Oral Presentation ESA-SRB Conference 2015

Like mother like son? Variable expression and phenotype of an inactivating dominant ATP-binding cassette sub-family C member 8 (ABCC8) gene mutation within a single family. (#47)

Jessica L Stranks 1 , Anthony T Zimmermann 1 , Anjana Radhakutty 1 , Parind Vora 1 , Peak Mann Mah 1
  1. Lyell McEwin Hospital, Elizabeth Vale, SA, Australia

Background

Congenital hyperinsulinism (CHI) comprises a heterogenous group of rare disorders characterised by inappropriate insulin secretion secondary to mutations in several genes1. Inactivating mutations in the ABCC8 and KCNJ11 genes (encoding for sulphonylurea receptor 1 (SUR1) and K+ inward-rectifying (Kir6.2) subunits respectively of the ATP-sensitive potassium channel on the pancreatic beta cell), account for 40-45% of cases1. Disease-causing ABCC8 mutations may be inherited in an autosomal recessive or dominant fashion. Biallelic recessively-inherited disease is more common and causes severe, medically unresponsive disease2.  Monoallelic (dominant) disease is variable in presentation depending on the specific mutation; most cases are mild although rarer cases of medically-unresponsive disease have been reported3. Even amongst patients with identical mutations, expression can be variable4. We present a case of an identical dominant ABCC8 mutation harboured by mother and son, with different phenotypic expression.

Case

A 26 year old Caucasian woman (G1P0) was referred for assessment of possible CHI. She’d given birth to a large-for gestational age (2630g) male infant at 34 weeks gestation, who had required dextrose infusions for severe neonatal hypoglycaemia. Molecular genetic testing detected a dominant missense ABCC8 mutation (p.Arg521Gln) and he was diagnosed with diazoxide-responsive CHI. Parental testing confirmed maternal inheritance, our patient found to be heterozygous for the same mutation. Her history was significant for temporal lobe epilepsy; we wondered whether these episodes were in fact previously unrecognised hypoglycaemia. Multiple attempts to document fasting hypoglycaemia (including continuous glucose monitoring and a supervised fast) revealed no evidence of endogenous hyperinsulinism. Her fast showed appropriate ketogenesis with suppression of insulin and C-peptide – in stark contrast to her son. We find no objective evidence for hypoglycaemia in this patient, who appears to exhibit normal regulation of insulin secretion despite an identical ABCC8 mutation to a proband with severe hypoglycaemia and clearly disordered beta cell regulation.

  1. Arnoux JB, Verkarre V, Saint-Martin C, Montravers F, Brassier A et al. 2012. Congenital hyperinsulinism: current trends in diagnosis and therapy. Orphanet Journal of Rare Diseases. 6:63-77
  2. Pinney SE, MacMullen C, Becker S, Lin YW, Hanna C et al. 2008. Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations. J Clin Invest. 118: 2877-2886
  3. MacMullen C, Zhou Q, Snider KE, Tewson PH, Becker SA et el. 2011. Diazoxide-Unresponsive Congenital Hyperinsulinism in Children With Dominant Mutations of the Beta Cell Sulfonylurea Receptor SUR1. Diabetes. 60: 1797-1804
  4. Shemer R, Ziv CA, Laiba E, Zhou Q, Gay J et al. 2012. Relative Expression of a Dominant Mutated ABCC8 Allele Determines the Clinical Manifestations of Congenital Hyperinsulinism. Diabetes. 61:258-263