Genetic Causes of Hypoglycemia in Children

Hypoglycemia in children is a clinically significant condition caused by abnormally low blood glucose levels.¹ Diagnosing hypoglycemia in children can be challenging because symptoms are often nonspecific and younger children may struggle to communicate how they feel.²

Persistent or recurrent hypoglycemia may indicate an underlying endocrine, metabolic, or genetic disorder. In such cases, endocrine genetic testing can help identify the underlying cause at an earlier stage .

This article explores the clinical presentation, diagnosis, and treatment of hypoglycemia, while also highlighting which patients may benefit from genetic testing and how newborn screening can support early diagnosis.

What Is Hypoglycemia in Children?

Hypoglycemia occurs when blood glucose levels fall below the range required for the body to function properly. Normal glucose levels can vary in children depending on age, nutritional status, and underlying health conditions.

According to the British Association of Perinatal Medicine, low blood sugar (hypoglycaemia) in full-term newborns (birth to 72 hours) is diagnosed when:

Blood sugar is below 18 mg/dL at any time, even if the baby appears well.³
A single blood sugar reading is below 45 mg/dL in a baby showing symptoms or signs of illness.³
Two or more blood sugar readings are below 36 mg/dL in babies who are at risk but do not yet show symptoms.³

Glucose is the brain’s main source of energy. Unlike adults, children, especially infants, have lower glycogen stores and use glucose more quickly.

Hypoglycemia can be described as either:

Transient: Occurring due to short-term causes like fasting and disease.⁴
Persistent: Occurring due to metabolic and endocrine disorders.⁴

Signs and Symptoms of Low Blood Sugar in Infants and Children

The symptoms of hypoglycemia can vary depending on a child’s age and the severity of the condition. In infants, the signs are often nonspecific and can be easily overlooked.⁵

Age	Neuroglycopenic	Neurogenic (Autonomic)
Newborn	Sucking failure or poor sucking Feeble or shrill cry Alteration in the level of consciousness (lethargy, coma) Seizures;	Jittering/ tremors Paleness Sweating Irritability
Infants – Children	Weakness Difficulty in thinking Confusion Fatigue Lethargy	Sweating Loss of appetite Tingling sensation

Neuroglycopenic symptoms arise when the brain itself is deprived of glucose. Neurogenic (Autonomic) symptoms are the body’s automatic stress response to falling blood sugar levels.⁵

When Should a Genetic Cause Be Suspected?

A genetic cause should be considered when a child’s hypoglycemia keeps coming back, lasts longer than expected, or has no clear explanation. The earlier it appears, particularly in newborns, the more likely an underlying genetic condition is responsible.

Risk factors that suggest a genetic cause include:

Babies born prematurely (before 37 weeks of pregnancy).²
Babies who were smaller than expected at birth due to poor growth in the womb.²
Babies born well past their due date (after 42 weeks of pregnancy).²
Mothers who took certain medications during pregnancy, such as blood pressure drugs or diabetes medications.²
A family history of genetic hypoglycemia.²
Babies born with certain congenital (present from birth) conditions are associated with low blood sugar.²

Common Genetic Causes of Hypoglycemia in Children

Congenital Hyperinsulinism

Congenital hyperinsulinism is a condition that affects infants genetically due to a mutation of genes (namely ABCC8, KCNJ11, GCK, GLUD1, HADH, HNF4A, etc.) regulating insulin secretion. It is manifested by excessive insulin secretion in the presence of low levels of glucose in the bloodstream.

This can cause repeated episodes of low blood sugar, even in newborns. If severe or untreated, hypoglycemia can damage the brain and lead to long-term neurological problems.⁶

Glycogen Storage Disorders

Glycogen storage disorders (GSD) refer to inherited metabolic disorders that result in an abnormal accumulation or breakdown of glycogen, with an overall incidence of about 1:25,000 births.

Children suffering from GSDs have difficulties breaking down stored glycogen into glucose during fasting. This causes hypoglycemia, which might be accompanied by symptoms such as hepatomegaly (an abnormally enlarged liver) and cardiomyopathy (a condition in which the heart muscle becomes weakened or thickened, affecting its ability to pump blood).⁵

Fatty Acid Oxidation Disorders (FAOD)

The inability to generate energy through the metabolism of fats when fasting is referred to as fatty acid oxidation disorder. Several enzyme deficiencies fall under this category, including:⁷

MCAD deficiency (Medium-Chain Acyl-CoA Dehydrogenase deficiency, which affects the breakdown of medium-length fat molecules)⁷
VLCAD (Very Long-Chain Acyl-CoA Dehydrogenase deficiency, affecting very long fat chains)⁷
LCHAD (Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase deficiency, affecting long-chain fats)⁷

Each refers to a missing or faulty enzyme responsible for breaking down a specific type of fatty acid for energy.

Once the stored glucose is exhausted, children with these metabolic disorders are not able to utilise fatty acids for generating energy. As a result, children with these metabolic disorders suffer from hypoglycemia. MCAD deficiency is one of the most common FAODs and is included in standard newborn screening panels.⁷

How Doctors Diagnose Hypoglycemia in Children

Diagnosis of hypoglycemia can be achieved through a mixture of clinical assessment and laboratory work. The objective of diagnosing this condition is not just confirming hypoglycemia but determining the cause and treating it.

Some of the factors used to diagnose this disorder are:²

Measurement of blood glucose in cases where symptoms manifest
Clinical findings
Neonatal screening
Insulin, cortisol, and growth hormone levels
Levels of ketones (chemical substances the body produces when it breaks down fat for energy instead of glucose, which can indicate how the body is responding to low blood sugar) and other metabolic products
Special imaging or other tests, if necessary

Lab plasma glucose measurement by the hexokinase method is considered to be a gold standard test while screening neonatal hypoglycemia⁸. A correct diagnosis will require linking biochemical results to clinical manifestations.

Blood Tests and Genetic Testing

Investigations conducted in the laboratory are of critical importance in diagnosing hypoglycemia. Blood tests allow for determining various issues in the functioning of the endocrine glands and metabolic disturbances that cause hypoglycemia.

Due to difficulties that arise during the diagnosis and the high degree of clinical similarity between the different disorders affecting glucose metabolism, recurrent patients should undergo further diagnostic studies using next-generation sequencing (NGS).⁹

What Role Does Genetic Testing Play?

Genetic testing can help identify the underlying genetic cause of unexplained or persistent hypoglycemia in children by detecting changes in specific genes. It also supports accurate diagnosis in conditions with similar clinical features and laboratory findings, such as congenital hyperinsulinism and inherited metabolic disorders.⁹

The purpose of performing genetic tests is to:

Identify the specific genetic defect responsible for the child’s hypoglycemia.⁹
Enable faster and more effective diagnosis through a metabolic gene panel, which detects the underlying cause in approximately 45% of patients with unexplained or recurrent hypoglycemia.⁹
Reduce the need for invasive and costly diagnostic procedures.⁹
Support genetic counselling , including assessing the likelihood of the condition recurring in future pregnancies and exploring options such as prenatal or preimplantation diagnosis.⁹
Detect mutations early, before symptoms progress further.⁹
Guide the development of a personalised treatment plan for the child.⁹
Determine the child’s outlook and assess the risk of recurrence.⁹

Genetic testing can help guide treatment decisions, predict disease outcomes, and provide important information for genetic counselling.

Treatment Options and Emergency Management

The main goal of treating hypoglycemia in children is to prevent repeated episodes and keep blood sugar levels within a safe range, reducing the risk of both immediate and long-term complications.

In severe cases, the priority is to raise blood sugar quickly. This is done by giving glucose directly into the bloodstream through a drip.¹⁰
Long-term management depends on the underlying cause and may include medication, dietary changes, or, in cases where the pancreas continues to overproduce insulin and does not respond to medication, surgery.¹⁰
If a child experiences repeated episodes of low blood sugar linked to low-fat energy (ketotic hypoglycemia), doctors will look more carefully for an underlying metabolic condition. Giving steroid medications to newborns without a confirmed diagnosis is not recommended.¹⁰

For newborns considered at risk of low blood sugar:

In the first 48 hours after birth, blood sugar should be kept above 50 mg/dL (2.8 mmol/L).¹⁰
After 48 hours, the target rises to above 60 mg/dL (3.3 mmol/L).¹⁰
If the baby is receiving glucose through a drip, blood sugar should be maintained above 60 mg/dL.¹⁰
Once the baby is stable, the glucose drip is gradually reduced and the baby is moved back to normal feeding.¹⁰

How Can Hypoglycemia in Children Be Prevented?

Preventing hypoglycaemia involves keeping blood sugar levels stable and managing the underlying condition causing it. General preventive measures include ⁸:

Identifying babies at risk before birth or as soon as possible after delivery.
Starting feeding early and ensuring the baby gets enough energy through appropriate feeding.
Checking blood sugar levels regularly using quick and reliable methods.
Monitoring the baby’s feeding patterns and overall condition consistently.

Managing hypoglycemia in infants and children means acting quickly when blood sugar drops, keeping levels within a safe range, and addressing the root cause to prevent future episodes. Extra care is needed for high-risk newborns, with blood sugar targets adjusted for the baby’s age and close monitoring in the first days after birth.

Advances in genetic testing, such as the prenatal exome sequencing offered by MedGenome, now allow for earlier and more accurate identification of the genetic or metabolic conditions behind hypoglycemia, particularly when episodes keep recurring or the cause remains unclear.

FAQs

What are the criteria for hypoglycemia in children?
Blood glucose levels are below 45 mg/dL in newborns and below 60 mg/dL in older children. Diagnosis is confirmed when low blood sugar is documented, symptoms such as jitteriness or lethargy are present, and those symptoms resolve once glucose is restored.

What are the two most common causes of hypoglycemia in children?
Congenital hyperinsulinism, where the pancreas produces too much insulin, and metabolic disorders such as Glycogen Storage Disease. In older children, ketotic hypoglycemia is also common, occurring when energy stores run out during fasting or illness.

What is the treatment for hypoglycemia in children?
In emergencies, fast-acting carbohydrates such as juice or glucose gel, or a glucose drip in a hospital. Long-term treatment targets the root cause and may include dietary changes, cornstarch therapy, or medication to reduce insulin secretion.

What foods can trigger hypoglycemia?
In children with certain metabolic conditions, specific foods can trigger a drop in blood sugar. Fructose (fruit sugar) affects children with Hereditary Fructose Intolerance, and galactose (found in milk) affects those with Galactosemia.

What are the three levels of hypoglycemia?
Hypoglycemia typically progresses through three stages: early symptoms such as sweating and shakiness; reduced brain function causing confusion and behavioural changes; and severe hypoglycemia leading to seizures and loss of consciousness.

What is the emergency risk of severe hypoglycemia?
Severe untreated hypoglycemia is a medical emergency. Prolonged low blood sugar can cause permanent brain damage, developmental delays, seizures, respiratory failure, and life-threatening heart rhythm problems.

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