Differences between transient neonatal diabetes mellitus subtypes can guide diagnosis and therapy

Abstract

Objective: Transient neonatal diabetes mellitus (TNDM) is caused by activating mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We wanted to assess whether these different genetic aetiologies result in distinct clinical features. Design: Retrospective analysis of the Italian data set of patients with TNDM. Methods: Clinical features and treatment of 22 KATP/ TNDM patients and 12 6q24/TNDM patients were compared. Results: Fourteen KATP/TNDM probands had a carrier parent with abnormal glucose values, four patients with 6q24 showed macroglossia and/or umbilical hernia. Median age at diabetes onset and birth weight were lower in patients with 6q24 (1 week; -2.27 SD) than those with KATP mutations (4.0 weeks; -1.04 SD) (p=0.009 and p=0.007, respectively). Median time to remission was longer in KATP/TNDM than 6q24/TNDM (21.5 vs 12 weeks) (p=0.002). Two KATP/TNDM patients entered diabetes remission without pharmacological therapy. A proband with the ABCC8/L225P variant previously associated with permanent neonatal diabetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with KATP mutations were successfully treated with sulfonylurea monotherapy; four cases with relapsing 6q24/TNDM were treated with insulin, metformin or combination therapy. Conclusions: If TNDM is suspected, KATP genes should be analyzed first with the exception of patients with macroglossia and/or umbilical hernia. Remission of diabetes without pharmacological therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remission of diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy.

Monogenic diabetes clinic (MDC): 3-year experience

“…There are two other genetic forms of diabetes not strictly under the MDM definition but considered part of this group of diseases: chromosome 6 aberrations and mutations of mitochondrial DNA. Chromosome 6 defects include uniparental paternal unidisomy, microduplications and methylation defects (collectively known as 6q24), all causing transient neonatal diabetes mellitus (TNDM), whereas mutations in mitochondrial DNA, such as the recurrent m.3243G > A, cause the maternally inherited diabetes and deafness (MIDD) [ 6 , 7 ].…”

Sulfonylurea for improving neurological features in neonatal diabetes: A systematic review and meta‐analyses

“…Older children started on sulfonylurea therapy need higher dosages to achieve similar glycaemic control 59–61 . Chronic hyperglycemia leads to β‐ cell destruction via increased apoptosis, oxidation, and protein glycation 61 . Early initiation at high dosages may be needed 62–64 .…”

“…[59][60][61] Chronic hyperglycemia leads to βcell destruction via increased apoptosis, oxidation, and protein glycation. 61 Early initiation at high dosages may be needed. [62][63][64] Glibenclamide was recently made available as an oral formulation allowing more accurate dosage adjustment in neonates.…”

Predominant genetic mutations leading to or predisposing diabetes progress: A Review

“…Blood glucose is between 200 and 1000 mg/ dL and is needed to control insulin requirements, but insulin needs to be reduced quickly. In the phase of patient improvement, care should be taken 65 . Treatment with sulfonylureas and metformin has not been appropriately evaluated.…”