ESPE Abstracts (2016) 86 P-P1-229

Phenotypic Variability of Identical Mutations in the ABCC8 Gene in Two Families

Klara Rozenkovaa, Jirina Zapletalovab, Lenka Dusatkovaa, Petra Dusatkovaa, Barbora Obermannovaa, Stepanka Pruhovaa, Jan Lebla & Zdenek Sumnika

aDepartment of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic; bDepartment of Paediatrics, Faculty of Medicine, Palacky University, Olomouc, Czech Republic

Background: Mutations in the SUR1 subunit of the KATP channel encoded by the ABCC8 gene can result in diverse phenotypes ranging from Transient Neonatal Diabetes (TNDM) to type 2 diabetes in adulthood. These patients may benefit from sulphonylurea treatment.

Objective and hypotheses: To describe the course of diabetes in two families with ABCC8 gene mutations and to assess the effect of sulphonylurea treatment.

Method: Direct sequencing of the ABCC8 gene. Trial of sulphonylurea treatment.

Results: Family 1: a boy presented with TNDM at the age of 12 days with glycaemia of 25mmol/l (BW 2240g at 35 weeks gestation). Genetic analysis revealed mutation F132V in ABCC8 in this patient. Although this mutation had been previously described in a case of Permanent NDM unresponsive to sulphonylurea (Klupa et al., Clinical Endocrinology, 2009), we performed test with glibenclamide with C-peptide increase (63 to 502 pmol/l). The boy was then successfully treated with gliclazide which could be stopped at the age of 5 weeks. The same mutation was indentified in his mother having diabetes since the age of 13 years. She was treated with insulin pump and after her son’s diagnosis she was started on gliclazide which let to significant insulin dose reduction. Family 2: a girl presented with TNDM immediately after birth with glycaemia of 30 mmol/l (BW 1530 g at 37 weeks gestation). Novel mutation R933Q in ABCC8 was identified and the response to glibenclamide was positive (C-peptid increase from 199 to 776 pmol/l). She was successfully treated with gliclazide until the age of 7 weeks when the treatment could be stopped. The same mutation was found in her father who had been on sulphonylurea treatment for diabetes since the age of 39 years.

Conclusion: Identical mutations in the ABCC8 gene show different phenotypic expressivity and responsiveness to sulphonylurea therapy. The predictors that influence the diabetic phenotype remain unclear. We have shown that the F132V mutation previously described as unresponsive could be responsive to sulphonylurea.

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