Mutational Analysis of KATP Channel in Patients with Transient Neonatal Diabetes and Assessment of Minimal Incidence of Neonatal Diabetes in Italy

Results: Neonatal/Infancy onset diabetes mellitus (NDM) is a genetic form of diabetes with onset within 6 months from birth. Two distinct types of NDM are recognized: permanent (PNDM) and transient (TNDM). In TNDM remission of hyperglycemia usually occurs within 6 months from diagnosis. TNDM is frequently caused by paternal isodisomy of chromosome 6 and PNDM by mutations of insulin gene, but both condition can be associated with gain-of-function mutations in genes encoding the subunits of the KATP channel, KCNJ11 and ABCC8. Incidence of PNDM in Italy is 1:210.000. ABCC8 and KCNJ11 genes were screened in 14 patients with TNDM. Minimal incidence of NDM was calculated counting patients with PNDM and TNDM born in Italy between 2005 and 2009 and referred to our laboratory for genetic screening by members of the Italian study group on diabetes of ISPED. We identified mutations in 10 patients with TNDM: three heterozygous mutations of KCNJ11 (R50Q [x2], E229K, E179K) in 4 subjects and 7 heterozygous mutations of ABCC8 (H105Y, S459R, T540I, R826W, R1380C, R1380H, V1523M) in 6 patients (1 compound het. for H105 and T540I). In these 10 patients, duration of insulin therapy ranged between 17 day and 8 months. No difference in mode of presentation of diabetes was found between patients with TNDM or PNDM (29 subjects) due to mutations of KATP channel identified in our laboratory. Mild hyperglycemia (<400 mg/dl) was distinctive of patients of both groups who received diagnosis of diabetes in the first 2 weeks from birth. However, mutations found in patients with TNDM were all different from those detected in PNDM. Minimal incidence of NDM was calculated at 1:117.000. We conclude that before remission of diabetes, no specific clinical feature allows us to distinguish TNDM from PNDM due to KATP channel mutations. With the inclusion of data on chromosome 6 defects we are collecting through a questionnaire, we estimate that global incidence of NDM in Italy could range between 1:90.000 and 1:80.000 live births.