Clinical characteristics and molecular genetic analysis of 22 patients with neonatal diabetes from the South-Eastern region of Turkey: predominance of non-KATP channel mutations

Eur J Endocrinol. 2015 Jun;172(6):697-705. doi: 10.1530/EJE-14-0852. Epub 2015 Mar 9.

Abstract

Background: Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes and usually presents in the first 6 months of life. We aimed to describe the clinical characteristics and molecular genetics of a large Turkish cohort of NDM patients from a single centre and estimate an annual incidence rate of NDM in South-Eastern Anatolian region of Turkey.

Design and methods: NDM patients presenting to Diyarbakir Children State Hospital between 2010 and 2013, and patients under follow-up with presumed type 1 diabetes mellitus, with onset before 6 months of age were recruited. Molecular genetic analysis was performed.

Results: Twenty-two patients (59% males) were diagnosed with NDM (TNDM-5; PNDM-17). Molecular genetic analysis identified a mutation in 20 (95%) patients who had undergone a mutation analysis. In transient neonatal diabetes (TNDM) patients, the genetic cause included chromosome 6q24 abnormalities (n=3), ABCC8 (n=1) and homozygous INS (n=1). In permanent neonatal diabetes (PNDM) patients, homozygous GCK (n=6), EIF2AK3 (n=3), PTF1A (n=3), and INS (n=1) and heterozygous KCNJ11 (n=2) mutations were identified. Pancreatic exocrine dysfunction was observed in patients with mutations in the distal PTF1A enhancer. Both patients with a KCNJ11 mutation responded to oral sulphonylurea. A variable phenotype was associated with the homozygous c.-331C>A INS mutation, which was identified in both a PNDM and TNDM patient. The annual incidence of PNDM in South-East Anatolian region of Turkey was one in 48 000 live births.

Conclusions: Homozygous mutations in GCK, EIF2AK3 and the distal enhancer region of PTF1A were the commonest causes of NDM in our cohort. The high rate of detection of a mutation likely reflects the contribution of new genetic techniques (targeted next-generation sequencing) and increased consanguinity within our cohort.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child, Preschool
  • Consanguinity
  • Diabetes Mellitus / genetics*
  • Diabetes Mellitus / physiopathology
  • Diabetes Mellitus, Type 1 / genetics
  • Epiphyses / abnormalities
  • Female
  • Germinal Center Kinases
  • Humans
  • Incidence
  • Infant
  • Infant, Newborn
  • Infant, Newborn, Diseases / genetics*
  • Infant, Newborn, Diseases / physiopathology
  • Male
  • Mutation / genetics
  • Osteochondrodysplasias / genetics
  • Protein-Serine-Threonine Kinases / genetics
  • Transcription Factors / genetics
  • Turkey
  • eIF-2 Kinase / genetics

Substances

  • Germinal Center Kinases
  • Transcription Factors
  • transcription factor PTF1
  • EIF2AK3 protein, human
  • Protein-Serine-Threonine Kinases
  • eIF-2 Kinase

Supplementary concepts

  • Diabetes Mellitus, Permanent Neonatal
  • Diabetes Mellitus, Transient Neonatal, 1
  • Wolcott-Rallison syndrome