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

Abstract

Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare, autosomal recessive inherited disease caused by the mutation of the FBP1 gene, the incidence is estimated to be between 1/350,000 and 1/900,000. The symptoms of affected individuals are non-specific and are easily confused with other metabolic disorders. The present study describes the clinical features of four Chinese pediatric patients who presented with hypoglycemia, hyperlactacidemia, metabolic acidosis, and hyperuricemia. Targeted-next generation sequencing using the Agilent SureSelect XT Inherited Disease Panel was used to screen for causal variants in the genome, and the clinically-relevant variants were subsequently verified using Sanger sequencing. Here, DNA sequencing identified six variations of the FBP1 gene (NM_000507.3) in the four patients. In Case 1, we found a compound heterozygous mutations of c.704delC (p.Pro235GlnfsX42) (novel) and c.960_961insG (p.Ser321Valfs) (known pathogenic). In Case 2, we found a compound heterozygous mutations of c.825 + 1G>A and c.960_961insG (both were known pathogenically). In Case 3, a homozygous missense mutation of c.355G>A (p.Asp119Asn) (reported in ClinVar database without functional study) was found. Case 4 had a compound heterozygous mutations c.720_729del (p.Tyr241GlyfsX33) (novel) and c.490G>A (p.Gly164Ser) (known pathogenically). Further in vitro studies in the COS-7cell line demonstrated that the mutation of ASP119ASN had no impact on protein expression, but decreased the enzyme activity, and with which the clinical significance of Asp119Asn can be determined to be likely pathogenic. This report not only expands upon the known spectrum of variation of the FBP1 gene, but also deepens our understanding of the clinical features of FBPase deficiency.

Status epilepticus due to fructose‐1,6‐bisphosphatase deficiency caused by FBP1 gene mutation

“…Since the first three mutations reported by Kikawa et al, 48 different mutations have been described and enrolled in Human Gene Mutation Database (HGMD) professional 2018.4. Most of the mutations are widespread throughout the FBP1 gene, and c.959dupG, c.490G>A and c.704delC are hot‐spot mutations that occur primarily in East Asian populations . Here, we report a case of FBPase deficiency with compound heterozygous mutations, c.333+1_333+2delinsTC and c.490G>A (p.Gly164Ser), which were inherited from the mother and father, respectively.…”

“…Most of the mutations are widespread throughout the FBP1 gene, and c.959dupG, c.490G>A and c.704delC are hot-spot mutations that occur primarily in East Asian populations. 4,5,14 Here, we report a case of FBPase deficiency with compound heterozygous mutations, c.333+1_333+2delinsTC and c.490G>A (p.Gly164Ser), which were inherited from the mother and father, respectively. The mutation 490G>A c.333+1_333+2delinsTC was inherited from a heterozygous father, and c.490G>A (p.Gly164Ser) was inherited from a heterozygous mother.…”

“…The missense mutation c.490G>A (p.Gly164Ser) in exon 5 was inherited from the patient's mother, which has previously been identified to be disease-causing. 4,5 The brother was found to carry the same compound heterozygous variants in FBP1 with the patient. The splicing mutation c.333+1_333+2delinsTC has never been reported in the literature, single nucleotide polymorphism databases, or our in-house data from more than 500 healthy individuals.…”

“…Here, we report a case of FBPase deficiency with compound heterozygous mutations, c.333+1_333+2delinsTC and c.490G>A (p.Gly164Ser), which were inherited from the mother and father, respectively. The mutation 490G>A (p.Gly164Ser) has previously been identified to be a disease‐causing mutation . The glycine at position 164 is well‐conserved, and the mutation Gly164Ser results in the formation of an FBPase protein with negligible enzymatic activity.…”

“…The splicing mutation c.333+1_333+2delinsTC in exon 3‐intron 3 was inherited from the patient's father, and the splice site mutation was speculated to result in the skipping of exon 3 in mRNA splicing. The missense mutation c.490G>A (p.Gly164Ser) in exon 5 was inherited from the patient's mother, which has previously been identified to be disease‐causing . The brother was found to carry the same compound heterozygous variants in FBP1 with the patient.…”