Fanconi or not Fanconi? Lowe Syndrome Revisited

Renal Fanconi syndromes are both clinically challenging and physiologically fascinating. The diagnosis requires a certain index of suspicion to correctly identify the clinical symptomatology and pursue the appropriate laboratory evaluations. With regard to the pathophysiology, the renal proximal tubule is the site of action. Through a complex and coordinated machinery of luminal and basolateral transport proteins, the proximal tubule has established a monopoly for reclaiming amino acids, phosphate, and glucose. The reabsorption of proteins also occurs only in the proximal tubule, but the issue of how much protein, e.g., albumin, is normally reabsorbed remains contentious (1,2). Over the years, many but not all of the pieces of this puzzle have been assembled. Recent studies have defined the molecular identity of most luminal transporters involved in glucose, amino acid, and phosphate transport. In contrast, the characterization of molecular contributors to basolateral transport mechanisms remains limited. Perhaps because of the complexity of renal proximal tubular physiology, many aspects are not yet understood. Studies of single-gene disorders should help elucidate the pathophysiology. There are at least two different forms of primary renal Fanconi syndrome in humans. Both are transmitted as autosomal dominant traits. Luder-Sheldon syndrome (OMIM %134600), associated with progression to end-stage renal disease, has been linked to chromosome 15 (3). The second disorder, not associated with loss of renal function, has yet to be mapped (4). Thus, elucidation of the molecular pathogenesis involved in primary proximal tubular damage must await identification of these disease-causing genes.