Absence of Renal Fructose-1-phosphate Aldolase Activity in Hereditary Fructose Intolerance

Abstract

HEREDITARY fructose intolerance (HFI) is a genetically transmitted metabolic disorder known to be characterized biochemically by the virtual inactivity of hepatic fructose-1-phosphate aldolase^1–3. Fructose-1 -phosphate (F-1-P), the initial reaction product of administered fructose, accumulates intracellularly behind this enzymatic defect⁴, much as galactose-1-phosphate (Gal-1-P) accumulates intracellularly behind the block of Gal-1-P uridyl transferase in galactosaemia^5,6. The kinds and similarities of the metabolic and clinical abnormalities of patients with HFI and galactosaemia suggest that the cellular accumulation of hexose-1-phosphate is central in the pathogenesis of the multiple cellular disturbances of both disorders. Increased amounts of Gal-1-P were demonstrated in the kidneys, as well as in the liver, of two infants with galactosaemia diagnosed before death⁷. In both galactosaemia and HFI, a reversible hexose induced proteinuria and amino-aciduria have been reported^8,9. Komrower et al.¹⁰ reported that in two infants with galactosaemia dietary restriction of galactose was followed by disappearance of the biochemical characteristics of renal tubular acidosis (RTA) (a clinical disorder of renal acidification characterized by minimal to absent azotaemia, hyperchloraemic acidosis and alkaline or minimally acid urine). Subsequent experimental ingestion of galactose (as milk) for 10 days by these children, however, did not result in the recurrence of hyperchloraemic acidosis. Mass et al. recently described a 41 year old woman with HFI and apparently long standing RTA which persisted after dietary restriction of fructose¹¹. In three unrelated adults with HFI it has recently been demonstrated that the experimental administration of fructose immediately but reversibly subverts normal renal function into a state of tubular dysfunction with the biochemical and physiological characteristics of RTA and Fanconi's syndrome (impaired renal tubular reabsorption of alpha amino nitrogen, uric acid, phosphate and glucose)^12,13. The tubular dysfunction occurred in the absence of the hypoglucosaemia characteristic of HFI. Because F-1-P aldolase is detectable in mammalian kidney¹⁴ and is presumably critical in the renal metabolism of F-1-P (ref. 15), the fructose-induced tubular dysfunction of HFI might be mediated by renal accumulation of F-1-P behind a defect of renal F-1-P aldolase.