Genetics and stem cells

Gene for 'rare form of hypoglycaemia found'

“The cause of a rare and severe form of hypoglycaemia – or very low levels of sugar in the blood – is genetic,” reported BBC News. It said that mutations in the AKT2 gene are to blame, and that drugs are available that target a related protein. One expert predicted that there could be a treatment for the condition within a year.

These findings come from a study that looked for genetic mutations in three children with a rare collection of symptoms. The children had repeated episodes of very low blood sugar levels leading to fits, as well as overgrowth of one side of the body. The researchers identified a mutation in the AKT2 gene that is thought to cause the cells to take up sugar from the bloodstream constantly, rather than just when exposed to the hormone insulin.

This research appears to have identified the cause of the children’s rare syndrome. As there are already drugs in use that target a related protein, it is possible that a treatment for this condition may be developed more quickly, but only further research can confirm this. The mutation is not related to most cases of hypoglycaemia, which are usually caused by diabetics injecting more insulin than they need for the amount of sugar they have in their bloodstream.

Where did the story come from?

The study was carried out by researchers from University College London, the University of Cambridge and other research centres in the UK and France. The researchers were supported by grants from the Wellcome Trust, the Medical Research Council Centre for Obesity and Related Disorders, the UK National Institute for Health Research (NIHR), Cambridge Biomedical Research Centre and the Gates Cambridge Trust. The study was published in the peer-reviewed journal_ Science_ .

The BBC coverage of this study was generally accurate and appropriate, pointing out the rarity of this condition along with the scale and implications of the research. It reported that 1 in 100,000 children have a genetic defect that leads to hypoglycaemia even when there is no insulin in the blood. The research paper itself does not estimate how common (or uncommon) the condition they studied is – it is a very specific syndrome involving severe recurrent low blood sugar. The study identified a mutation in three children with this condition. It is not yet clear how common this mutation is, as it has only yet been found in these three children.

What kind of research was this?

This was a genetic study looking for mutations in three children who had a specific group of symptoms, which included severe repeated episodes of very low blood sugar (hypoglycaemia).

This type of study is used to identify genetic mutations in people with very defined and unusual patterns of symptoms that researchers think could be caused by a mutation in a single gene. Researchers look at the sequence of genes that could be related to the symptoms, to see if they can find any mutations.

What did the research involve?

The researchers looked at the DNA of three children who had a very specific pattern of symptoms arising early in life. The first child they identified was a boy who had a heavy birth weight, and had had several episodes of severely low blood sugar (hypoglycaemia) since infancy. The researchers found that although the boy had very low levels of sugar in his blood, he also had no detectable insulin. Insulin is the hormone that normally causes cells to take up sugar from the blood, and in a healthy person the lack of insulin would normally mean very high blood sugar levels. The hypoglycaemia led to the boy having seizures and reduced consciousness. The boy also had overgrowth of the left side of his body compared to the right side. The researchers later identified two more children who had a similar pattern of symptoms. Two of the children were aged 17 by the time of this research and the third was around six years old.

The researchers looked at the sequence of genes involved in regulating sugar levels in each child’s body. When they found no mutations in any of these individual genes, they looked at the rest of the sections of the human genetic code (DNA) that give instructions for producing proteins. They did this because mutations that cause disease are usually found within the DNA that contains protein-making instructions. They identified any genetic mutations in one of the children first, then went on to look at the DNA from the other two to see if they had any of the mutations. The researchers also looked at DNA from the children’s parents and from 1,130 other healthy volunteers to see if the mutation was only found in the three affected children.

What were the basic results?

The researchers found no mutations in the sugar-regulating genes they tested. When they sequenced all the protein-coding regions of one affected child’s DNA they found 326 rare changes in the DNA that would be predicted to affect the proteins produced. Because of how the genetic code is read by the cell, some changes in the DNA do not lead to any changes in the protein that the gene encodes. The researchers were only interested in DNA changes that would lead to changes in the protein, as these changes are the ones that are likely to affect whether the protein works normally or not, and therefore have an effect on the person’s health.

One of these mutations was in a gene called AKT2, and this mutation was also found in the DNA of the other two children with the same pattern of symptoms. None of the children’s parents carried the mutation, which meant that it had arisen in either the sperm, egg or fertilised embryo rather than being passed on. None of the healthy control individuals had the mutation.

The AKT2 gene encodes a protein that is involved in how insulin signals to cells to take up sugar from the blood. The researchers said that the mutation that these children had led to this protein being active all of the time. This is likely to result in the cells always taking up sugar from the blood, which gave the children low blood sugar levels.

Recently, the equivalent mutation in a related gene called AKT1 was found to be involved with Proteus syndrome, where certain tissues overgrow. The researchers suggested that the mutation in AKT2 could also promote growth, leading to the children having overgrowth on one side of their bodies, although why this occurs on just one side is unexplained.

How did the researchers interpret the results?

The researchers concluded that the mutation in AKT2 leads to a mainly metabolic disorder including severe recurrent hypoglycaemia. They said that the difference in the effects of mutations in AKT1 and AKT2 emphasises their different functions in the body.


This study has identified a mutation in the AKT2 gene that gives rise to a very specific pattern of symptoms, including severe recurrent hypoglycaemia and overgrowth on one side of the body. This research highlights the role of the AKT2 protein in regulating sugar levels in the body. It is important to note that the syndrome that these three children had is rare, and the mutation identified will not be responsible for most people’s episodes of hypoglycaemia. Episodes of hypoglycaemia will usually occur in people who have diabetes if they inject more insulin than they need for the amount of sugar they have in their bloodstream.

These findings may help to find ways to treat the children who carry this rare mutation, but it seems unlikely that the findings will have any implications for other patients with hypoglycaemia.

NHS Attribution