Endocrine Abstracts

Background: HADH encodes for the enzyme 3-hydroxyacyl-coenzyme A dehydrogenase (HADH) and catalyses the penultimate reaction in the beta-oxidation of fatty acids. Mutations in the HADH gene have recently been described to cause protein sensitive hyperinsulinaemic hypoglycaemia (HH). Protein sensitive HH (specifically leucine sensitivity), is also associated with the hyperinsulinism-hyperammonaemia syndrome (HI/HA syndrome) caused by activating mutations of GLUD1 that encodes the enzyme glutamate dehydrogenase (GDH).

Aims: (i) To investigate whether the patients with protein sensitive HH due to HADH mutations are leucine sensitive. (ii) To evaluate whether patients with HADH mutations have increased basal GDH activity and loss of GTP inhibition, as seen in patients with HI/HA syndrome.

Research design and methods: An oral leucine tolerance test was conducted in three patients with HH due to HADH mutations (P258L, IVS6-2a>g, M188V). The serum ammonia level was measured in all 3 patients. The activity of GDH and the effect of added GTP were determined in lymphoblast homogenates from all three patients.

Results: In response to the oral leucine load, all three patients demonstrated severe hypoglycaemia with simultaneous increase in the serum insulin concentrations, demonstrating leucine sensitivity. None of the controls showed leucine sensitivity. The basal GDH activity and the half-maximal inhibitory concentration of GTP expressed in nmol/l (IC50) were similar to that of controls. The serum ammonia level was normal in all patients.

Conclusions: Mutations in the HADH gene are associated with severe leucine induced HH. The mechanism of leucine hypersensitivity does not involve excessive activity of GDH, as observed in patients with HI/HA syndrome and is currently not known. Understanding this mechanism of leucine induced HH in patients with HADH mutations will provide further novel insights into fatty acid and protein interactions in the pancreatic beta-cell. These observations also have important implications for patient management.