Endocrine Abstracts

Introduction: Hyperinsulinaemic hypoglycaemia (HH), characterized by unregulated insulin secretion from pancreatic β-cells, is an important cause of hypoglycaemia in children. Mutations in the K_ATP channel genes (ABCC8/KCNJ11) are the most common cause of congenital HH. The second common cause, hyperinsulinism hyperammonaemia (HIHA) syndrome caused by mutations in GLUD1 gene, is associated with elevated serum ammonia and protein sensitivity. We describe four patients with severe protein sensitive hyperinsulinaemic hypoglycaemia (HH) with normal serum ammonia and no mutation in the ABCC8/KCNJ11/GLUD1 genes.

Methods: Patients were investigated with 24-h blood glucose profile, controlled diagnostic fasting studies and protein load test. Molecular genetic testing for ABCC8/KCNJ11/GLUD1 was undertaken on diagnosis of HH. Glutamate dehydrogenase (GDH; encoded by GLUD1) activity was measured in lymphoblasts and liver tissue in one patient.

Results: All four patients (three females/one male), born from non-consanguinous Caucasian parents, presented with symptomatic hypoglycaemia within first year of life. They had random episodes of hypoglycaemia, not necessarily related to fasting. Controlled fasting studies revealed appropriate suppression of serum insulin and elevation of β-hydroxybutyrate and non-esterified fatty acids. Serum cortisol, lactate, plasma aminoacids, acylcarnitine profile and urine organic-acids were normal. Serum ammonia was persistently normal in all patients. Oral protein load testing unmasked severe protein sensitive HH. Molecular genetic testing for ABCC8, KCNJ11 and GLUD1 was negative. Measurement of GDH activity was normal in lymphoblasts and liver tissue in one patient, not suggestive of mosaicism for GLUD1. All patients responded well to diazoxide treatment. Follow up testing of these patients showed persistence of protein sensitive HH.

Conclusions: We describe a case-series of four patients with normoammonaemic protein sensitive HH with negative molecular genetics for ABCC8/KCNJ11/GLUD1. These clinical and biochemical observations are suggestive of a possible new syndrome of protein induced HH with normal serum ammonia. Further research is required to understand the molecular basis.