3-Hydroxyacyl-coenzyme A dehydrogenase deficiency and hyperinsulinemic hypoglycemia: characterization of a novel mutation and severe dietary protein sensitivity

J Clin Endocrinol Metab. 2009 Jul;94(7):2221-5. doi: 10.1210/jc.2009-0423. Epub 2009 May 5.


Background: HADH encodes for the enzyme 3-hydroxyacyl-coenzyme A dehydrogenase (HADH) and catalyses the penultimate reaction in the beta-oxidation of fatty acids. All previously reported patients with mutations in HADH gene and hyperinsulinemic hypoglycemia (HH) showed raised plasma hydroxybutyrylcarnitine and urinary 3-hydroxyglutarate.

Aims: The aims of the study were: 1) to report a novel HADH gene mutation not associated with abnormal acylcarnitine or urinary organic acid profile; and 2) to report the novel observation of severe protein-sensitive HH in three patients with HADH gene mutations.

Research design and methods: The index case presented at 4 months of age with hypoglycemic seizures. Her HH responded to diazoxide, but she continued to have episodes of hypoglycemia even on diazoxide, especially when consuming high-protein foods.

Results: Investigations confirmed HH (blood glucose level of 1.8 mmol/liter with simultaneous serum insulin level of 58 mU/liter) with normal acylcarnitines and urine organic acids. Sequencing of the HADH gene identified a homozygous missense mutation (c.562A>G; p.Met188Val). Hydroxyacyl-coenzyme A dehydrogenase activity was significantly decreased compared with controls (index patient, mean +/- sem, 26.8 +/- 4.8 mU/mg protein; controls, 48.0 +/- 8.1 mU/mg protein; P = 0.029) in skin fibroblasts. This patient was severely protein sensitive. Two other children with HH due to HADH gene mutations also demonstrated marked protein sensitivity.

Conclusions: Mutations in the HADH gene are associated with protein-induced HH, and patients with HH due to HADH gene mutations may have normal acylcarnitines and urine organic acids.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxyacyl CoA Dehydrogenases / deficiency
  • 3-Hydroxyacyl CoA Dehydrogenases / genetics*
  • Congenital Hyperinsulinism / complications
  • Congenital Hyperinsulinism / genetics*
  • DNA Mutational Analysis
  • Dietary Proteins / adverse effects*
  • Female
  • Food Hypersensitivity / complications*
  • Food Hypersensitivity / genetics
  • Humans
  • Infant
  • Mutation, Missense*


  • Dietary Proteins
  • 3-Hydroxyacyl CoA Dehydrogenases