Orphanet Journal of Rare Diseases | Clinical and Molecular Characteristics of Fructose-1,6-Bisphosphatase Deficiency in 6 Egyptian Patients

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The first report on clinical and molecular features of fructose-1,6-bisphosphatase deficiency in Egyptian patients, revealing two common variants that may improve diagnostic efficiency.

 

Literature Overview
This article reviews the clinical and molecular characteristics of six Egyptian patients with fructose-1,6-bisphosphatase (FBPase) deficiency, published in the Orphanet Journal of Rare Diseases. The study highlights the similarity of clinical manifestations to other inherited metabolic disorders, leading to delayed diagnosis. Molecular analysis confirmed two common variants, providing new directions for future screening and prevention.

Background Knowledge
Fructose-1,6-bisphosphatase deficiency is a rare autosomal recessive disorder caused by mutations in the FBP1 gene. It is mainly characterized by hypoglycemia, ketosis, and metabolic acidosis, often triggered by infections, fasting, or fructose intake, leading to acute metabolic decompensation. Due to overlapping symptoms with other metabolic disorders, diagnosis is frequently delayed. In recent years, molecular genetic testing has become a key diagnostic tool, especially in cases with overlapping inherited metabolic disease (IEM) phenotypes. However, no public data on the prevalence of this disease in Egypt is available. This study suggests that consanguineous marriages may increase the disease incidence. It is the first to confirm the molecular basis of the disease in the Egyptian population and identifies two common variants, offering important clues for future research and screening.

 

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Study Methods and Experiments
The study retrospectively analyzed six Egyptian patients, all female, who presented with hypoglycemia and metabolic acidosis. All patients underwent clinical evaluation and extended metabolic screening (EMS), followed by next-generation sequencing (NGS) to detect mutations in genes associated with inherited metabolic diseases, focusing on the FBP1 gene. The study also analyzed patients’ demographics, biochemical findings, and genotype-phenotype correlations.

Key Findings and Perspectives

• All six patients were female, with most presenting before age 2. The average age at diagnosis was 62 months, indicating an average diagnostic delay of nearly 3 years
• The most common symptoms included vomiting, fever, and drowsiness. Physical exams frequently revealed hepatomegaly, although some patients showed no obvious hepatomegaly
• All patients exhibited ketotic hypoglycemia and metabolic acidosis in biochemical tests, while extended metabolic screening showed no significant abnormalities
• Molecular analysis confirmed two common mutations in the FBP1 gene: c.469G>C (p.Gly157Arg) and c.902_904del (p.Glu301del). One patient was found to have a deletion in exon 1
• These two common variants were identified across different families, suggesting the disease may be more prevalent in the Egyptian population than previously thought
• Early adoption of a fructose-free diet, avoidance of prolonged fasting, and supplementation with uncooked cornstarch effectively controlled the disease. All patients showed normal neurocognitive development

Implications and Future Directions
This study provides the first molecular evidence of FBPase deficiency in the Egyptian population and identifies two potentially common variants. These findings offer important references for future screening and genetic diagnosis, especially in regions with high rates of consanguineous marriages. Further epidemiological and molecular screening studies are needed to understand the true incidence and variant distribution of the disease, which will support carrier screening and genetic counseling for affected families.

 

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Conclusion
Fructose-1,6-bisphosphatase deficiency is a rare genetic metabolic disorder that is easily misdiagnosed. Common symptoms include hypoglycemia, ketosis, and metabolic acidosis. Due to its overlapping clinical features with other inherited metabolic diseases, patients often experience prolonged diagnostic delays. This study, for the first time in the Egyptian population, confirmed two common mutation types in the FBP1 gene via molecular testing, suggesting that the disease may be more prevalent in this region. Early recognition of the clinical triad combined with molecular testing can significantly improve diagnostic efficiency, and also aids in carrier screening for family members. Future large-scale screening studies are necessary to clarify the true incidence and variant distribution in Egypt and the Middle East. Additionally, as genetic sequencing becomes more widespread, NGS will play an increasingly important role in diagnosing similar rare diseases.

 

Solaf M Elsayed, Radwa G Mahmoud, and Yasmeen Abdelaziz Fereig. Clinical and molecular characteristics of fructose 1, 6 bisphosphatase deficiency in 6 Egyptian patients and two common variants. Orphanet Journal of Rare Diseases.