Fructose 1,6-bisphosphatase deficiency: enzyme and mutation analysis performed on calcitriol-stimulated monocytes...

Fructose 1,6-bisphosphatase (FBPase) deficiency is an inborn error of metabolism in the gluconeogenetic pathway. During periods of low food intake or infections, a defect in FBPase can result in hypoglycemia, ketonuria and metabolic acidosis. We established a diagnostic system for FBPase deficiency consisting of enzyme activity measurement and mutation detection in calcitriol-stimulated monocytes. In healthy individuals, we showed that FBPase activity is present in monocytes but not in other leukocytes. We describe the clinical course of four individuals from two Swedish families with FBPase deficiency. Family 1: patient 1 died at the age of 6 months after a severe episode with hypoglycemia and acidosis; patients 2 and 3 were followed for >30 years and were found to have a very favorable long-term prognosis. Their FBPase activity from jejunum (residual activity 15-25% of healthy controls), mixed leukocytes (low or normal levels), and calcitriol-stimulated monocytes (no detectable activity) was compared. Mutation analysis showed they were heterozygous for two genetic alterations (c.778G>A; c.881G>A), predicting amino acid exchanges at position p.G260R and p.G294E, originating from their parents. Family 2: patient 4 had no detectable levels of FBPase in stimulated monocytes. A mutation (c.648C>G) predicting a premature stop codon at position p.Y216X was found in one allele and a large deletion of about 300 kb, where the genes FBP2, FBP1 and a part of ONPEP are located, in the other. In conclusion, we present a reliable diagnostic system to verify an FBPase deficiency and find the genetic aberration.