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Background  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.    Methods  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.    Results  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.    Conclusions  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).

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