Cystinosis: a review of the different forms and of recent advances.

Abstract

Cystinosis, an autosomal recessively inherited disease, with cystine crystals in the conjunctiva, bone marrow, lymph nodes and reticuloendothelial cells, occurs in at least three different forms. The nephropathic type is clinically characterized by progressive renal tubular failure with Fanconi syndrome and serious rickets. The excessive glomerular damage leads to uremic death within the first decade of life. In adults, cystinosis is seen as a completely benign variant. Patients with the late-onset (intermediate) type show an attenuated form of the disease that allows them to survive into the second or third decade of life. The characteristic patchy depigmentation in the peripheral retina is found consistently in the nephropathic form, in some cases in the late-onset form, but never in the benign form. Rickets is present in the nephropathic and in the late-onset variant, but is absent again in the benign type. Cystine crystals in the bone marrow and conjunctiva are features common to all three forms of the disease. Though the primary biochemical defect in cystinosis is still unclear, it has been demonstrated that leukocytes and cultured fibroblasts of patients with all three forms of cystinosis have elevated free cystine levels. The concentrations range from 30 times normal in the benign up to 100 times normal in the nephropathic disorder. The late-onset type falls between these ranges. Heterozygotes for all three types show modest increases in cystine concentration. An autosomal recessive pattern of inheritance seems to be implicated in the three forms of cystinosis. Clinical examination of pedigrees are substantiated by biochemical proof of elevated free cystine in leukocytes and fibroblasts from heterozygotes for the different forms. Genetic heterogeneity is suggested by the differences in clinical and biochemical expression in different families. Experimental treatment with a diet restricted in cystine and methionine and administration of D-penicillamine failed to influence the course of the disease. Dithiothreitol has been suggested as a useful form of therapy, but is still in an experimental stage. At present, renal homotransplantation performed in children with nephropathic and intermediate type of cystinosis appears to offer the best opportunity for extended survival of these children and is the only effective treatment in terminal renal failure.