Polyol metabolism and neurotoxicity in inherited metabolic diseases
10 / 1999 - 04 / 2004
Polyols are sugar alcohols, which are produced by the reduction of sugars. They are present in all living organisms in different concentrations. In humans they are present in low concentrations, mainly in the central nervous system. We described a boy with a slowly progressive neurological disorder, who appeared to have large quantities of polyols, mainly D-arabitol and ribitol, in his body fluids (van der Knaap et al., 1999). MRI scans showed an abnormal and slightly swollen white matter of the brain, which could suggest myelin splitting and vacuolization. It is suspected that polyols may play a role in the pathophysiology of some of the white matter diseases of now unknown origin. Unfortunately, little is known about the polyol metabolism in humans. Some research has been done on polyol metabolism in fungi, which utilize polyols as intracellular osmoregulators and storage or transport capacity of carbohydrates. The main metabolic route, in which C5-polyols and their precursors arise, is the pentose phosphate pathway (PPP). This pathway is an alternative route for the metabolism of glucose. Deficiency of enzymes in the PPP could explain the accumulation of certain polyols. Recently, we found a transaldolase (TALDO1) deficiency in a 10 year old girl clinically presenting with liver cirrhosis (Verhoeven et al, 2001). In urine and plasma, highly elevated levels of D-arabitol, ribitol and erythritol were found. The deficiency of TALDO was found by an enzyme assay in the patient's erythrocytes and lymphoblasts. A mutation in the TALDO1 gene was detected by sequence analysis. Based on these findings, polyols are hypothesized to derive from sugar phosphate precursors formed through the PPP. To study sugar phosphates in cells and to distinguish potential other patients with disturbances in the PPP, a sensitive method to analyze intracellular sugar phosphates in human blood cells using tandem mass specrometry is developed. In the future we will focus on revealing the exact metabolism of polyols, by using analytical chemistry and enzyme assays.