Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood

Abstract

Transient neonatal diabetes mellitus (TNDM) is diagnosed in the first 6 months of life, with remission in infancy or early childhood. For approximately 50% of patients, their diabetes will relapse in later life. The majority of cases result from anomalies of the imprinted region on chromosome 6q24, and 14 patients with ATP-sensitive K+ channel (K(ATP) channel) gene mutations have been reported. We determined the 6q24 status in 97 patients with TNDM. In patients in whom no abnormality was identified, the KCNJ11 gene and/or ABCC8 gene, which encode the Kir6.2 and SUR1 subunits of the pancreatic beta-cell K(ATP) channel, were sequenced. K(ATP) channel mutations were found in 25 of 97 (26%) TNDM probands (12 KCNJ11 and 13 ABCC8), while 69 of 97 (71%) had chromosome 6q24 abnormalities. The phenotype associated with KCNJ11 and ABCC8 mutations was similar but markedly different from 6q24 patients who had a lower birth weight and who were diagnosed and remitted earlier (all P < 0.001). K(ATP) channel mutations were identified in 26 additional family members, 17 of whom had diabetes. Of 42 diabetic patients, 91% diagnosed before 6 months remitted, but those diagnosed after 6 months had permanent diabetes (P < 0.0001). K(ATP) channel mutations account for 89% of patients with non-6q24 TNDM and result in a discrete clinical subtype that includes biphasic diabetes that can be treated with sulfonylureas. Remitting neonatal diabetes was observed in two of three mutation carriers, and permanent diabetes occurred after 6 months of age in subjects without an initial diagnosis of neonatal diabetes.

Figure 1. Number of patients diagnosed with transient neonatal diabetes and results of genetic testing.

Figure 2. Partial pedigrees of families showing inheritance of KCNJ11 or ABCC8 mutations.

Squares represent male family members, and circles represent females. Filled symbols denote patients with diabetes. Genotype is shown underneath each symbol, residue number and amino acid change are given for the mutation carriers, N/N denotes no mutation identified. Directly below the genotype is the age of initial diagnosis for the mutation carriers, followed by the age of remission and the age of relapse, a dash represents a non-event, N/A denotes information not available. An arrow with the letter P points to the proband in each family.

Figure 3

a Representation of the percentage of patients with diabetes at any given age for patients diagnosed before the age of 6 months with subsequent remission of diabetes. The calculation for the percentage number of patients diabetic is based on patients who have reached that given age. Black columns represent the initial diagnosis and grey columns represent the 2nd episode of diabetes (relapse). b Percentage of patients diabetic at any given age, results are for patients whose initial diagnosis was not before 6 months. Percentages were calculated according to the number of patients who had reached that given age.