Sulfonylurea-insensitive permanent neonatal diabetes caused by a severe gain-of-function Tyr330His substitution in Kir6.2

Background/Aims: Mutations in KCNJ11, the gene encoding the Kir6.2 subunit of pancreatic and neuronal KATP channels, are associated with a spectrum of neonatal diabetes diseases. Methods: Variant screening was used to identify cause of neonatal diabetes, and continuous glucose monitoring used to assess effectiveness of sulfonylurea treatment. Electrophysiological analysis of variant KATP channel function was used to determine molecular basis. Results: We identified a previously uncharacterized KCNJ11 mutation, c.988T>C [pTyr330His], in an Italian child diagnosed with sulfonylurea-resistant permanent neonatal diabetes and developmental delay (iDEND). Functional analysis of recombinant KATP channels reveals that this mutation causes a drastic gain-of-function, due to a reduction in ATP-inhibition. Further, we demonstrate that the Tyr330His substitution causes a significant decrease in sensitivity to the sulfonylurea, glibenclamide. Conclusions: In this subject, the KCNJ11(c.988T>C) mutation provoked neonatal diabetes, with mild developmental delay, which was insensitive to correction by sulfonylurea therapy. This is explained by the molecular loss of sulfonylurea sensitivity conferred by the Tyr330His substitution, and highlights the need for molecular analysis of such mutations.

Neonatal Diabetes due to a Mutation in the Distal PTF1A Enhancer: A Case Report and Literature Review

: Biallelic variants in the pancreas-specific transcription factor 1A (PTF1A) gene are a rare cause of permanent neonatal diabetes. We report a case of neonatal diabetes with unique clinical manifestations. The clinical diagnosis of the affected infant was confirmed by insufficient endocrine and exocrine pancreas activity; however, the pancreas was normal in imaging. Molecular analyses identified a novel homozygous single nucleotide variant (Chr10, g.23508441T > G), affecting a highly conserved nucleotide within a distal enhancer of the PTF1A gene. The literature review showed that most of these patients had IUGR and imaging evidence of pancreatic agenesis or hypoplasia. We suggest that pancreatic imaging and evaluation of exocrine pancreas function can help early confirmation of the diagnosis in patients with permanent neonatal diabetes.

Long-term follow-up of a child with Wolcott-Rallison syndrome

Wolcott-Rallison syndrome (WRS), the most common cause of permanent neonatal diabetes mellitus (DM) in consanguineous families, has a poor prognosis, with a mean survival of 5.8 years. Majority of children with WRS succumb to the disease in the first decade of life. We present the long-term follow-up of an 8-year-2-month-old girl with genetically proven WRS who was born to a non-consanguineous parentage. She is on basal bolus regimen of insulin therapy for DM. In addition, she was noted to have features of skeletal dysplasia at 3 years and 3 months of age, which has led to her short stature. Surprisingly, she has had no episodes of hepatitis or liver dysfunction so far, which is frequently seen in children with WRS. To the best of our knowledge, she is the oldest surviving patient with WRS reported in India and South Asia.

Successful Use of a GLP-1 Receptor Agonist as Add-on Therapy to Sulfonylurea in the Treatment of KCNJ11 Neonatal Diabetes

Sulfonylurea monotherapy is the standard treatment for patients with the most common form of permanent neonatal diabetes, KCNJ11 neonatal diabetes, but it is not always sufficient. For the first time, we present a case of successful use of a GLP-1 receptor agonist as add-on therapy in the treatment of a patient with KCNJ11 neonatal diabetes and insufficient effect of sulfonylurea monotherapy. Good glycaemic control was maintained with a HbA1c level of 48 mmol/mol (6.5%) at the end of 26 months’ follow-up.