Cystinosis is a rare, autosomal recessively inherited lysosomal storage disorder due to defective carrier-mediated transport of the amino acid cystine across the lysosomal membrane. The major clinical manifestation of cystinosis is renal failure at approximately 9 to 10 years of age. The cystinosis gene has been isolated, and several different mutations identified.
In cystinosis, free, nonprotein cystine accumulates to 10 to 1000 times normal levels and forms crystals within the lysosomes of most tissues, which are damaged at different rates. The diagnosis is made by demonstrating an elevated cystine content in polymorphonuclear leukocytes or cultured fibroblasts or by slit-lamp examination showing corneal crystals which are generally present in patients over 1 year of age. Cystinosis can be diagnosed in utero by cystine measurements in amniocytes or chorionic villi, or at birth by cystine measurements of the placenta.
Children with cystinosis are normal at birth but develop signs of the renal tubular Fanconi syndrome, usually between 6 and 12 months of age. These include dehydration, acidosis, vomiting, electrolyte imbalances, hypophosphatemic rickets, and failure to grow. Weight is proportional to height. Head circumference and intelligence are spared. Other manifestations of cystinosis include photophobia, hypothyroidism, and decreased ability to sweat. Renal glomerular damage progresses inexorably, requiring dialysis or transplantation at 6 to 12 years of age.
Cystine storage does not occur in the donor kidney, but continued accumulation in the host tissue can result in retinal blindness, corneal erosions, diabetes mellitus, a distal myopathy, swallowing difficulties, decreased pulmonary function, pancreatic insufficiency, primary hypogonadism in males, and neurologic deterioration in a significant number of post-renal transplant patients 13 to 40 years old.
The cystinosis gene, CTNS, is located on chromosome 17p13, has 12 exons spanning 23 kb of genomic DNA, and codes for a 367-amino-acid protein called cystinosin, with 7 transmembrane domains and 8 potential glycosylation sites. Approximately 40 percent of cystinosis patients from northern Europe are homozygous for a 57-kb deletion that disrupts CTNS. Twelve percent of the 216 alleles of an American-based cystinosis population contain a 753G → A (W138X) mutation. Twenty-nine other mutations have been identified to date.
Therapy for cystinosis includes replacement of renal losses due to the Fanconi syndrome; provision of thyroxine, insulin, pancreatic enzymes, and testosterone for deficient patients; and symptomatic care of ophthalmic complaints. Chronic cystine-depleting therapy with the aminothiol cysteamine significantly lowers leukocyte and parenchymal cystine levels, improves growth, and obviates the need for thyroid hormone replacement. More importantly, oral cysteamine therapy preserves renal function and, if initiated in the first 2 years of life, can allow for a net increase in the glomerular filtration rate. Side effects include nausea and vomiting. Cysteamine eyedrops can dissolve corneal crystals in young children and remove the haziness from the corneas of older patients.
The clinical course and severity of cystine accumulation in cystinosis vary in different kindreds, from ocular cystinosis in adults with corneal crystals but no renal disease to intermediate cystinosis in adolescents with late-onset renal deterioration, and finally to classic nephropathic cystinosis in infants. Heterozygotes for all types of cystinosis are clinically normal.