Fructose-1,6-bisphosphatase deficiency is a rare autosomal recessive disorder characterized by impaired gluconeogenesis. Fructose-1,6-bisphosphatase 1 (FBP1) mutations demonstrate ethnic patterns. For instance, Turkish populations commonly harbor exon 2 deletions. We present a case report of whole exon 2 deletion in a Syrian Arabian child as the first recording of this mutation among Arabian ethnicity and the first report of FBP1 gene mutation in Syria.
Case presentation
We present the case of a 2.5-year-old Syrian Arab child with recurrent hypoglycemic episodes, accompanied by nausea and lethargy. The patient’s history, physical examination, and laboratory findings raised suspicion of fructose-1,6-bisphosphatase deficiency. Whole exome sequencing was performed, revealing a homozygous deletion of exon 2 in the FBP1 gene, confirming the diagnosis.
Conclusion
This case highlights a potential novel mutation in the Arab population; this mutation is well described in the Turkish population, which suggests potential shared mutations due to ancestral relationships between the two ethnicities. Further studies are needed to confirm this finding.
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Abkürzungen
FBP1
Fructose-1,6-bisphosphatase 1
Background
Fructose-1,6-bisphosphatase deficiency is a rare autosomal recessive inherited disorder that results in impaired gluconeogenesis. This disorder is caused by mutations in the gene that encodes for fructose-1,6-bisphosphatase 1 (FBP1). It was first described in 1970 as recurrent episodes of fasting hypoglycemia and metabolic and lactic acidosis manifesting as hyperventilation, apneic spells, seizures, or coma, which take place usually early in childhood [1, 2]. Episodes might be triggered by fever, fasting, decreased oral intake, vomiting, infections, and ingestion of large amounts of fructose, untreated patients are at risk of multiorgan failure (especially liver and brain), and morbidity and mortality are high. Reye syndrome-like presentations have been reported [2]. With early diagnosis and exact management, the long-term prognosis is excellent, which highlights the importance of early diagnosis [3]. Fructose-1,6-bisphosphatase gene is composed of eight exons located on chromosome 9q22.2-q22.3 [4]. Many FBP1 gene mutations have been described for each ethnic group; exon 2 deletion is a common mutation among Turkish populations, and has been reported in Armenian populations as well [5, 6]. Here we report an FBP1 gene mutation in a Syrian Arabian child where DNA sequencing of the FBP1 gene identified a homozygous 170 base pair deletion encompassing whole exon 2 (previously termed exon 1) of the FBP1 gene (Chr9: 94,639,141–94,639,310). This mutation has not been reported before among people of Arabian ethnicity, and this is the first documentation of the FBP1 mutation in Syria.
Case presentation
A 2.5-year-old Syrian Arab child presented to the outpatient clinic in our hospital with nausea, lethargy, and an acutely sick appearance. The patient has a 6-month history of recurrent episodes of hypoglycemia sometimes accompanied by fever and intestinal infection, and required hospitalization. The patient was born by cesarean delivery after normal history of pregnancy; he weighed 2400 g at birth. The patient was previously diagnosed with growth hormone deficiency on the basis of a laboratory evaluation (Table 1) and was administered replacement therapy 6 months before presentation. Before coming to our hospital, the patient was admitted to a local hospital due to episodes of vomiting, seizures, and deteriorating condition, where he was treated with intravenous fluids by glucose 5% solution, antibiotics, and antiemetics. Family history showed a kinship relationship between the parents; they have another girl and lost a boy 15 days after birth due to dehydration and poor breastfeeding, and the mother is currently pregnant (Fig. 1). Otherwise, his family and psychosocial history were insignificant as the parents were healthy and no abnormal conditions in his family were reported. Physical examination revealed asthenia and hepatomegaly. Laboratory evaluation results are presented in Tables 2, 3 and 4. Cardiac ultrasound and electrocardiogram were normal, whereas abdomen ultrasound showed homogeneous hyperechoic hepatomegaly 15.7 cm in the right anterior axillary line. Fructose-1,6-bisphosphatase deficiency was suspected. As testing of FBP1 activity in liver or mononuclear white blood cells was not available, genetic testing was suggested. The patient underwent whole exome sequencing, showing a homozygous 170 base pair deletion encompassing whole exon 2 of the FBP1 gene (Chr9: 94,639,141–94,639,310). On the basis of the genetic test, the 6-bisphosphatase deficiency was confirmed. Follow-up included recommendations to avoid fasting particularly during febrile episodes, frequent feeding, the use of slowly absorbed carbohydrates (such as uncooked starch), and gastric drip, if necessary. Three months of follow-up revealed that the patient’s condition improved significantly with the disappearance of episodes of hypoglycemia. Table 5 presents laboratory evaluation for follow-up of the patient.
Table 1
Laboratory test results before presenting
Test
Glucose
Insulin
Cortisol
Ketone bodies
Growth hormone
Result
36
0.2
21.8
Negative
2.86
Normal value
(65–110)
mg/dl
(0–30)
uIU/ml
(5–25)
Ug/dl
(0.03–0.3)
mmol/l
(0–7)
ng/ml
Fig. 1
Pedigrees of the family
Table 2
Laboratory test results at presenting
Test
GRA
WBC
CRP
UA
AST
ALT
CREA
BUN
GLU
Result
55
7900
0.09
5
48
61
049
11
60–240
Unit
%
103/ml
m/l
mg/dl
U/l
U/l
mg/dl
mg/dl
mg/dl
GRA glucocorticoid-remediable aldosteronism, WBC white blood cells, CRP C-reactive protein, UA uric acid, AST aspartate aminotransferase, ALT alanine transaminase, CREA creatinine, BUN blood urea nitrogen, GLU glucose
Table 3
Laboratory test results at presenting
Cl
K
Na
KBU
KBB
Lactate
GLU*
98.5
3.2
138
Negative
Positive
36
106
mmol/l
mmol/l
mmol/l
mg/dl
mg/dl
KBU ketone bodies in urine, KBB ketone bodies in blood, GLU glucose
*After 18 hours fasting
Table 4
Laboratory test results at presenting
PTT
PT
ALP
CHOL
TG
P
Ca
CK
Alb
TP
30
100
137
133
301
3.1
9.61
43
3.9
5.38
27 seconds
%
U/l
mg/dl
mg/l
mg/dl
mg/dl
U/l
g/dl
g/dl
PPT partial thromboplastin time, PT prothrombin time, ALP alkaline phosphatase, CHOL cholesterol, TG triglyceride, P phosphate, Ca calcium, CK creatine kinase, Alb albumin, TP total protein
Table 5
Laboratory test results tow months after treatment
Test
Result
Units
Glucose
105
mg/dl
Triglyceride
75
mg/l
Cholesterol
178
mg/dl
Uric acid
3.5
mg/dl
Lactate
28.8
mg/dl
KBB
0.11
mg/dl
NH4
42
mg/dl
pH
7.4
pCO2
33.7
mmHg
HCO3
22.4
mmol/l
BE
−1
mmol/l
NH4 Ammonia, HCO3 Bicarbonate, pH potential of Hydrogen
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Discussion
This case presents the first reported FBP1 gene mutation in Syria, and report a novel FBP1 gene mutation in the Arabian population. The FBP1 gene is located on chromosome 9 and encodes the fructose-1,6-bisphosphatase enzyme, which plays a crucial role in the regulation of glucose metabolism [1, 2].
In this case report, whole exome sequencing revealed a homozygous 170 base pair deletion of exon 2 of the FBP1 gene (Chr9: 94,639,141–94,639,310) in a 2.5-year-old Syrian Arab child. This deletion results in a frame shift mutation, leading to a premature stop codon and the production of a truncated nonfunctional fructose-1,6-bisphosphatase enzyme [3].
The molecular basis of FBP1 deficiency lies in the disruption of the gluconeogenic pathway. Fructose-1,6-bisphosphatase is a key enzyme in this pathway, responsible for the conversion of fructose-1,6-bisphosphate to fructose-6-phosphate, which is an essential step in gluconeogenesis. Mutations in the FBP1 gene impair the enzymatic activity of fructose-1,6-bisphosphatase, leading to decreased glucose production and subsequent hypoglycemia [2].
FBP1 mutations among the Arabian population were identified in a study conducted on Arab patients with fructose-1,6-bisphosphatase deficiency. Two novel mutations were identified in the FBP1 gene. A novel six-nucleotide repetitive insertion, c114_119dupCTGCAC, was identified in patients from three families. This mutation encodes for the duplication of two amino acids (p.Cys39_Thr40dup) in the N-terminal domain of FBP1. Another novel nonsense c.841G > T mutation encoding for a p.Glu281X truncation in the active site of FBP1 was discovered in patients from two families. These newly identified mutations were predicted to produce FBP1 deficiency and were the only known genetic causes of FBP1 deficiency in Arab patients [6].
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Importantly, the identification of this specific mutation in the Syrian Arab population highlights the ethnic diversity of FBP1 mutations. Previously, this mutation has been reported in the Turkish population. The presence of the same mutation in different ethnic groups suggests either a common ancestral origin or a recurrent mutational event. The occurrence of FBP1 deficiency-associated mutations in distinct populations underscores the significance of genetic heterogeneity and highlights the need for expanded genetic screening programs across diverse ethnic backgrounds [3, 6].
Understanding the molecular basis of FBP1 mutations is crucial for accurate diagnosis, prognosis, and management of affected individuals. Molecular genetic testing, such as whole exome sequencing, enables the identification of specific mutations, facilitating precise diagnosis and appropriate management strategies tailored to the individual patient’s needs [4].
The identification of a homozygous exon 2 deletion in the FBP1 gene in a Syrian Arab child with FBP1 deficiency highlights the ethnic diversity of FBP1 mutations. This case emphasizes the importance of considering population-specific variations in the diagnosis and management of rare genetic disorders. Further studies and collaborative efforts involving diverse populations are necessary to unravel the complete spectrum of FBP1 mutations, enabling comprehensive genetic counseling, early detection, and optimal management of affected individuals worldwide.
Conclusion
FBP1 exon 2 deletion mutation is well described in the Turkish population but not in the Arabian population. This suggests potentially shared mutations due to ancestral relationships between the two ethnicities. We suggest conducting further studies to confirm this finding.
Acknowledgements
Not applicable.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests.
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