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

Demirbilek, Huseyin; Arya, Ved Bhushan; Ozbek, Mehmet Nuri; Houghton, Jayne A L; Baran, Riza Taner; Akar, Melek; Tekes, Selahattin; Tuzun, Heybet; Mackay, Deborah J; Flanagan, Sarah E; Hattersley, Andrew T; Ellard, Sian; Hussain, Khalid

doi:10.1530/EJE-14-0852

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

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Author(s): Huseyin Demirbilek ¹ ^, ² ^, ³ ^, ^* , Ved Bhushan Arya ¹ ^, ² ^, ^* , Mehmet Nuri Ozbek ³ , Jayne A L Houghton ⁴ , Riza Taner Baran ³ , Melek Akar ⁵ , Selahattin Tekes ⁶ , Heybet Tuzun ⁵ , Deborah J Mackay ⁷ , Sarah E Flanagan ⁴ , Andrew T Hattersley ⁴ , Sian Ellard ⁴ , Khalid Hussain ¹ ^, ² ^, ^†

Publication date (Print): June 2015

Journal: European Journal of Endocrinology

Publisher: Bioscientifica Ltd

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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.

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Most cited references 31

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Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.

Anna L Gloyn, Ewan R Pearson, Jennifer F Antcliff … (2004)

Patients with permanent neonatal diabetes usually present within the first three months of life and require insulin treatment. In most, the cause is unknown. Because ATP-sensitive potassium (K(ATP)) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, we hypothesized that activating mutations in the gene encoding the Kir6.2 subunit of this channel (KCNJ11) cause neonatal diabetes. We sequenced the KCNJ11 gene in 29 patients with permanent neonatal diabetes. The insulin secretory response to intravenous glucagon, glucose, and the sulfonylurea tolbutamide was assessed in patients who had mutations in the gene. Six novel, heterozygous missense mutations were identified in 10 of the 29 patients. In two patients the diabetes was familial, and in eight it arose from a spontaneous mutation. Their neonatal diabetes was characterized by ketoacidosis or marked hyperglycemia and was treated with insulin. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; three of them also had epilepsy and mild dysmorphic features. When the most common mutation in Kir6.2 was coexpressed with sulfonylurea receptor 1 in Xenopus laevis oocytes, the ability of ATP to block mutant K(ATP) channels was greatly reduced. Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. Identification of the genetic cause of permanent neonatal diabetes may facilitate the treatment of this disease with sulfonylureas. Copyright 2004 Massachusetts Medical Society

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Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations.

Ewan Pearson, Isabelle Flechtner, Pål R. Njølstad … (2006)

Heterozygous activating mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (K(ATP)) channel, cause 30 to 58 percent of cases of diabetes diagnosed in patients under six months of age. Patients present with ketoacidosis or severe hyperglycemia and are treated with insulin. Diabetes results from impaired insulin secretion caused by a failure of the beta-cell K(ATP) channel to close in response to increased intracellular ATP. Sulfonylureas close the K(ATP) channel by an ATP-independent route. We assessed glycemic control in 49 consecutive patients with Kir6.2 mutations who received appropriate doses of sulfonylureas and, in smaller subgroups, investigated the insulin secretory responses to intravenous and oral glucose, a mixed meal, and glucagon. The response of mutant K(ATP) channels to the sulfonylurea tolbutamide was assayed in xenopus oocytes. A total of 44 patients (90 percent) successfully discontinued insulin after receiving sulfonylureas. The extent of the tolbutamide blockade of K(ATP) channels in vitro reflected the response seen in patients. Glycated hemoglobin levels improved in all patients who switched to sulfonylurea therapy (from 8.1 percent before treatment to 6.4 percent after 12 weeks of treatment, P<0.001). Improved glycemic control was sustained at one year. Sulfonylurea treatment increased insulin secretion, which was more highly stimulated by oral glucose or a mixed meal than by intravenous glucose. Exogenous glucagon increased insulin secretion only in the presence of sulfonylureas. Sulfonylurea therapy is safe in the short term for patients with diabetes caused by KCNJ11 mutations and is probably more effective than insulin therapy. This pharmacogenetic response to sulfonylureas may result from the closing of mutant K(ATP) channels, thereby increasing insulin secretion in response to incretins and glucose metabolism. (ClinicalTrials.gov number, NCT00334711 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.

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Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57.

J Hahnemann, Andrew Hattersley, J Goodship … (2008)

We have previously described individuals presenting with transient neonatal diabetes and showing a variable pattern of DNA hypomethylation at imprinted loci throughout the genome. We now report mutations in ZFP57, which encodes a zinc-finger transcription factor expressed in early development, in seven pedigrees with a shared pattern of mosaic hypomethylation and a conserved range of clinical features. This is the first description of a heritable global imprinting disorder that is compatible with life.

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Author and article information

Journal

Journal ID (nlm-ta): Eur J Endocrinol

Journal ID (iso-abbrev): Eur. J. Endocrinol

Journal ID (publisher-id): EJE

Title: European Journal of Endocrinology

Publisher: Bioscientifica Ltd (Bristol )

ISSN (Print): 0804-4643

ISSN (Electronic): 1479-683X

Publication date (Print): June 2015

Publication date (Electronic preprint): 09 March 2015

Volume: 172

Issue: 6

Pages: 697-705

Affiliations

[1]Departments of Paediatric Endocrinology , Great Ormond Street Hospital for Children NHS Trust , London, WC1N 3JH, UK

[2]The Institute of Child Health , University College London , London, WC1N 1EH, UK

[3]Departments of Paediatric Endocrinology , Children State Hospital , Diyarbakir, 21100, Turkey

[4]Institute of Biomedical and Clinical Science , University of Exeter Medical School , Exeter, EX2 5DW, UK

[5]Departments of Neonatology , Children State Hospital , Diyarbakir, 21100, Turkey

[6]Department of Medical Biology and Genetics , Dicle University , Diyarbakir, 21100, Turkey

[7]Faculty of Medicine , University of Southampton , Southampton, SO16 6YD, UK

Author notes

Correspondence should be addressed to K Hussain Khalid.Hussain@ 123456ucl.ac.uk

Article

Publisher ID: EJE140852

DOI: 10.1530/EJE-14-0852

PMC ID: 4411707

PubMed ID: 25755231

SO-VID: cbc1057d-fff2-45b6-9924-07590b6064e1

License:

This work is licensed under a Creative Commons Attribution 3.0 Unported License

History

Date received : 8 October 2014

Date revision received : 13 January 2015

Date accepted : 9 March 2015

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