CONGENITAL HYPERINSULINISM


Congenital  hyperinsulinism of infancy
is a disease of newborn children where life-threatening hypoglycemia (low blood glucose) arises because insulin secretion from the pancreas is inappropriately elevated. We are studying families with this condition. In 2004, by genome-wide genetic screening in one such family, we identified that mutations in the HADH gene can cause the disease. These mutations lead to deficiency of short-chain hydroxy-acyl-dehydrogenase (SCHAD), an enzyme which participates in mitochondrial fatty acid oxidation. Studies on the disease mechanism are now ongoing in cellular and mice models.

 

We have also characterized the mutation spectrum of the sulfonylurea receptor-1 gene (ABCC8) in Norway. Diagnostic screening is offered for mutations in the ABCC8 gene as well as in other genetic causes of congenital  hyperinsulinism (KIR6.2/KCNJ11, GLUD1, GCK, HADH and HNF4A)

Lysbilde 1
Example of a family with congenital hyperinsulinism of infancy. Family trees
like this are an important tool when determining which genes to examine.

 

Participants/collaborators

Postdoc Kelly Velasco, Gade Laboratory for Pathology, UoBergen
PhD student Johanna Lüdeke, Gade Laboratory for Pathology, UoBergen
Technician Benedict Man Hung Choi, Gade Laboratory for Pathology, UoBergen
Fulbright student Nels Thompson, Gade Laboratory for Pathology, UoBergen
Senior scientist Ingvild Aukrust, Center for Medical Genetics, Haukeland Univ. Hospital, Bergen
Researcher Karianne Fjeld, Section for Pediatrics, Dept. of Clinical Science, UoBergen
Professor Pål R. Njølstad, Section for Pediatrics, Dept. of Clinical Science, UoBergen
Professor Rohit N. Kulkarni, Joslin Diabetes Center, Harvard Medical School, Boston, USA

Publications

Molven A, Hollister-Lock J, Hu J, Martinez R, Njølstad PR, Liew CW, Weir G & Kulkarni RN (2016). The hypoglycemic phenotype is islet cell-autonomous in short-chain hydroxyacyl-CoA dehydrogenase-deficient mice. Diabetes 65: 1672-1678.

Molven A, Helgeland G, Sandal T & Njølstad PR (2012). The molecular genetics and pathophysiology of congenital hyperinsulinism caused by short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency. Pp. 137-145 in Monogenic Hyperinsulinemic Hypoglycemia Disorders (Eds. Stanley CA, De Leon DD). Vol. 21 in Frontiers in Diabetes. Karger, Basel, Switzerland 2012. ISBN 978-3-8055-9943-6.

Pörksen S, Laborie LB, Nielsen L, Andersen ML, Sandal T, de Wet H, Schwarz E, Åman J, Swift P, Kocova M, Schönle EJ, de Beaufort C, Hougaard P, Ashcroft F, Molven A, Knip M, Mortensen HB, Hansen L, Njølstad PR & Hvidøre Study Group on Childhood Diabetes (2010). Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 antibodies. BMC Endocrine Disorders 10: 16 (1-10).

Sandal T, Laborie LB, Brusgaard K, Eide SÅ, Christesen HBT, Søvik O, Njølstad PR & Molven A (2009). The spectrum of ABCC8 mutations in Norwegian patients with congenital hyperinsulinism of infancy. Clinical Genetics 75: 440-448.

Christesen HB, Tribble ND, Molven A, Siddiqui J, Sandal T, Brusgaard K, Ellard S, Njølstad PR, Alm J, Jacobsen BB, Hussain K & Gloyn AL (2008). Activating glucokinase (GCK) mutations as a cause of medically responsive congenital hyperinsulinism: prevalence in children and characterisation of a novel GCK mutation. European Journal of Endocrinology 159: 27-34.

Molven A, Matre GE, Duran M, Wanders RJ, Rishaug U, Njølstad PR, Jellum E & Søvik O (2004). Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. Diabetes 53: 221-227.

Molven A, Rishaug U, Matre GE, Njølstad PR, Søvik O (2002). Hunting for a hypoglycemia gene: Severe neonatal hypoglycemia in a consanguineous family. American Journal of Medical Genetics 113: 40-46