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The prevalence at birth is estimated at around 1/100,000- 1/200,000.

In the infantile form (the most common), the first clinical signs appear between 3 and 6 months of age, with a polyuria-polydipsia syndrome and marked growth delay secondary to a generalized proximal tubular dysfunction with severe fluid-electrolyte balance alterations (renal Fanconi syndrome). Hypophosphatemic rickets causing bone deformities are also observed. Ocular involvement caused by cystine deposits in the cornea is responsible for photophobia which usually appears after 3 years of age. Cystine deposits in various organs progressively lead to hypothyroidism, insulin-dependent diabetes, hepatosplenomegaly with portal hypertension in some patients, and muscle and cerebral involvement. In the absence of specific treatment, the disease progresses to end stage renal failure before the age of 10. The first symptoms of juvenile cystinosis (< 5% of patients), typically appear around 6-8 years of age with a milder form of proximal tubulopathy and/or proteinuria in nephrotic syndrome. Progression to renal failure occurs later than in the infantile form. Finally, the ocular form is observed in adults who are generally asymptomatic and may suffer only from photophobia.

Cystinosis is due to a defect in cystine transport out of lysosomes. The causative gene, CTNS (17p13), encodes cystinosin, a lysosomal membrane protein. Mutations in this gene have been detected for all 3 forms of the disease, with a 57-kb deletion detected in 60%-70% of alleles in patients from Northern Europe. Severe truncating mutations cause a more severe disease (infantile form) while mutations allowing the protein residual function cause milder phenotypes (juvenile or ocular).

The diagnosis is based on blood and urine analysis showing features of renal Fanconi syndrome (metabolic acidosis, hypokalemia, hypophosphatemia, hyperaminoaciduria, glycosuria, low molecular weight proteinuria), detection of cystine crystals in the cornea and determination of elevated cystine levels in leucocytes. It is confirmed by CTNS gene analysis.

Differential diagnosis includes other diseases causing renal Fanconi syndrome (Lowe syndrome, Dent disease, galactosemia, fructose intolerance, thyrosinemia, mitochondrial nephropathies, Wilson disease, Fanconi-Bickel syndrome, lysinuric protein intolerance, idiopathic Fanconi syndromes, secondary Fanconi syndrome due to drug toxicity or substance abuse, recovery of acute tubulus necrosis), diseases causing phosphaturia and rickets, and proteinuria of unknown etiology.

A prenatal, genetic diagnosis is possible in families with a previously affected child.

Transmission is autosomal recessive. Genetic counseling is recommended for affected families. The risk of disease transmission is 25% where both parents are unaffected carriers; disease severity depends on the mutation.

Treatment consists of administering electrolytes, alkali, phosphate and vitamin D supplements; indomethacin, which improves the general status and growth; and cysteamine. Cysteamine lowers the cystine content in the lysosomes, thereby slowing or even stopping the progression to renal failure and the development of extra-renal manifestations. The side effects of cysteamine include gastrointestinal symptoms, bad breath, sweat odor and allergic reactions. A delayed-released formulation has been developed and approved in the USA and Europe, which allows patients to receive cysteamine twice a day, thus improving compliance and quality of life. Topical cysteamine eye drops (0.5%) are also needed as systemic cysteamine has no effect on cystine corneal deposits.

Life expectancy has significantly improved with therapy. Cysteamine delays the need for renal replacement therapy. The disease does not recur in the graft after renal transplantation but continues to progress in other organs and may cause complications (swallowing dysfunction, neurologic complications, lung disease) that may worsen the prognosis.