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Leucine-sensitive hyperinsulinaemic hypoglycaemia in patients with loss of function mutations in 3-Hydroxyacyl-CoA Dehydrogenase

Amanda J Heslegrave12, Ritika R Kapoor12, Simon Eaton12, Bernadette Chadefaux3, Teoman Akcay4, Enver Simsek5, Sarah E Flanagan6, Sian Ellard6 and Khalid Hussain127*

Author Affiliations

1 The Institute of Child Health, University College London, London, WC1N 1EH, UK

2 London Centre for Paediatric Endocrinology and Metabolism, Hospital for Children NHS Trust, Great Ormond Street, London, WC1N 3JH, UK

3 Metabolic Biochemistry, Hôpital Necker–Enfants Malades, Université Paris Descartes, Paris, France

4 Dept of Endocrinology, Sıslı Etfal Education and Research Hospital, Istanbul, Turkey

5 Department of Pediatrics and Division of Pediatric Endocrinology Eskisehir, Osmangazi University School of Medicine, Eskisehir, Turkey

6 Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter EX2 5DW, Exeter, UK

7 Developmental Endocrinology Research Group Molecular Genetics Unit Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK

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Orphanet Journal of Rare Diseases 2012, 7:25  doi:10.1186/1750-1172-7-25

Published: 14 May 2012



Loss of function mutations in 3-Hydroxyacyl-CoA Dehydrogenase (HADH) cause protein sensitive hyperinsulinaemic hypoglycaemia (HH). HADH encodes short chain 3-hydroxacyl-CoA dehydrogenase, an enzyme that catalyses the penultimate reaction in mitochondrial β-oxidation of fatty acids. Mutations in GLUD1 encoding glutamate dehydrogenase, also cause protein sensitive HH (due to leucine sensitivity). Reports suggest a protein-protein interaction between HADH and GDH. This study was undertaken in order to understand the mechanism of protein sensitivity in patients with HADH mutations.


An oral leucine tolerance test was conducted in controls and nine patients with HADH mutations. Basal GDH activity and the effect of GTP were determined in lymphoblast homogenates from 4 patients and 3 controls. Immunoprecipitation was conducted in patient and control lymphoblasts to investigate protein interactions.


Patients demonstrated severe HH (glucose range 1.7–3.2 mmol/l; insulin range 4.8-63.8 mU/l) in response to the oral leucine load, this HH was not observed in control patients subjected to the same leucine load. Basal GDH activity and half maximal inhibitory concentration of GTP was similar in patients and controls. HADH protein could be co-immunoprecipitated with GDH protein in control samples but not in patient samples.


We conclude that GDH and HADH have a direct protein-protein interaction, which is lost in patients with HADH mutations causing leucine induced HH. This is not associated with loss of inhibitory effect of GTP on GDH (as in patients with GLUD1 mutations).

Hyperinsulinism; Hypoglycaemia; Leucine tolerance