Transient neonatal diabetes: widening the understanding of the etiopathogenesis of diabetes.

Abstract

Transient neonatal diabetes (TND) is a rare type of diabetes that presents soon after birth, resolves by 18 months, and predisposes to diabetes later in life. A total of 30 patients were ascertained and investigated for aberrations of chromosome 6. A genotype/phenotype study was also performed. Genotypically, these patients can be classified into 4 etiologic groups. Group 1 had paternal uniparental isodisomy of chromosome 6 (11 cases, including 1 set of identical twins). Group 2 had a duplication involving chromosome band 6q24, which was paternal in origin where tested (4 sporadic cases and 7 familial cases from 2 families). Group 3 consisted of 1 patient with a loss of methylation at a CpG island within the TND critical region (1 sporadic case). Group 4 had no identifiable rearrangement of chromosome 6 (7 sporadic cases). Most patients were growth retarded at birth, presented at a median age of 3 days, and recovered at a median age of 12 weeks. In group 2, 2 relatives of the TND patients who presented with type 2 diabetes and no early history of TND had inherited an identical duplication. An abnormality of chromosome 6 was identified in approximately 70% of sporadic TND cases and in all familial cases. No significant clinical differences were found between the 4 etiological groups. The study has broadened the clinical spectrum of TND to include type 2 diabetes presenting in later life with no neonatal presentation. The findings are consistent with an imprinted gene for diabetes mapping to 6q24, which we predict will have an important function in normal pancreatic development.

Genetics of type 1 diabetes mellitus

“…Interestingly, it has also been suggested that this region on chromosome 6 contains a gene responsible for transient neonatal diabetes mellitus, which could also be a candidate gene for IDDM15 in this region. 200,201 A very recent report provides evidence for a locus in the immunoglobin heavy chain region on chromosome 14q32.3 producing susceptibility to T1D, 30 this locus has been designated IDDM16. Support for linkage was obtained in 351 North American and UK families (P = 0.002).…”

Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes

“…Some of these mutations lead to a more severe syndrome in which developmental delay and epilepsy accompany neonatal diabetes, a condition known as DEND syndrome [9]. Mutations in KCNJ11 can also result in transient neonatal diabetes mellitus (TNDM) [14], although in most patients TNDM is caused by an abnormality of the imprinted region on chromosome 6q24 [15]. Kir6.2 associates with the sulphonylurea receptor SUR1 (ABCC8) to form the K ATP channel of the pancreatic beta cell [16,17] and mutations in ABCC8 can also cause neonatal diabetes [18].…”

Clinical presentation of 6q24 transient neonatal diabetes mellitus (6q24 TNDM) and genotype–phenotype correlation in an international cohort of patients

“…The rarity of TNDM (1:200,000 to 1:400,000 live births) poses challenges for data collection about clinical features, outcome and management. Until now the clinical features of 6q24 TNDM have been defined in small case studies, some including patients without a molecularly confirmed diagnosis [6,7]; therefore trends in birthweights, presentation, remission and clinical features, particularly comparing different 6q24 TNDM aetiologies, has been limited by low statistical power. Here we describe the clinical presentation of the largest worldwide cohort of confirmed 6q24 TNDM cases, the majority of whom have not been previously reported, which enables us for the first time to quantify genotype-phenotype correlations.…”