A Novel Therapeutic Approach in Triosephosphate Isomerase Deficiency.

Triosephosphate isomerase (TPI) deficiency is an autosomal recessive disorder characterised by congenital haemolytic anaemia and progressive neuromuscular dysfunction. No specific treatment exists to alter the natural history and death usually follows in infancy or early childhood. Biochemically TPI deficiency is distinguished by dramatic accumulation of the triose phosphate dihydroxyacetonephosphate (DHAP). DHAP undergoes spontaneous catabolism to methylglyoxal (MG) a potent mediator of protein and nucleotide glycation. MG levels are elevated in TPI deficiency and correlate with neuromuscular dysfunction. Accumulation of triose phosphates may be inhibited through stimulation of the pentose phosphate pathway by maximizing the activity of transketolase which converts glyceraldehyde-3-phosphate into ribose-5-phosphate. Transketolase activity can be enhanced by supplementation with the co-factor thiamine. Thiamine has been shown to reduce triosephosphate accumulation in human red blood cells in vitro but hitherto this not been studied in vivo. We report the outcome of a trial of thiamine supplementation in a female infant born to consanguineous south Asian parents who presented with a haemolytic anaemia at 3 weeks of age followed by neurological symptoms at 11 months culminating in respiratory failure requiring long-term mechanical ventilation. The diagnosis of TPI deficiency was made on the basis of enzyme assay and subsequent genetic analysis which demonstrated homozygosity for the Glu105Asp mutation of the TPI gene previously described in kindreds of European origin. There was marked elevation of red cell DHAP (550 % normal mean). Oral supplementation was commenced at 12 months of age with a lipophilic thiamine derivative - benzoyloxymethylthiamine - chosen to maximize potential CNS bioavailability at a dose of 5mg/kg/day. Response was assessed clinically and by assay of intermediates and metabolites in urine, blood, and CSF on day 0,1,7 and 14. Following thiamine supplementation there was a transient reduction in ventilatory requirement. A maximal (2–3 fold) increase in red cell thiamine and thiamine diphosphate (TPP) concentration was seen at 7 days. Red cell transketolase activity below that of saturation with TPP cofactor was 10% at day 0 and decreased to 0% thereafter. Despite persistently elevated DHAP levels a marked reduction in the MG metabolite D-Lactate of 90% in urine and 57% in the CSF was seen at day 14. Glyoxal a product of lipid peroxidation was also significantly reduced in CSF (70%). After 6 weeks the patient remained dependent on mechanical ventilation and the trial was discontinued. In conclusion oral thiamine supplementation was well tolerated and led to enhanced transketolase activity associated with indicators of reduced MG flux. Intervention preceding the onset of irreversible neuronal damage should be evaluated. Thiamine supplementation holds promise for the prevention and treatment of other neurodegenerative diseases and diabetic complications in which MG-mediated protein glycation is implicated.