BioWorld International Correspondent
LONDON - A genetic defect that results in faulty secretion of insulin is likely to account for diabetes in up to half of all children who develop the disease in the first six months of life.
The defect affects an ion channel that already is the target of oral medication used to treat adult-onset Type II diabetes, meaning that many children who develop diabetes in the first six months of life could be successfully switched from insulin injections to treatment with oral drugs.
Anna Gloyn, Diabetes UK RD Lawrence research fellow at the University of Oxford in the UK, told BioWorld International: "The mutations we have identified will give clues to those working on the structure of the protein, about which residues are important for the operation of this ion channel. In addition, our experience so far tells us that if we keep looking for genes involved in susceptibility to Type II diabetes, it may be possible to manipulate many of these for therapeutic intervention."
The finding also is important clinically, Gloyn added, because children with these mutations may show additional neurological features that are not due to the diabetes. These include developmental delay and epilepsy. Physicians now can be on the alert for that cluster of signs, and will be able to tailor treatment accordingly.
Gloyn and her colleagues reported their work in a paper in the European Journal of Human Genetics, titled "KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features."
The paper described a fourth example of a child with neonatal diabetes, who has a mutation in the gene encoding a subunit of the potassium channel known as Kir6.2. That ion channel plays an important role in the secretion of insulin. The gene encoding Kir6.2 is called KCNJ11.
Gloyn and colleagues previously had identified three other patients with mutations affecting KCNJ11, as reported in 2004 in the New England Journal of Medicine.
Earlier studies had shown that Kir6.2 is expressed in muscle, neuron and brain, as well as in the beta-cells of the pancreas, so they had set out to identify neurological signs and symptoms in patients with KCNJ11 mutations.
Working with collaborators elsewhere in the UK and in France, Gloyn and her colleagues now suggested that a discrete neurological syndrome exists, which they call DEND - developmental Delay, Epilepsy and Neonatal Diabetes. Neonatal diabetes - diabetes diagnosed within the first six months of life - occurs in one in 400,000 live births, and the researchers believe that between a third and a half of all cases are due to genetic mutations in KCNJ11.
Kir6.2 forms part of the ATP-sensitive potassium (KATP) channel, which also is the target for the drugs known as sulphonylureas, which are used to treat adult-onset diabetes. Those work by closing the KATP channel.
Gloyn's clinical colleagues, Andrew Hattersley, of the Peninsula Medical School in Exeter, UK, and Ewan Pearson, of the University of Dundee in the UK, now are working on setting up an international consortium to standardize protocols for transferring children with neonatal diabetes from insulin injections to oral sulphonylurea therapy. There is uncertainty about whether children with mutations causing the most severe symptoms will respond to oral treatment.
"One way forward will be to look at which children respond to sulphonylureas and which don't," Gloyn said. "We may gain insights into how to modify existing drugs to work more effectively."
The study reported in the European Journal of Human Genetics described how the team sequenced the DNA of 10 children with neonatal diabetes. The patients were recruited in France. Four of the 10 had heterozygous missense mutations in KCNJ11, as did the mother of one of those children.
In all the families, only those people with diabetes had KCNJ11 mutations, and no one without those mutations had diabetes. No mutations in KCNJ11 were seen in 100 nondiabetic Caucasian controls from the general population.
Four out of five of the individuals identified as having mutations in KCNJ11 had neurological features including muscular weakness. One of the children died at 6 months from aspiration pneumonia, which was probably caused by a reduced ability to cough as a result of muscle weakness.
"Our study suggests that the functional consequences of the different mutations varies," Gloyn added. "The most severe mutations cause the full-blown DEND syndrome; milder mutations cause an intermediate form with developmental delay and diabetes but no epilepsy. And then there are mutations which are not quite as severe, but which cause isolated diabetes."