Metabolic Diseases in Hypoglycemic Newborns



  • Hypoglycemia is a frequent finding in the neonatal period, which results from the imbalance between carbohydrate intake, endogenous glucose production, and tissue usage.
  • Neonates stabilize their serum glucose levels by about 12 hours after birth to 45 mg/dL (2.6 mmol/L). In a healthy state, glucose homeostasis underlays tight regulation through glucose-lowering hormones (insulin) and counterregulatory, glucose-mobilizing hormones (cortisol, growth hormone, and others) by acting on glycolysis, gluconeogenesis, glycogenolysis, and many other metabolic pathways involved in the biosynthesis, catabolism, or transport of carbohydrates, lipids, and amino acids.
  • Hence, many inborn errors of metabolism can present with episodes of hypoglycemia during metabolic crises, which can be life threatening if not treated promptly.
  • First presentation of an inborn error of metabolism can be at any age, with most cases presenting during times of metabolic stress or transition, as in infancy, illness, and dietary changes. Therefore, it is prudent to quickly establish a tentative diagnosis and initiate treatment in a sick neonate.


  • Incidence of hypoglycemia is estimated at 1 to 3/1,000 live births.
  • Incidence of inherited forms is estimated at 1/50,000 live births in sporadic populations and higher in Ashkenazi Jews.
  • The incidence of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency ranges from 1:4,900 to 1:17,000 live births.
  • Incidence of familial hyperinsulinism is 1 in 2,500 live births.



  • Almost all inborn errors of metabolism causing hypoglycemia are autosomal recessive.
  • Congenital hyperinsulinism can be autosomal dominant or recessive.
  • Glycerol kinase deficiency is X-linked.


  • Through glycolysis and oxidative phosphorylation, glucose is a major source of cellular energy (ATP). Failure to produce ATP is probably the main source of hypoglycemia-associated tissue dysfunction.
  • The brain preferentially uses glucose metabolism to produce energy and is particularly sensitive to hypoglycemia.
  • A long list of metabolic disturbances in a variety of pathways can result in hypoglycemia.
  • Neonates are at particular risk for hypoglycemia because they use glucose more rapidly than adults and have immature ability to obtain energy from other sources (glycogen, muscle protein, adipose tissue).


  • Inherited defects in biochemical pathways affecting metabolism of fats, amino acids, or carbohydrates
  • Mutations in genes known to be involved in glucose metabolism, for example, congenital hyperinsulinism (ABCC8, KCNJ11, GLUD1, CAK, HADH, SLC16A1, HNF4A) and Fanconi-Bickel syndrome (GLUT2, SCLA2)

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