research update - February 2013

You may be aware that there has been some significant progress in research on Proteus Syndrome over the past 18mths.

 In July 2011, the US team led by Les Biesecker published a paper reporting on the identification of a gene mutation which had been found in 26 out of 29 patients with Proteus Syndrome in the US. The paper entitled ‘ A mosaic activating mutation in AKT1 associated with the Proteus Syndrome’  can be found here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170413/

We asked our research team at the Institute of Child Health in London to write a shorter version in layman’s language and we thank Ryan O’Shaughnessy for the following report.

Update on Proteus Syndrome Research - Scientific Update

Proteus Syndrome is one of a family of mosaic overgrowth syndromes. What this means is that not all cells in the person are affected and the overgrowth only occurs in these affected regions. It has long been suspected that the specific changes in the DNA in the overgrowth regions were responsible. In the last few years scientists worldwide have found evidence that specific DNA mutations associate with the overgrowth regions.

The most important finding is that of the molecular switch AKT1, which activates key pathways in cell growth, which is always on in the regions of overgrowth. The Biesecker group in the US looked for DNA changes in the overgrowth regions that were not present in the normal regions of Proteus Syndrome patients. They found a specific change in the DNA in the AKT1 gene in 26/29 patients examined. This fitted very well with earlier studies on another overgrowth syndrome called SOLAMEN Syndrome, where the protein responsible for turning the AKT1 switch off, called PTEN, was reduced. Another mosaic overgrowth syndrome, called Fibroadipose Hyperplasia, associated with mutations in the P13 kinase (P13K) gene that make the protein hyperactive. This protein is necessary for activating AKT1. Therefore all these genes defects are linked in a ‘pathway’ that leads to overgrowth.

What this means for patients:

As all the genes mutated in overgrowth syndromes are in an associated pathway, then there is promise that a single therapy may be effective in a range of overgrowth syndromes. Rapamycin is a drug that inhibits the mTOR protein, the last step in the overgrowth pathway above. The US group, amongst others, have suggested that drugs such as these should show promise in treating diseases such as Proteus Syndrome. This would be a significant advance beyond the current treatment for such diseases, which involve removal of tissue from the overgrowth regions. However, the association of a DNA mutation with a disease is not the same as  a cause and to date there is no direct proof in humans that activation of this pathway leads to overgrowth. Experiments to tset this will need to be performed before there is any justification to go ahead with clinical trials with toxic agents such as Rapamycin. Of course, knowing that these genetic changes and changes in the AKT pathway are present in Proteus Syndrome, we can make steps towards diagnostic that would indicate whether Rapamycin treatment will work for a particular patient.

Future Planned Work:

We are going to investigate the overgrowth pathway at Great Ormond Street Hosiptal in children with Proteus Syndrome. We will look for specific mutation in AKT1 found in 90% of patients. We will see if the overgrowth pathway is active, even in children without the AKT1 mutation. This is important as it will indicate that the child would be amenable to Rapamycin-type treatment in the future.                                                                                                                                                                                                                                                                                                                                                                                                                           

Ryan O'Shaughnessy,

Senior Research Associate in Skin Biology Immunology,

UCL Institute of Child Health

Research is ongoing in the Netherlands into identifying the cause of Kt and there appear to be similarities to the AKT1 pathway seen in Proteus. We hope to bring you more information at our Family Weekend in June.