THE FANCONI-SYNDROME OF CYSTINOSIS - INSIGHTS INTO THE PATHOPHYSIOLOGY

Cystinosis is a lysosomal storage disease which is the most-common inh erited cause of the Fanconi syndrome. Insights into the pathophysiolog y of the proximal tubular defect have come from in vitro studies of th e cystine-loaded tubule. Proximal tubules loaded with cystine have a g eneralized proximal tubule transport defect characteristic of the Fanc oni syndrome. The decrease in proximal tubular transport with cystine loading is not due to an increase in paracellular permeability with ba ckflux of solute transport from the blood to the tubular lumen, but du e to a decrease in active transport. The Na-K-ATPase activity is intac t under V-max conditions in cystine-loaded tubules; however, the produ ction of ATP is severely compromised. The cystine-loaded tubule has a lower intracellular phosphate concentration than that of control tubul es. This low intracellular phosphate concentration in cystine-loaded t ubules likely plays a critical role in the decrease in intracellular A TP. Preservation of intracellular phosphate at control levels prevents the decrease in intracellular ATP and the proximal tubule respiratory dysfunction with cystine loading. The clinical significance and futur e directions for investigation are discussed.