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

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This study is the first to report molecularly confirmed cases of fructose-1,6-bisphosphatase deficiency in the Egyptian population, identifying two common variants and suggesting the disease may be underdiagnosed in the Middle East, offering new insights for rare disease research and molecular diagnostics.

 

Literature Overview

The article titled Clinical and molecular characteristics of fructose 1,6 bisphosphatase deficiency in 6 Egyptian patients and two common variants, published in Orphanet Journal of Rare Diseases, reviews and summarizes the clinical and molecular features of six Egyptian patients with fructose-1,6-bisphosphatase (FBPase) deficiency. The study reveals that the disease might be underdiagnosed in the Egyptian population and identifies two common pathogenic variants, suggesting a higher carrier frequency in the Middle East. Early diagnosis and molecular testing are crucial to avoid misdiagnosis, guide treatment, and enable family screening.

Background

Fructose-1,6-bisphosphatase deficiency is a rare autosomal recessive disorder caused by mutations in the FBP1 gene, which encodes a key enzyme in the gluconeogenic pathway. The disease exhibits significant clinical heterogeneity and is classically characterized by the triad of hypoglycemia, ketosis, and metabolic acidosis, often triggered by infection, fasting, or fructose intake. Patients are frequently misdiagnosed with mitochondrial diseases or other inherited metabolic disorders, leading to treatment delays. Current diagnosis mainly relies on biochemical screening and molecular analysis, with NGS technology becoming the primary diagnostic tool. The estimated incidence in European populations ranges from 1/350,000 to 1/900,000, while no epidemiological data exist for Middle Eastern countries like Egypt. However, due to high rates of consanguineous marriages, the actual incidence may be higher. This study aims to identify the mutational spectrum of FBP1 in Egyptian patients and provide evidence for clinical diagnosis and genetic counseling.

 

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Study Methods and Experiment

Six Egyptian female patients were enrolled from outpatient clinics affiliated with Ain Shams University and Children's Hospital in Cairo. All patients underwent extended metabolic screening (EMS) and organic acid analysis to exclude other common metabolic diseases, and were ultimately diagnosed with FBPase deficiency through targeted next-generation sequencing (NGS) of inherited metabolic disease genes. Clinical and laboratory data, including age at symptom onset, biochemical markers, imaging findings, and follow-up information, were collected retrospectively.

Key Findings and Perspectives

• The average age at onset among the six patients was 22.8 ± 16.16 months, with an average diagnostic age of 62 ± 45.16 months, resulting in an average diagnostic delay of 39 ± 44.66 months
• The most common initial symptoms were vomiting, fever, and lethargy, while the most frequent biochemical abnormalities were ketotic hypoglycemia and metabolic acidosis
• Mitochondrial DNA mutations were not detected in any of the patients, although some were previously misdiagnosed with mitochondrial diseases and received corresponding treatments
• Molecular analysis identified two common FBP1 variants: c.469G > C (p.Gly157Arg) and c.902_904del (p.Glu301del), with one patient showing homozygous deletion of exon 1
• Despite overlapping biochemical features, all patients achieved normal neurocognitive development following appropriate management
• This study is the first to report genetically confirmed cases of FBPase deficiency in the Egyptian population, suggesting the disease may be underdiagnosed in the Middle East. Population-based screening studies are recommended to assess carrier frequency

Significance and Future Directions

The study highlights the high clinical heterogeneity of FBPase deficiency and its overlapping features with other inherited metabolic disorders, which complicate early diagnosis. Molecular testing (NGS) is essential for confirmation, especially in regions with high consanguinity rates such as Egypt, where early use of genetic testing is advised to prevent misdiagnosis. Future research should include population-based screening to determine the carrier frequency and prevalence of FBP1 variants in the Middle East. Additionally, clinicians should be more aware of FBPase deficiency in children presenting with hypoglycemia and metabolic acidosis.

 

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Conclusion

This study reports, for the first time, the clinical and molecular features of fructose-1,6-bisphosphatase (FBPase) deficiency in Egyptian patients, indicating that the disease may be underdiagnosed in the Middle East. The clinical presentation overlaps significantly with other inherited metabolic disorders, particularly mitochondrial diseases, leading to misdiagnosis and treatment delays. All cases were confirmed via NGS, identifying two common pathogenic variants: c.469G > C and c.902_904del, which may have higher frequencies in Arab populations. Early molecular diagnosis is crucial not only for patient management but also for enabling family screening and genetic counseling. Further large-scale epidemiological studies are needed to determine the true incidence and carrier frequency in Egypt and the broader Middle East, and to optimize clinical screening protocols.

 

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.