Novel compound heterozygous mutations in the fructose-1,6-bisphosphatase gene cause hypoglycemia and lactic acidosis

Fructose-1,6-bisphosphatase (FBPase) deficiency is an autosomal recessive disorder caused by a mutation of the fructose-1,6-bisphosphatase 1 (FBP1) gene and results in impaired gluconeogenesis. We describe a male patient with typical FBPase deficiency who presented with hypoglycemia and lactic acidosis. The FBPase activity in his peripheral leukocytes and liver was very low. We amplified and sequenced the entire FBP1 coding region of the patient and his family members. Direct and allele-specific sequence analysis of the FBP1 gene revealed that the proband had a compound heterozygote for the G164S and 838delT, which he inherited from his carrier parents. His father and mother had heterozygous 838delT and G164S mutations, respectively, without any symptoms of hypoglycemia. Gene tracking within the family revealed that his elder sister had a heterozygous G164S mutation without symptoms of hypoglycemia. A G164S mutation of FBP1 in a heterozygous pattern (G164S and InsG960_961) has been reported previously, but the heterozygous 838delT mutation is novel. Transient transfection studies using COS-7 cells demonstrated that FBPase proteins with G164S or 838delT mutations were enzymatically inactive. In conclusion, we report a new case of molecular diagnosis of FBPase deficiency and provide evidence that impaired FBPase activity may be caused by novel compound heterozygous mutations in the FBP1 gene.