Background: Advances in genomic technologies combined with tandem mass newborn screening have enabled early detection and management of several common inborn errors of metabolism. Fructose-1,6-bisphosphatase deficiency, an autosomal recessive treatable disorder reported in around 150 patients worldwide, remains underdiagnosed despite an excellent prognosis with early detection. Although common in highly consanguineous populations, diagnosis is often delayed due to the non-specific clinical and biochemical profile. Methods: This report explores the diagnostic pathway using first-tier next-generation sequencing of three novel cases of fructose-1,6-bisphosphatase deficiency in a tertiary care center in Lebanon. Results: Two patients were diagnosed with first-tier exome sequencing within one month of presentation and had an excellent outcome at 6 years of follow-up. The third patient, undiagnosed for 10 years, suffered from neurological sequalae. The molecular profile was remarkable in two patients for exon 2 deletion in the FBP1 gene, a founder mutation reported in Turkish and Armenian patients, and a rare frameshift mutation in the third case. Conclusions: The use of next-generation sequencing as as a first-tier test for FBP deficiency is a non-invasive and rapid method for early diagnosis and management of this rare yet treatable disorder. It can detect both disease-causing variants and large deletions, founder mutations as well, delineating the molecular profile in populations where this disorder is highly prevalent.

Fructose-1,6-bisphosphatase (FBP1) deficiency is a rare inherited disease characterized by recurrent episodes of lactic acidosis and ketotic hypoglycemia. To date, no cases have been reported in the Egyptian population. This study aimed to elucidate the phenotypic and molecular spectrum of FBP1 deficiency in Egypt. This observational study included children with FBP1 deficiency diagnosed and managed at an Egyptian medical center between 2022 and 2024. Clinical and laboratory data of acute metabolic episodes were thoroughly reviewed. All patients underwent blood acylcarnitine assay, urinary organic acids analysis, and whole-exome sequencing. Patients' outcomes were classified into favorable, neurodevelopmental impairment, and death. This cohort included 14 Egyptian children (from 11 families) with FBP1 deficiency. The median age at disease onset was 13 months, ranging from the first week of life to 36 months. All patients exhibited acute lactic acidosis, and most (13/14) had hypoglycemia. Four FBP1 variants were identified: c.88G > T (p.Glu30Ter), c.652_661delinsTCACGAGGGCT (p.Arg218SerfsTer9), c.960delinsGG (p.Ser321ValfsTer13), and c.902_904del (Glu301del). The c.960delinsGG variant was detected in nine cases, suggesting a founder effect. The c.652_661delinsTCACGAGGGCT is a novel variant. One case had a coexisting partial biotinidase deficiency. Regarding outcome, two patients died during the neonatal period, while the remainder achieved normal neurodevelopment. This is the first study of FBP1 deficiency in Egypt, which expands the demographic, clinical, and genetic spectrum of this rare disease.

Fructose 1, 6 bisphosphatase (FBPase) deficiency is a rare autosomal recessive disease caused by mutations in the FBP1 gene. Symptoms of this disease are heterogeneous, with a variable age of onset, and are often confused with those of other inborn errors of metabolism. Biochemical testing is not conclusive, and patients usually need molecular testing for proper diagnosis and management. To describe clinical and molecular characteristics of patients with FBPase deficiency. The study included six female patients diagnosed with FBPase deficiency, all recruited from the outpatient genetics clinic and the Children's Hospital at Ain Shams University, Faculty of Medicine. The mean age at presentation was 22.8 ± 16.16 months, while the mean age at diagnosis was 62 ± 45.16 months, indicating an average diagnostic delay of three years. The most common presenting symptoms were vomiting, fever, and lethargy. Hepatomegaly was the most frequently observed clinical sign on examination. Initial laboratory investigations commonly revealed ketotic hypoglycemia and metabolic acidosis. Molecular testing confirmed the diagnosis in all cases. Encouragingly, with appropriate management, all patients achieved normal neurocognitive outcomes. Fructose 1,6-bisphosphatase deficiency should be considered in children presenting with hypoglycemia and metabolic acidosis. Early molecular diagnosis is recommended to confirm the condition and to facilitate carrier screening and preventive strategies for at-risk family members.

Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare gluconeogenic disorder characterized by hypoglycemia, lactic acidosis, hyperuricemia, and ketosis, triggered by fasting or infection. Although dietary management aims to prevent hypoglycemia, accurate tools to monitor asymptomatic episodes are lacking. Continuous glucose monitoring (CGM) has not been systematically evaluated in FBPase deficiency. This study aimed to assess the utility of CGM in detecting silent hypoglycemia and its relationship with dietary management. Ten genetically confirmed patients underwent blinded CGM using the Medtronic iPro2™ system. CGM metrics included time below range (TBR <70 mg/dL [<3.9 mmol/L]), time in range (TIR 70-150 mg/dL [3.9-8.3 mmol/L]), and time above range (TAR >150 mg/dL [>8.3 mmol/L]). Correlations with biochemical, clinical, and nutritional variables were analyzed using Pearson or Spearman tests, and categorical comparisons were conducted with Fisher's exact test. Multiple testing was controlled using the Benjamini-Hochberg procedure (significance at FDR-adjusted p<0.05). Despite using uncooked/modified cornstarch (UCCS/MCS) and frequent feeding (all but one patient), asymptomatic hypoglycemia occurred in some patients. Mean TBR was 11.2 ± 31.2% (Median: 1, Range:0-100). Higher UCCS/MCS dosing correlated with fewer annual metabolic attacks (ρ=-0.854, p-adj=0.002), higher TIR (ρ=0.899, p-adj=0.002), and lower TBR (ρ=-0.917, p-adj=0.003). Patients with TBR≥2% had more annual crises (p=0.003), lower UCCS/MCS dosing frequency (p=0.019), and more hepatic steatosis (p=0.048). Ketonuria correlated with attack frequency (r=0.846, p-adj=0.026). Hepatosteatosis was associated with greater annual attacks (p-adj=0.028). This, to the best of our knowledge, is the first systematic pilot study of CGM in FBPase deficiency, suggesting a potential role in detecting silent hypoglycemia and informing individualized dietary strategies.