As those of you who attended the meetings or watched the talks on-­line (see link below) may know, all of us in the NIH Proteus group are very excited about new avenues of research that have opened to us since we identified the genetic cause of Proteus syndrome.  We are very hopeful that this discovery will improve our understanding of why patients with Proteus syndrome have overgrowth and that this knowledge may lead to better treatments for the condition.

Dr. Biesecker and Julie Sapp recently met with a drug company to start talking about a possible drug treatment for Proteus syndrome.   Because of confidentiality agreements, we cannot share lots of concrete details at this time, but we left the meeting  quite  encouraged  about  the  potential  to  start  a  trial  of  a  new  drug  in patients with Proteus syndrome and we are optimistic that this trial could have promising results.

One  thing  that  we  talked  about  at  the  PSF  meetings  was  how  the  research  here  at NIH could evolve as we orient ourselves around the goal of trying new treatments for Proteus syndrome.  There are still many experiments we need to do and many procedures we need to put in place before we can start seeing patients as part of a drug trial, but we are working very hard on these problems and hope that we can provide more information soon.  In the meantime, it is a great idea to be sure that Kim and/or Tracey have up-­‐to-­‐date contact information for your family so that they can keep in touch with you about our progress.  As well, an important goal for the foundations is to help identify as many patients as possible who might be eligible for the next phase of the research.  It is often said that there is emotional power in numbers,  but  in  this  case  it  is  emotional  and  scientific  power  that  we  need  to generate!

Thank  you  again  to  the  PSF  Board  and  Membership  for  a  great  set  of  meetings  and for all you do to partner with us in our research!

http://www.youtube.com/user/GenomeTV#g/c/0DDE1062F45B0D7E

Jordan and I attended the Proteus conference in USA last weekend (8th Oct). We were very lucky to have volunteers to both record and edit the footage.

This means you can listen to all the speakers in the comfort of your own home!

There are talks by Les Biesecker, Dr Michael Cohen, Laura Tosi (orthopaedic surgeon), Barbara Biesecker (genetic counsellor), Tom Darling (dermatology) and also by individuals affected by Proteus. You can hear first hand about the research and the way forward.

I hope you enjoy watching and listening. Our videographer offers her apologies that there may be some places in the video that are not perfect but hopes it is a wonderful experience for all.

Enjoy!

Tracey

When you open the site below, look on the right of the home page and select each topic individually when you are ready to listen and watch.

To view and download, go to:
http://www.youtube.com/user/GenomeTV#p/c/0DDE1062F45B0D7E

Huge thanks to Kirsty and Zoey (Jordan’s auntie and cousin) who held a sponsored swimathon and raised an amazing £627.12 for PSF UK.  They swam one and a half miles to raise money for us.  Thanks ladies!

SUSSEX POLICE

Thanks again to Kirsty who arranged for proceeds from the station’s new tuck shop to come to PSF UK – £100 received with grateful thanks to everyone at Crowhurst Road Police station

Ellen’s fete

Jordan’s friend Ellen organised a fete in Jordan’s honour to raise money for PSF UK.  We had to keep this a complete secret from Jordan who was very surprised to find Ellen dressed up as a bear and to find family and friends there in support.  Thank you to everyone who came – the morning raised £140

Ellen and her friend stayed up all night baking! Thanks to Mary and everyone who helped out!

Crazy Golf

Colleagues from CSA arranged a Charity golf event and raised £360.40

It was lovely sunny day and everyone enjoyed themselves. There was also a raffle and beautiful cakes courtesy of Lynn Meadows

Huge thanks to the Charity Committee, Anna Evett and Andy Godfrey and to all who took part.

Collins’ strawberry tea

Donna & Paul Collins thank all their friends for their support at their Proteus Syndrome Foundation UK Strawberry Cream Tea.  Special thanks to Lesley, for the Scones, to Karon for her hard work with the drinks, to Carole for the ‘loan’ of the tables & chairs and to Scott for handling the raffle tickets & entrance money.  They had just over 30 people popping in during the afternoon.  Many other friends also passed on donations abd the event rasied £236.

Benfleet Baptist Church Coffee Morning – raised £305

Staff of C J Coleman & Co Ltd. – Sale of Second Hand Mobiles £215

C & C Marshall LTD – Mufti day raised £36.55

P Sturge, Taichi Coffee Morning, raised £70

Paul and Donna  – fundraiser party

On 15 March 1986 Halleys Comet was to be seen overhead, Diana Ross,singing Chain Reaction was the UK no 1 and Paul & Donna got hitched.  What is the best way to celebrate but by holding a big party and invite family and friends to celebrate the event.  Family from Scotland , London & Kent joined our good friends for a wonderful party on Saturday March 19th at our local hall.  The happy couple lead the evening by dancing again to Jennifer Rush’s ‘Power of Love’ and was joined by the Best man and Chief Bridesmaid on the dance floor.  Of course, the big change was our three boys who celebrated with us and we decided that we did not want any presents, so all those that were invited were asked to donate to PSF UK .  So Ross’ godparents, Geoffrey and Andrea took on checking the money and chasing after those guests who were able, to complete a Gift Aid form.  The net result was a marvellous £1,060 raised on the night and with Gift Aid, the final total to be over £1,200.

We were so pleased to do this for PSF UK, as the charity has been such a support to Ross and us over the years….and we all had a great time dancing the night away…..now for the next 25 years!!!

Paul & Donna

Contact Tracey whitewood-Neal for more information – traceywhitewoodneal@yahoo.co.uk

Bethesda, Md., Wed., July 27, 2011 — A team of researchers has identified the genetic mutation that causes Proteus syndrome, a rare disorder in which tissue and bone grows massively out of proportion. The discovery, which has implications for potential drug therapies and even cancer, appears in the July 27, 2011, early online edition of The New England Journal of Medicine. The team was led by researchers at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health.

Proteus syndrome gained wide public attention in 1980, through the movie “The Elephant Man,” about a man depicted as having the disease. Researchers found that a point mutation — a single-letter misspelling in the DNA of the genetic code — in the AKT1 gene activates the sporadic tissue growth characteristic of Proteus syndrome. Physicians named the condition for the Greek god who could transform his shape. There are fewer than 500 people with the disease in the developed world, where it can be tracked.

Unlike inherited disease-causing mutations, the gene variant that triggers Proteus occurs spontaneously in each affected individual during embryonic development. The severity of the disease depends on the timing during embryonic development that the genetic mistake occurs in a single cell and in which part of the developing organism. Only the cells that descend from the cell with the original AKT1 gene mutation display the hallmarks of the disease, leaving the individual with a mixture of normal and mutated cells.

The affected newborn appears normal, but symptoms arise in the child’s first two years. The mutation in AKT1 alters the ability of affected cells to regulate their own growth, leading some parts of the patient’s body to grow to abnormal and even enormous sizes, while other parts of the body remain normal. The irregular overgrowth worsens with age and increases the susceptibility to tumors.

“This study resolves a daunting challenge in clinical genetics and offers hope for patients with Proteus syndrome,” said NHGRI Director Eric D. Green, M.D., Ph.D. “This rare disorder has been the focus of curiosity and medical observation for decades but until now has never been biologically explained. With the analysis reported here, patients and families who face this condition have hope for future therapies.”

As follow up to the current study, NHGRI researchers plan to test DNA from the skeleton of Joseph Merrick to determine whether Proteus syndrome caused his dramatic disfigurement. Merrick gained celebrity — and for a time earned his livelihood in England and Europe — by being displayed in human novelty exhibitions as the Elephant Man. He died in 1890 at the age of 27 in London Hospital, now the Royal London Hospital, where he resided at the end of his life. The hospital preserved his skeleton in its pathology collection, providing modern researchers a chance to test his century old DNA.  Merrick’s life has been portrayed on stage, and in a 1980 Hollywood movie titled “The Elephant Man.”

Diagnosing Merrick will be no simple study.  Because of the way the mutation occurs during embryonic development, the NHGRI-led team found that the gene variant of Proteus syndrome occurs in only a subset of the body’s cells rather than in every cell, a condition called genetic mosaicism. There are only a small number of known mosaic disorders in which an individual’s cells have a different genetic composition from one another. Essentially, the person develops more than one genome. Since only a subset of the body’s cells harbor the mutation, it is possible that during a medical biopsy, in which bits of tissue are cut out for analysis, the diagnosis may be missed because only normal cells are sampled.

“Diagnosis in our patients has been really difficult,” said senior author Leslie Biesecker, M.D., chief of NHGRI’s Genetic Diseases Research Branch. “This molecular discovery gives us a basis for objective molecular diagnosis for patients with perplexing forms of overgrowth.”

Until now, clinical diagnosis has been based on observation of patient features. Besides overgrowth of limbs, the condition is characterized by a variety of skin lesions and thickening of the soles of the feet. Some patients have neurological complications, such as mental retardation, seizures and vision loss.

To find the single-letter misspelling among the 3 billion letters that make up the human genome, the researchers performed whole-exome sequencing on the DNA of seven patients with Proteus syndrome. Whole-exome sequencing determines the sequence of letters that make up the 1 to 2 percent of the genome that contains protein-coding genes. The research team then analyzed more than 20 additional affected individuals, finding the same gene variant in DNA in more than 90 percent of these individuals. The team suspects that the three individuals so far negative for the mutation may actually have the mutation at low levels or in different tissues than those sampled in the initial biopsy. By contrast, the variant is never found in unaffected people, including a random study population of more than 400 individuals and in thousands of DNA sequences maintained in public genome research databases.

The mutated gene, AKT1, is an oncogene, meaning that it can promote the kind of uncontrolled cell growth associated with cancer. The variant of AKT1 that causes Proteus syndrome is part of a cascade of mutations that also promotes metastasis, the process by which cancer cells spread to healthy parts of the body. AKT1 mutations have been detected in about two percent of cancer samples.

In cancer, an AKT1 mutation develops as part of a chain of mutation events that occurs in a limited number of normal cells of a particular organ of the body. In Proteus syndrome, because the mutation occurs in embryonic development, many more tissues of the body are impacted by the gene variant, though not all have overgrowth. According to Dr. Biesecker, a person could not survive if the variant that causes Proteus syndrome occurred so early as to be in all cells of the body.

Previous research demonstrated that the AKT1 mutation changes the cell growth-promoting activity of the AKT protein. NHGRI researchers found that cells from patients with Proteus syndrome had increased AKT activity at times when AKT would normally be inactive in unaffected individuals. The mutation acts like an accelerator of cell growth, but only in some tissues of the body.

To study the mosaicism affect of Proteus syndrome, the researchers tested cells derived from affected tissue and unaffected tissue of individuals with the disease. They analyzed the level of activation of AKT, confirming that affected tissue had increased AKT protein activity.

“We now have a better chance of making or finding a drug that can arrest this overgrowth and begin to use it early on in the disease progression,” Dr. Biesecker said. “A factor in our favor is that it is much easier to find a drug that inhibits the activity of a protein, which is what we want to do with AKT in Proteus syndrome, than to activate a protein.”

In the cancer field, there are a number of potential therapeutics being developed to inhibit the pathway involving this gene, some of them by inhibiting AKT1 itself. “For Proteus syndrome, AKT1 will likely need to be targeted for optimal benefit to affected patients,” Dr. Biesecker said.

The researchers further demonstrated that tissue biopsies are required to genetically diagnose Proteus syndrome, since the variant that causes the AKT1 mutation is infrequently present in white blood cells typically sampled for genome analysis.

“During the past 15 years, Proteus syndrome patients have come to the NIH Clinical Center, where we have operated to help stop bones from overgrowing,” Dr. Biesecker said. “Our tissue bank has grown during this period because we have been able to obtained samples of affected tissue during surgeries that we would otherwise not have had for this study. If we just asked pediatricians to mail to us blood samples of children with Proteus syndrome we would not have found the mutation. The NIH Clinical Center was essential in providing support and expert colleagues to allow us to do this research.”

In addition to patients seen at NIH, the study included the efforts of collaborators from eight community hospitals and five university medical centers in four countries. Contributors to the study also included investigators from the NIH Intramural Sequencing Center, administered by NHGRI, and from the National Cancer Institute and the National Institute of Dental and Craniofacial Research. In addition to the hospitals and medical centers, the study authors also included representatives from two independent research groups and the Proteus Syndrome Foundations of the United States and the United Kingdom.

NHGRI is one of the 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at its website at www.genome.gov.

The National Institutes of Health – “The Nation’s Medical Research Agency” – includes 27 institutes and centers, and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more, visit www.nih.gov.

For more information visit: http://www.genome.gov/proteus/

News reports

http://health.usnews.com/health-news/family-health/cancer/articles/2011/07/27/scientists-id-gene-linked-to-syndrome-behind-elephant-man-disease

When Jordan’s form teacher Jo Symons left the school to start a new life in the Falklands with husband Mark and son Miles, she started to spread the word about Jordan and the PSF UK! Mandy Ford from Stanley in the Falkland Islands wrote to me explaining that some kids had done a 14 mile walk for us. Caitlin, Kieran and Jessica organised the walk which was across country in miserable conditions but they did it in in 5 hours and raised £160 for the PSF UK – thank you all so much!!!!!!!!!!!!! They were joined by Tasmin, Javiera and Clodagh

A teacher called Cindy from Chile and her students found Jordan on the web page when they were researching Proteus syndrome. The class started emailing us as they were very interested in Jordan’s story. Stranger still was that there were coming to the UK, and staying just 7 miles away in Hastings!

Cindy came to visit Jordan with two of her students, bringing letters, photos and gifts from the pupils back home. They continue to take an interest in Jordan’s progress. Thank you to our new friends in Chile!

Jordan and I were delighted to visit Joel, Lisa and Julian in hospital.

We drove up after Jordan finished his first lot of rehab and stayed in a premier inn hotel only a short walk from the hospital. Jordan and Joel played in the hospital play room, played pool, karaoke and computer games too.

We went to dinner with Lisa in the evening whilst dad Julian sat with Joel. We went shopping with them on the Saturday and had coffee and donuts too, a trip to the Bear factory completed our expedition and good fun was had by all. Joel is a real little character and likes to play tricks on the doctors and nurses, like his Sponge Bob door bell that’s squirts out water!