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

Abstract

BackgroundNeonatal 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 methodsNDM 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.ResultsTwenty-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.ConclusionsHomozygous 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.

Congenital imprinting disorders: Application of multilocus and high throughput methods to decipher new pathomechanisms and improve their management

“…ZFP57 was independently shown in mouse to be essential for maintenance of imprinting marks in early development [37]. Moreover, in ethnicities with a high social rate of consanguineous union, ZFP57 mutations may be the major cause of transient neonatal diabetes [38].…”

Phenotypic variability in two siblings with monogenic diabetes due to the same ABCC8 gene mutation

“…Indeed, in a study by Johannson et al the prevalence of monogenic diabetes in 469 Norwegian children with antibody‐negative diabetes was found to be 6.5% and importantly one‐third of these cases had not been recognized by clinicians . Parental consanguinity should also be taken into account, as it affects the relative frequencies of different causative mutations and, as a consequence, the DNA sequences on which genetic testing should be focused …”

“…22 Parental consanguinity should also be taken into account, as it affects the relative frequencies of different causative mutations and, as a consequence, the DNA sequences on which genetic testing should be focused. 23 In addition, some patients with KCNJ11-and ABCC8-dependent neonatal diabetes mellitus experience a variable degree of neurological impairment that in its more severe expression comprises a triad of developmental delay, epilepsy, and neonatal diabetes known with the acronym of DEND syndrome. As significant improvements in the cognitive performances of patients diagnosed with DEND syndrome have been reported once treatment with sulfonylureas has been started, a prompt screening for monogenic diabetes in patients with early onset diabetes and signs of neurological impairment is warranted.…”

Conventional insulin pump therapy in two neonatal diabetes patients harboring the homozygous PTF1A enhancer mutation: Need for a novel approach for the management of neonatal diabetes

“…10,11 This experience appears to be similar to others who have also managed infants with neonatal diabetes. [6][7][8][9] It has been difficult to manage these infants with CSII because of inconsistency of appetite and feeding schedule, malabsorption, subcutaneous infections at the pump site insertion, and frequent illnesses.…”

“…Our patients had no additional clinical features, consistent with the reported clinical phenotype of isolated pancreatic agenesis with distal enhancer PTF1A mutations. 4,6 Continuous subcutaneous insulin infusion (CSII) pump was applied to one of the cases in the newborn period and the other one in the 9 th month. We aimed to discuss the difficulties in managing the treatment and the methods that could solve these problems.…”