Alternating hypoglycemia and hyperglycemia in a toddler with a homozygous p.R1419H ABCC8 mutation: An unusual clinical picture

Shira Harel, Ana S.A. Cohen, Khalid Hussain, Sarah E. Flanagan, Kamilla Schlade-Bartusiak, Millan Patel, Jaques Courtade, Jenny B.W. Li, Clara Van Karnebeek, Harley Kurata, Sian Ellard, Jean Pierre Chanoine, William T. Gibson

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Background: Inheritance of two pathogenic ABCC8 alleles typically causes severe congenital hyperinsulinism. We describe a girl and her father, both homozygous for the same ABCC8 mutation, who presented with unusual phenotypes. Methods: Single nucleotide polymorphism microarray and Sanger sequencing were performed. Western blot, rubidium efflux, and patch clamp recordings interrogated the expression and activity of the mutant protein. Results: A 16-month-old girl of consanguineous descent manifested hypoglycemia. She had dysregulation of insulin secretion, with postprandial hyperglycemia followed by hypoglycemia. Microarray revealed homozygosity for the regions encompassing KCNJ11 and ABCC8. Her father had developed diabetes at 28 years of age. Sequencing of ABCC8 identified a homozygous missense mutation, p.R1419H, in both individuals. Functional studies showed absence of working KATP channels. Conclusion: This is the first description of a homozygous p.R1419H mutation. Our findings highlight that homozygous loss-of-function mutations of ABCC8 do not necessarily translate into early-onset severe hyperinsulinemia.

Original languageEnglish
Pages (from-to)345-351
Number of pages7
JournalJournal of Pediatric Endocrinology and Metabolism
Volume28
Issue number3-4
DOIs
StatePublished - 1 Mar 2015
Externally publishedYes

Keywords

  • ABCC8
  • diabetes
  • hyperglycemia
  • hyperinsulinism
  • hypoglycemia

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