Introduction:
Fructose 1,6-biphosphatase (FBP) deficiency is an inherited disorder that affects fructose metabolism and results in frequent episodes of fasting hypoglycemia and lactic acidosis. This genetic disorder has been reported in Asian, Japanese, Arab, European, Moroccan, and North American patients. Individuals with fructose 1,6-biphosphatase deficiency cannot make glucose, resulting in impaired glucose production. Deficiency of the enzyme fructose 1,6-phosphatase leads to acute crises of ketotic hypoglycemia and lactic acidosis manifesting as hyperventilation and seizures. Around half of the affected children may have hypoglycemia in the initial neonatal period (first four days). However, in some patients, there will be severe complications such as metabolic acidosis, ketosis, tachypnea, seizures, and coma.
What Is Fructose 1,6-Biphosphatase?
Fructose 1,6-biphosphatase is an enzyme involved in converting fructose 1,6-biphosphate into fructose 6-phosphate. Fructose 1,6-biphosphatase catalyzes different metabolic pathways and is found in most organisms. It is a key enzyme in the anabolic pathways in living cells, like gluconeogenesis and the Calvin cycle.
What Are the Functions of Fructose 1,6-Biphosphatase?
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Fructose 1,6-biphosphatase functions as a key enzyme in gluconeogenesis. It catalyzes the hydrolysis reaction of fructose 1,6-biphosphate to fructose 6-phosphate.
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Fructose 1,6-biphosphatase is a potential drug target in type II diabetes treatment.
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The deficiency of fructose 1,6-biphosphatase is associated with the incidence of rare inherited metabolic disorders.
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Studies suggest that in clear renal cell carcinoma (kidney cancer), the cancer cells lack the fructose 1,6-biphosphatase enzyme resulting in prolonged survival of the cancer cells.
What Is Fructose 1,6-Biphosphatase Deficiency?
Fructose 1,6-biphosphatase deficiency is characterized by a lack of fructose 1,6-biphosphatase enzyme for gluconeogenesis (synthesis of glucose from non-carbohydrate substrates). Fructose 1,6 biphosphatase is involved in the catalysis of fructose 1,6 biphosphate into fructose phosphate, which is an important step in gluconeogenesis. The liver's glycogen stores are exhausted, and the body relies on gluconeogenesis for glucose needs. Without proper gluconeogenesis, hypoglycemia may occur within 12 hours of fasting.
In individuals with fructose 1,6-biphosphatase deficiency, there will be normal glucose and galactose metabolism. Still, the liver cells cannot use glycerol and fructose to maintain normal blood glucose levels. Thus if glycerol or fructose is given to the patients, there will be an accumulation of phosphorylated sugars in the blood. This may lead to the depletion of phosphate ions in the cells, disrupting cellular processes. However, three-carbon molecules that cannot be used to produce glucose may get converted to pyruvate and lactate. These acid molecules may cause a reduction in the blood pH and metabolic acidosis.
Acute crises due to fructose 1,6-biphosphatase deficiency and resultant metabolic effects are common in early childhood. Infections, fever, reduced oral intake, ingested large quantities of fructose, and vomiting trigger acute episodes. The affected children may have lactic acidosis, hyperventilation, ketotic hypoglycemia, seizures, and coma. In untreated patients, the symptoms gradually worsen, and continued catabolism may cause multiorgan failure involving the brain, liver, and heart. Most children with fructose 1,6-biphosphate deficiency are asymptomatic in between the acute episodes. They may have normal growth and neurological development. However, a few children have shown developmental defects and intellectual disability due to prolonged hypoglycemia.
What Are the Causes of Fructose 1,6-Biphosphatase Deficiency?
Fructose 1,6-biphosphate deficiency occurs due to mutations in the FBP1 gene coding for fructose 1,6-biphosphatase. The mutations in the FBP1 gene may cause a deficiency of fructose 1,6-biphosphatase and alterations in the enzyme function resulting in impaired gluconeogenesis and glucose levels. Till now, 11 mutations have been reported. Fructose 1,6-biphosphatase deficiency is inherited in an autosomal recessive pattern. Thus affected individuals may receive a gene with variations from their parents.
What Are the Symptoms of Fructose 1,6-Biphosphatase Deficiency?
The most common symptoms associated with fructose 1,6-biphosphatase deficiency are the following.
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Vomiting.
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Tachycardia.
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Diarrhea.
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Dyspnea.
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Drowsiness.
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Hypotonia.
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Respiratory distress.
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Reduced consciousness.
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Irritability.
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Confusion.
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Fasting hypoglycemia.
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Excess sleepiness.
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Pallor.
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Ventriculomegaly.
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Reye syndrome-like episodes.
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Intermittent hyperventilation.
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Hepatomegaly.
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Intellectual disability.
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Elevated hepatic transaminase.
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Seizure.
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Coma.
How Can We Diagnose Fructose 1,6-Biphosphatase Deficiency?
Diagnosis of fructose 1,6-biphosphatase deficiency can be made based on clinical presentation and other metabolic tests. In addition, fructose 1,6-biphosphate levels can be evaluated in cultured lymphocytes and thus can be used as a diagnostic tool. Genetic testing can also be done to rule out mutations involving the FBP1 gene coding for the fructose 1,6-biphosphatase enzyme and to confirm the deficiency.
What Are the Treatment Options for Fructose 1,6-Biphosphatase Deficiency?
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Routine daily management involves measures to prevent hypoglycemia and safety measures to avoid infections.
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Routine immunizations to avoid infections.
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Consumption of uncooked starch overnight.
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Eating frequent meals.
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Management of infections.
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Monitoring developmental milestones of children with fructose 1,6-phosphatase deficiency and use of physical and occupational therapies to improve outcome.
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Avoid food items that contain sucrose, fructose, sorbitol, and glycerol to reduce complications.
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In pregnant women with fructose 1,6-biphosphatase deficiency, home glucose monitoring is done routinely to avoid implications.
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Pregnant women with fructose 1,6-biphosphatase deficiency are given uncooked starch at night to meet the increased carbohydrate requirements.
Conclusion:
Fructose1,6-biphosphatase is an important enzyme that is involved in the regulation of gluconeogenesis. The deficiency of fructose1,6-biphosphatase occurs due to mutations involving the FBP1 gene, which codes for the enzyme. The affected individuals may have frequent episodes of fasting hypoglycemia and lactic acidosis.
There is no definite treatment strategy for fructose 1,6-biphosphatase deficiency. Treatment options include routine measures to prevent hypoglycemia, having frequent meals, preventing infections, and reducing food items that contain fructose and sucrose. However, in severe cases, the patients experience metabolic acidosis, ketosis, tachypnea, seizures, and coma.
