Molecular Aetiologies of Hyperinsulinism of Infancy
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Hyperinsulinism of infancy (HI) is a metabolic syndrome of unregulated insulin secretion that causes mild to severe hypoglycaemia. HI is the most common cause of persistent hyperinsulinism in infancy, that has an prevalence of 1 in 50,000 live births in non-consanguineous human populations. Patients usually present in the first 72 hours of life with symptoms of hypoglycaemia, ranging from generalized tremors and vomiting to loss of consciousness and seizures. Failure to recognise and treat the hypoglycaemia carries a substantial risk of permanent brain damage and permanent neurological impairment is seen in up to 50% of all HI cases. Treatment initially employs increased carbohydrate intake as well as glucagon and glucose infusions. Drugs used to control insulin release include octreotide, somatostatin and the potassium channel agonist diazoxide. Patients who fail to respond to medical treatment may need a partial or subtotal pancreatectomy, with a resultant risk of iatrogenic diabetes. HI is often associated with architectural abnormalities of the pancreas - either focal adenomatous lesions or diffuse beta cell hyperplasia are commonly observed upon histological examination of affected pancreta. A variation in the architectural abnormalities that involves both focal and diffuse cell lesions n the same patient is believed to exist in two HI patients in the Australian cohort. Causes of this multigenic congenital syndrome are most commonly linked to genes encoding the ATP sensitive potassium channels of the beta cell (ABCC8 and KCNJ11), as well as to genes involved in nutrient metabolism within the beta cell (GLUD1, GCK and HADH). In this study, a retrospective genetic analysis of Australian HI patients was undertaken. The patients were segregated based on the treatment required (medical or surgical). Leukocyte derived DNA from the patients was genotyped by direct sequencing of coding and/or regulatory regions of ABCC8, KCNJ11, GLUD1, GCK and HADH. Immunohistochemical staining of preserved pancreatic sections from patients for the tumour suppressor gene – p57 was undertaken to further investigate the novel “focaldiffuse” architecture of the pancreas. Additionally, the possible impact of a silent KCNJ11 SNP, A190A was investigated by in vitro expression studies to demonstrate possible effects of synonymous gene variants on translation-related pathological mechanisms.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Physical Sciences
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Hyperinsulinism of infancy