This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Google Scholar Articles by Kapoor, R. R. Articles by Hussain, K. PubMed PubMed Citation Articles by Kapoor, R. R. Articles by Hussain, K. Related Collections Pediatric Endocrinology Metabolism

3-Hydroxyacyl-Coenzyme A Dehydrogenase Deficiency and Hyperinsulinemic Hypoglycemia: Characterization of a Novel Mutation and Severe Dietary Protein Sensitivity

London Centre for Paediatric Endocrinology and Metabolism (R.R.K., C.J., S.Ea., K.H.), Hospital for Children National Health Service Trust, London WC1N 3JH, United Kingdom; The Institute of Child Health (R.R.K., C.J., S.Ea., K.H.), University College, London WC1N 1EH, United Kingdom; and Institute of Biomedical and Clinical Science (S.E.F., S.El.), Peninsula Medical School, Exeter EX2 5DW, United Kingdom

Address all correspondence and requests for reprints to: Dr. K. Hussain, Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, United Kingdom. E-mail: K.Hussain{at}ich.ucl.ac.uk.

Background: HADH encodes for the enzyme 3-hydroxyacyl-coenzyme A dehydrogenase (HADH) and catalyses the penultimate reaction in the β-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.