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Fructose-1,6-bisphosphatase deficiency
This rare genetic condition affects the body's ability to produce glucose (sugar) from non-carbohydrate sources, a process called gluconeogenesis. It primarily affects infants and young children, leading to episodes of low blood sugar (hypoglycaemia) and other metabolic imbalances.
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Overview
Fructose-1,6-bisphosphatase deficiency is an inherited metabolic disorder that prevents the body from effectively creating glucose, which is a vital energy source, especially for the brain. This process, known as gluconeogenesis, is essential during periods of fasting, illness, or high energy demand when dietary carbohydrates are not available. People with this condition have a problem with a specific enzyme that plays a key role in this pathway [PMID:33008182].
When the body cannot perform gluconeogenesis properly, individuals can develop severe low blood sugar (hypoglycaemia) and a build-up of lactic acid (lactic acidosis). These metabolic crises are often triggered by fasting, illness, or consuming foods rich in fructose or other sugars that enter the gluconeogenesis pathway. The condition is rare, and its exact prevalence in the UK is not well established.
Symptoms & clinical features
Symptoms of fructose-1,6-bisphosphatase deficiency typically appear in infancy or early childhood. These can include episodes of severe low blood sugar (hypoglycaemia), which may manifest as lethargy, irritability, poor feeding, and in severe cases, seizures or coma [PMID:33008182].
Other common symptoms during a metabolic crisis include rapid breathing (due to acidosis), vomiting, and muscle weakness. In some instances, an enlarged liver (hepatomegaly) may be observed. If not managed carefully, recurrent episodes can potentially lead to developmental challenges, though prompt recognition and treatment can often prevent serious long-term complications.
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Affected organs
The primary organs affected by fructose-1,6-bisphosphatase deficiency are the liver and kidneys, as these are the main sites where gluconeogenesis occurs. The liver is particularly crucial for maintaining stable blood glucose levels.
During metabolic crisis, the brain is also significantly impacted due to its high demand for glucose. Prolonged or severe hypoglycaemia can lead to neurological damage. Without adequate glucose, muscle function can also be impaired, contributing to weakness and fatigue.
Risks & severity
The severity of fructose-1,6-bisphosphatase deficiency can vary, but it often presents in infancy as a life-threatening condition if not diagnosed and managed early. The main risks are severe hypoglycaemia and lactic acidosis, which, if untreated, can lead to seizures, brain damage, coma, and even death [PMID:19419106].
Episodes are typically triggered by factors like prolonged fasting, infections, or ingesting fructose-containing foods. With careful dietary management and avoidance of triggers, individuals can often lead relatively normal lives. However, ongoing vigilance is necessary throughout childhood and sometimes into adulthood, especially during times of illness.
Genetic causes
Fructose-1,6-bisphosphatase deficiency is caused by pathogenic variants in the FBP1 gene. This gene provides instructions for making the enzyme fructose-1,6-bisphosphatase 1 [PMID:33008182]. This enzyme acts as a crucial 'switch' in the gluconeogenesis pathway, enabling the body to produce glucose from lactate, amino acids, and glycerol when dietary carbohydrates are scarce.
Pathogenic changes in the FBP1 gene lead to a deficiency or complete absence of functional fructose-1,6-bisphosphatase 1. Without this enzyme, the gluconeogenesis pathway is severely impaired, preventing the liver and kidneys from producing enough glucose to meet the body's needs during fasting or illness. This inability to generate glucose then leads to the characteristic hypoglycaemic episodes and lactic acid build-up.
- FBP1 fructose-bisphosphatase 1
Inheritance pattern
Fructose-1,6-bisphosphatase deficiency follows an autosomal recessive inheritance pattern. This means that an individual must inherit two copies of a pathogenic FBP1 variant - one from each parent - to develop the condition.
Parents who each carry one copy of a pathogenic FBP1 variant are known as carriers. Carriers typically do not show symptoms of the condition themselves. With each pregnancy, there is a 25% chance of having a child affected by the condition, a 50% chance of having a child who is a carrier, and a 25% chance of having a child who does not inherit any pathogenic variants.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of fructose-1,6-bisphosphatase deficiency is typically suspected when an infant or young child presents with recurrent episodes of hypoglycaemia and metabolic acidosis, especially if triggered by fasting or illness. Initial blood tests may show low blood glucose, high lactate, and specific changes in other metabolites.
Definitive diagnosis is confirmed through genetic testing, which can identify pathogenic variants in the FBP1 gene. In the UK, genetic testing for inherited metabolic disorders is available through the NHS Genomic Medicine Service, often following referral from a metabolic specialist. The relevant R-code for this testing would fall under the inherited metabolic disorders category.
Management & lifestyle
Management of fructose-1,6-bisphosphatase deficiency primarily focuses on preventing metabolic crises and maintaining stable blood glucose levels. This typically involves a special diet that restricts fructose, sucrose, and sorbitol, and ensuring regular, frequent meals to avoid prolonged fasting. Cornstarch supplements may be used, particularly overnight, to provide a slow release of glucose.
During illnesses or other stressful periods, hospital admission may be necessary to administer intravenous glucose and manage any metabolic imbalances. Individuals with the condition are usually managed by a multidisciplinary team, including a metabolic specialist, a dietitian, and a genetic counsellor, as part of the NHS care pathway. Genetic counselling can provide information about the condition, inheritance, and family planning options.
UK care pathway
In the UK, individuals suspected of having fructose-1,6-bisphosphatase deficiency would typically be referred to a specialist metabolic centre, often through a paediatrician. The NHS Genomic Medicine Service provides comprehensive genomic testing, which can confirm the diagnosis by identifying pathogenic variants in the FBP1 gene, under relevant R-codes for inherited metabolic disorders. Genetic counsellors play a vital role in supporting families, explaining inheritance patterns, and discussing implications for other family members.
Frequently asked questions
What foods should be avoided if someone has fructose-1,6-bisphosphatase deficiency?
Individuals with this condition typically need to avoid or strictly limit foods containing fructose, sucrose (table sugar), and sorbitol. This includes many fruits, some vegetables, honey, and processed foods with added sugars. A registered dietitian specialising in metabolic disorders can provide a detailed dietary plan.
Is fructose-1,6-bisphosphatase deficiency always severe?
The severity can vary. While it often presents as a serious condition in infancy, with early diagnosis and strict adherence to dietary and management guidelines, many affected individuals can lead generally healthy lives. However, vigilance is always required, especially during periods of illness or fasting.
How often do people with this condition experience low blood sugar?
The frequency of hypoglycaemic episodes depends on how well the condition is managed. With careful dietary control, regular feeding, and avoidance of triggers like prolonged fasting, episodes can be significantly reduced. However, illnesses or unexpected fasting can still provoke a crisis.
Can adults develop symptoms of fructose-1,6-bisphosphatase deficiency?
While typically diagnosed in infancy or childhood, some individuals with milder forms might not be diagnosed until later in life, or they may experience symptoms again during adulthood, particularly during illnesses or prolonged fasting. Lifelong management is generally recommended.
Will my other children be affected if one child has fructose-1,6-bisphosphatase deficiency?
Since the condition is autosomal recessive, if you have one child with the condition, both parents are carriers. For each subsequent pregnancy, there is a 25% chance of having another affected child. Genetic counselling can provide specific risk information and options for future family planning.