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Nephropathic infantile cystinosis
Nephropathic infantile cystinosis is the most common and severe form of cystinosis (see this term), a metabolic disease characterized by an accumulation of cystine inside the lysosomes that causes damage in different organs and tissues, particularly in the kidneys and eyes.
ORPHA:411629Classification level: Subtype of disorder
The incidence of cystinosis is estimated at around 1/100,000- 1/200,000 live births. Around 95% of cases correspond to the infantile form.
The first clinical signs appear between 3 and 6 months of age, with polyuria and polydipsia, accompanied by anorexia, vomiting, dehydration, constipation, and marked growth delay secondary to a generalized impaired proximal tubular reabsorptive capacity with severe fluid-electrolyte balance alterations (Fanconi syndrome; see this term). Hypophosphatemic rickets, that causes bone deformities, is also observed. Ocular involvement, caused by cystine deposits in the cornea and conjunctiva, is responsible for photophobia which usually appears after 3 years of age. Cystine deposits in various organs progressively lead to additional manifestations such as hypothyroidism, hypogonadism and male infertility, insulin-dependent diabetes, hepatosplenomegaly with portal hypertension, muscle involvement with distal muscle weakness and atrophy, and later, pharyngeal and oral dysfunction, swallowing difficulties, cerebral involvement with hypotonia, speech and walking difficulties, and cerebellar syndrome that occur later during adulthood. In the absence of specific treatment, the disease progresses to end stage renal failure before the age of 10.
Cystinosis is due to a defect in cystine transport out of lysosomes. The causative gene, CTNS (17p13), encodes cystinosin, a lysosomal membrane protein.
The diagnosis is based on blood and urine analysis showing features of Fanconi syndrome (metabolic acidosis, hypokalemia, hyponatremia, hypophosphatemia, hyperaminoaciduria, glycosuria), detection of cystine crystals in the cornea by slit lamp examination, and determination of elevated cystine levels in leucocytes. The diagnosis is confirmed by CTNS gene analysis.
A prenatal diagnosis can be obtained by genetic analysis in families with a previously affected child.
Transmission is autosomal recessive and genetic counseling should be offered to the affected families informing them of the 25% risk of transmitting the disease.
Management and treatment
Treatment consists of administering electrolytes and vitamin supplements (including sodium and potassium bicarbonate, phosphate, vitamin D and carnitine); indomethacin, which improves the general status and growth of the patient; and cysteamine (given at a dose of 1,3 to 1,9 g/m2 per day, given in 4 doses every 6 hours), which lowers the cystine content in the lysosomes, thereby slowing or even stopping the progression to renal failure and the development of extra-renal manifestations and delaying the need for renal transplantation. The side effects of cysteamine include gastrointestinal symptoms, bad breath, sweat odor and allergic reactions. A delayed-release formulation has been developed and approved in the USA which allows patients to receive cysteamine only twice a day, thus improving compliance and quality of life. Topical cysteamine eye drops are also needed as systemic cysteamine has no effect on cystine corneal deposits.
Life expectancy is significantly improved with therapy. The disease does not recur in the graft after renal transplantation but continues to progress in other organs and may lead to complications (e.g. swallowing dysfunction, lung disease, cardiomyopathy) that may worsen the prognosis.