Fructose 1,6‐bisphosphatase deficiency: clinical, biochemical and genetic features in French patients

Abstract

Fructose-1,6-bisphosphatase (FBPase) deficiency is a very rare autosomal recessive disorder caused by a mutation of the fructose-1,6-bisphosphatase gene(FBP1). Disease is mainly revealed by hypoglycemia and lactic acidosis, both symptoms being characteristic for an enzymatic block in the last steps of the gluconeogenesis. Twelve patients with FBPase deficiency were diagnosed in France in the 2001-2013 period, using a diagnostic system based on a single blood sample which allows simultaneous enzyme activity measurement on mononuclear white blood cells and molecular analysis. Sequencing of exons and intron-exon junctions of FBP1 gene was completed in unsolved cases by a gene dosage assay developed for each exon. For most patients, first metabolic decompensation occurred before two years of age with a similar sequence: the triggering factors were fever, fasting, or decrease of food intake. However, diagnosis was made late at a mean age of 3 years, as mitochondrial defects or glycogen storage diseases were firstly suspected. Enzyme activity in leukocytes was dramatically decreased (<10%). Twelve different mutations were identified in 22 alleles among them seven were novels: one missense mutation c.472C > T, one point deletion c.48del, one point duplication c.865dupA, one deletion-insertion, and two splice mutations (c.427-1del and c.825 + 1G > A). We described the first intragenic deletion in FBP1 (g.97,364,754_97,382,011del) in homozygous state. Our report also confirms that this very rare disease is misdiagnosed, as other energetic defects are firstly suspected.

Clinical and Molecular Characterization of Patients with Fructose 1,6-Bisphosphatase Deficiency

“…The incidence is estimated to be between 1/350,000 and 1/900,000 [9,13], but no data is available in the Chinese population. The disorder is characterized by recurrent episodes of hypoglycemia and metabolic acidosis during fasting, with symptoms usually manifesting during the first days of life [12].…”

“…The disorder is characterized by recurrent episodes of hypoglycemia and metabolic acidosis during fasting, with symptoms usually manifesting during the first days of life [12]. Laboratory tests usually uncover marked hypoglycemia, lactic acidosis, and elevated levels of uric acid, while liver and kidney functions in most patients have always been reported to be normal [9]. Hypoglycemia-induced insulin drops in insulin and counter-regulatory hormones increase (ACTH, cortisol, and growth hormone) [14].…”

“…The attacks decrease with age, and most cases exhibit normal growth and development. If the treatment for hypoglycemia is properly administered, the prognosis is good [9,12]. …”

“…Genetic sequencing analysis of FBP1 gene showed Case 1 to have a compound heterozygous mutation involving c.704delC and c.960_961insG. c.960_961insG was found to be the most common causative mutant site described in patients from Asia, Europe, and North America [9,10,16], which was referenced in the ClinVar database as pathogenic (). It is also the only one reported in China [17].…”

“…Measurement of FBPase activity using liver biopsies or leukocytes is apparently the most reliable diagnostic approach to date, although its sensitivity remains relatively low and is generally considered as an invasive medical procedure [7,8]. In addition, the disorder may become fatal when patients develop severe hypoglycemia when glycogen reserves are insufficient (in newborns or fasting individuals) or after a fructose load [9]. Thus, the establishment of a rapid and accurate diagnostic method for FBPase deficiency is imperative.…”