stage renal failure. In untreated patients, renal insufficiency becomes apparent by 5 years of age.
Ocular Disease. As corneal crystal accumulation becomes severe, it may cause photophobia and blepharospasm. Visual loss may occur if the retina is involved. 
Endocrine Disease. Patients often develop hypothyroidism late in the first decade of life. Males develop primary testicular hypogonadism that leads to delayed puberty and infertility, while females have spared ovarian and reproductive functions. A subset of patients may develop pancreatic insufficiency, with resulting failure of endocrine function (leading to type 1 diabetes mellitus) and/or exocrine function (leading to intestinal malabsorption).
Muscle Disease. Patients develop myopathies later in life that begin as distal muscle weakness and atrophy, then progress to involve the oropharyngeal muscles, causing dysphagia, malnutrition, and risk of aspiration. Thoracic muscle weakness can cause restrictive pulmonary disease.
Cardiovascular Disease. Vascular calcification may occur, including in the coronary arteries.
Gastrointestinal Disease. Patients may develop hepatic nodular regenerative hyperplasia, leading to hepatomegaly and portal hypertension. Inflammatory bowel disease and bowel perforation have been noted in some patients.
Central Nervous System Disease. Cerebral atrophy, calcifications of the basal ganglia, and benign intracranial hypertension (causing headaches and papilledema) may be seen. Cognitive abilities are in the low-normal range in most patients, but specific neurologic and neurobehavioral issues are characteristic, including visual memory defects.
Hematologic Disease. Although cystine accumulates in bone marrow, hematopoietic function generally remains stable. Anemia may nonetheless occur, however, as chronic kidney disease becomes more advanced.

The treatment of cystinosis can be divided into symptomatic and pathophysiologic management.
Symptomatic management addresses the numerous complications of cystine accumulation in different organ systems. The major early complication is renal FS, as described previously, which must be treated with replacement of wasted fluids, electrolytes (including potassium, phosphate, and bicarbonate), vitamin D, and carnitine.
To address the many additional complications listed previously, follow-up care should include measurement of serum creatinine concentration, thyroid panels, insulin levels, lipid panels, testosterone, and sex hormone levels; glucose tolerance tests; electromyography; barium swallow studies; computed tomography of the brain and chest (for detecting calcification of cerebral and other major vessels); renal ultrasonography (to assess for nephrocalcinosis); and pulmonary function tests.
As renal disease progresses, renal replacement therapy is commonly required. Transplantation of both living donor and cadaveric kidneys has led to excellent out-comes, with no recurrence of renal FS in the donor kidney. Pathophysiologic management, meanwhile, involves the use of cystine-depleting agents to actually slow disease progression. Cysteamine, an aminothiol, reacts with cystine to form cystine-cysteamine mixed disulfide and cysteine, which exit the lysosome via lysine and cysteine transporters, respectively. As a result, cysteamine depletes intracellular cystine levels by 90%. Oral cysteamine is indicated for all patients, independent of age and transplantation status. Meanwhile, topical cysteamine eye drops can also dissolve corneal crystals and ameliorate the photophobia of cystinosis within a few weeks. Regular measurement of the leukocyte cystine level documents the efficacy of treatment.

The use of cystine-depleting therapy has revolutionized the prognosis of NC. With prompt and compliant cysteamine treatment, many children do not develop renal failure until their second or third decade of life. The severity of the various complications depends largely on genetic heterogeneity and compliance with medical therapy. Most complications are preventable and possibly even reversible with optimal treatment. Newborn screening for early diagnosis will further advance the treatment of cystinosis.