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PNDM is a genetically heterogeneous disorder due to mutations in 23 different genes described to date: KCNJ11, ABCC8, FOXP3, GCK, PDX1, pancreas-specific transcription factor 1A (PTF1A), EIF2AK3, SLC2A2, GATA6, GATA4, SLC19A2, WFS1, NEUROD1, NEUROG3, RFX6, LRBA, NKX2-2, MNX1, IER3IP1, INS, S T A T 3 , GLIS3 and HNF1B (3,4,5,6,7,8,9).
Physiological experiments in affected individuals highlighted the possibility that sulphonylureas, used in T2D to bind and close the [K.sub.ATP] channel, could be used as a targeted treatment option in KCNJ11 PNDM. This was confirmed in 2006 when the first large cohort study showed that 90% of patients were able to switch from insulin injections onto oral sulphonylureas with improvements in glycaemic control and less glycaemic variability [53, 59].
The repurposing of an existing oral diabetes therapy that resulted in near normalisation of blood glucose for the great majority of affected individuals with KCNJ11 PNDM was life-changing for patients and their families, and human research was crucial for this discovery.
Neonatal diabetes mellitus is a very rare entity with an incidence of 1/90,000 to 1/210,000 live births approximately and usually affects children in their first 6 months of life.1,2 It can be divided into Transient (TNDM) and Permanent (PNDM) types.
Permanent neonatal diabetes although less common does not go into remission.13 It accounts for nearly half of the NDM cases globally.14 To date, no specific clinical features have been identified that may help differentiate PNDM from TNDM.14 In a study by Metz et al, intrauterine growth retardation (IUGR) showed decreased association with PNDM when compared to TNDM.11 However, severe IUGR has been reported in some instances of PNDM associated with pancreatic agenesis.15 There are case reports presenting with NDM secondary to gene mutation but their long term outcome was not predictable.16
He developed PNDM at the age of four weeks, which was managed accordingly.
Activating mutations of the [K.sub.ATP] channel genes (either potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11), or ATP-binding cassette transporter subfamily C member 8 (ABCC8)) or insulin gene (INS) are the most common causes of permanent neonatal diabetes mellitus (PNDM), whilst KCNJ11 and ABCC8 mutations have been shown to account for a minority of cases of TNDM [35, 40, 42,43].
Therefore, special attention should be given to the appearance of neurological symptoms in children with PNDM. Although we did not include in this report a formal neurological evaluation, we speculate on the possibility of having an instance of the intermediate DEND syndrome (developmental delay, epilepsy and neonatal diabetes) in case 1, as described by Pearson at al.
PNDM = 1.44 aerobic N + 0.038 MBC - 6.4 ([R.sup.2] = 0.90) (1)
In children with PNDM diabetes does not remit, and about half of them have [K.sub.ATP] channel mutations (1).
transient (TNDM) or permanent (PNDM).5 The TNDM is a clinically defined group affecting approximately 50% of children with NDM.
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