Hypoglycemia in the neonate and infant

Persistent or recurrent hypoglycemia (plasma glucose < 50 mg/dL in a symptomatic neonate, lower transient thresholds in the first 48 hours) that does not resolve with feeding or that recurs once feeding is established. Transient hypoglycemia in the first day of life is common and resolves; the genetic presentations live in the persistent, recurrent, or unprovoked category. The single most useful question is what the patient is doing at the moment glucose drops (fasting? after protein? after fructose?), and what the critical sample shows.

Glucose can drop for one of four reasons. The differential follows the cause:

1. Too much insulin (hyperinsulinism): glucose drops while insulin is detectable. Ketones suppressed.
2. Can't make glucose from glycogen (glycogenolysis defect): fasting hypoglycemia after a few hours, hepatomegaly.
3. Can't make glucose from non-carbohydrate substrate (gluconeogenesis defect): fasting hypoglycemia after longer fasts, lactic acidosis.
4. Can't use fat for energy when glucose runs out (fatty acid oxidation defect): hypoketotic hypoglycemia with fasting/illness, often with cardiomyopathy and rhabdomyolysis in older patients.

The critical sample (blood drawn at the moment of hypoglycemia, before dextrose) is the test that breaks the case open. You want simultaneous: glucose, insulin, C-peptide, β-hydroxybutyrate (ketones), free fatty acids, lactate, ammonia, cortisol, growth hormone, acylcarnitine profile, urine organic acids, urine ketones.

Hyperinsulinism (insulin inappropriately detectable when glucose is low)

The hallmark: high glucose requirement (often > 8 mg/kg/min), suppressed ketones, suppressed free fatty acids. C-peptide is detectable confirming endogenous insulin.

• Congenital hyperinsulinism (ABCC8, KCNJ11, GLUD1, HNF4A, others): the most common cause of persistent neonatal hypoglycemia. Focal or diffuse forms. Diazoxide responsive vs unresponsive distinguishes GLUD1 and HNF4A from the K-ATP-channel cases.
• Beckwith-Wiedemann syndrome (11p15.5 imprinting): macrosomia + macroglossia + omphalocele + transient hyperinsulinism. Hypoglycemia usually self-resolves over weeks to months.
• Maternal diabetes: transient neonatal hyperinsulinism. History gives it away.

Glycogen storage diseases (fasting hypoglycemia + hepatomegaly)

• GSD type Ia / Ib (von Gierke): severe fasting hypoglycemia + lactic acidosis + hyperuricemia + hyperlipidemia + massive hepatomegaly + doll-like face. The first reach is GSD I.
• GSD type III (Cori): milder hypoglycemia, hepatomegaly, myopathy in older patients, ketotic.
• GSD type 0 (glycogen synthase deficiency, GYS2): fasting hypoglycemia, postprandial hyperglycemia/lactate, no hepatomegaly.

Gluconeogenesis defects

• Fructose-1,6-bisphosphatase deficiency: fasting hypoglycemia with metabolic acidosis and lactate, triggered by illness or fructose load.
• PEPCK and pyruvate carboxylase deficiency: rare; lactic acidosis predominates.

Fatty acid oxidation defects (hypoketotic hypoglycemia)

The key pattern: glucose low, but ketones inappropriately low or absent. Newborn screening catches most via the acylcarnitine profile.

• MCAD deficiency: the most common FAOD. Fasting / illness triggers; hypoketotic hypoglycemia, hyperammonemia, encephalopathy. Newborn screening prevents most morbidity.
• VLCAD deficiency: hypoketotic hypoglycemia + cardiomyopathy in the severe form.
• LCHAD / TFP deficiency: hypoketotic hypoglycemia + cardiomyopathy + peripheral neuropathy + retinopathy; maternal HELLP/AFLP in pregnancy.
• CPT1A, CPT2, CACT, CUD: carnitine-cycle defects with distinctive acylcarnitine signatures.

Amino acid / organic acid disorders

• Maple syrup urine disease: hypoglycemia can occur but the dominant picture is encephalopathy + branched-chain ketoacids.
• Propionic / methylmalonic acidemia / isovaleric acidemia: hypoglycemia is a feature, but acidosis + hyperammonemia + ketosis dominate.
• Tyrosinemia type 1, classic galactosemia, hereditary fructose intolerance: liver-failure picture with hypoglycemia.

Endocrine

• Cortisol deficiency (congenital adrenal hyperplasia, hypopituitarism): hypoglycemia with low cortisol on critical sample.
• Growth hormone deficiency: part of hypopituitarism (think optic nerve hypoplasia, midline defects).
• Septo-optic dysplasia: hypoglycemia + midline defects + optic nerve abnormalities.

At the time of hypoglycemia, before dextrose:

1. Glucose, insulin, C-peptide (confirms endogenous insulin).
2. β-hydroxybutyrate (ketones), free fatty acids (the ratio FFA:BHB > 2.5 is suggestive of FAOD).
3. Lactate, ammonia, pH/CO2/bicarb.
4. Cortisol, growth hormone.
5. Acylcarnitine profile (FAOD signatures).
6. Plasma amino acids, urine organic acids, urine reducing substances.
7. First-voided urine ketones post-recovery.

If FAOD suspected: send molecular FAOD panel; confirm if newborn screen abnormal. If hyperinsulinism: glucose response to glucagon (rise > 30 mg/dL supports hyperinsulinism); diazoxide trial; genetics; 18F-DOPA PET in diazoxide-unresponsive cases to identify focal disease.