Researchers Find Gene Behind Elephant Man's Disfigurement

Researchers have identified a gene variant in the rare tissue and bone overgrowth disorder Proteus syndrome that may confirm the cause of the severe disfigurement suffered by "Elephant Man", a 19th century Englishman whom experts believe may have had the disease. Called AKT1, the gene may be a target for future therapies, bringing hope to patients and their families. You can read a scientific paper about its discovery in the 27 July early online issue of the New England Journal of Medicine.

The study was led by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, in the United States. NHGRI Director, Dr Eric D. Green, told the press that:
"This study resolves a daunting challenge in clinical genetics and offers hope for patients with Proteus syndrome."

"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."

Proteus syndrome is a rare disorder where tissue and bone grow hugely out of proportion (Proteus is the name of the Greek god who could transform his shape). It is so rare estimates suggest there may be as few as 500 people around the world with the disorder, although it could be more, because the condition is very difficult to diagnose.

In this study, the researchers found that a single "point mutation" in the DNA of the AKT1 gene activates the sporadic tissue growth that characterizes Proteus syndrome. A point mutation is the equivalent of spelling one word differently in a large volume of text.

Proteus syndrome came to the public's attention in the 1980s through Davind Lynch's film "The Elephant Man", where John Hurt plays the part of Joseph (called John in the film) Merrick, a severely deformed Londoner discovered performing in a Victorian freak show. Experts believe Merrick may have had the disorder, and the team behind this study are planning to test DNA recovered from his skeleton to find out. Merrick died in 1890 in what is now the Royal London Hospital, where his skeleton has been preserved as part of the hospital's pathology collection.

But that will not be straightforward, because of something quite rare known as "genetic mosaicism", of which the AKT1 mutation is an example. In genetic mosaicism, the individual essentially harbours two genomes, such that a subset of the body's cells has a different genome to the rest. The AKT1 mutation behind Proteus syndrome is in one genome but not the other, so if you took biopsy samples from a person with Proteus syndrome, you could inadvertently only sample cells featuring the genome without the mutation, and conclude it wasn't present.

The AKT1 mutation in Proteus syndrome occurs spontaneously while the embryo is developing. It is not like genes that cause inherited diseases, where the mutation is passed on through the sperm or the egg. Also, the severity of the disease depends on when the "spelling mistake" occurs in a single cell in the embryo. All cells descended from that cell then inherit the mutation, and that is how the individual ends up with two genomes: the "normal" one and the one containing the mutation.

When a baby carrying the AKT1 mutation is born, he or she will appear normal at first, but during the first two years of life, the symptoms of Proteus syndrome will start showing themselves, as more and more cells with the mutation divide according to growth "rules" that are unlike those of the cells carrying the "normal" genome. Thus some parts of the child's body will start to grow and deform, sometimes massively out of proportion, while the rest of the body grows normally. This gets worse as the person gets older, and also makes them more vulnerable to tumors.

So far, the only way to diagnose the syndrome has been by observing these signs and symptoms. As well as abnormal growth, the condition causes skin lesions and thickening of the soles of the feet. Some patients also develop neurological problems, some have mental retardation, some can lose their sight.

Senior author Dr Leslie Biesecker, chief of Genetic Diseases Research at NHGRI, said they have great difficulty diagnosing Proteus syndrome, but this molecular discovery should really help conduct diagnoses more objectively, especially in patients with "perplexing forms of overgrowth".

For the study, Biesecker and colleagues scanned the "exomes" of seven patients with Proteus syndrome. The exome is that part of the genome that controls protein production, and contains less than 2% of the 3 billion "letters" in the "text" of a whole genome, making searching for a single letter gene mutation much easier. When they found the AKT1 mutation, they then confirmed it by scanning another 20 affected patients and showed it was present in more than 90% of them. However, the researchers suspect that the ones that did not appear to carry the mutation could actually have it, but at a low level, or perhaps, because of the genetic mosaicism, the tissue samples they gave happened to contain only cells with the "normal" genome.

They also tested this the other way around: by sampling people without the syndrome. In a random study population of more than 400 individuals, not one was found to be carrying the AKT1 mutation. And neither was it present in thousands of DNA sequences stored in public genome research databases.

The gene AKT1 is an oncogene, known to cause uncontrolled growth in cancer. The mutation present in Proteus syndrome is part of a cascade of mutations that foster metastasis, where cancer cells migrate from the primary tumor to seed new tumors in other parts of the body. AKT1 mutations have been found in about 2% of cancers. Biesecker said if the mutation that occurs in Proteus syndrome were to occur very early in the development of the embryo, it would affect so many cells of the body that it would be unlikely that a person could survive for long.

The researchers found that the AKT1 mutation in Proteus syndrome is an accelerator of cell growth. Stopping its activity should then stop the overgrowth activity of the protein. Biesecker said: "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."

"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," he explained. "A Mosaic Activating Mutation in AKT1 Associated with the Proteus Syndrome."

Marjorie J. Lindhurst, Julie C. Sapp, Jamie K. Teer, Jennifer J. Johnston, Erin M. Finn, and others.

NEJM, online first 27 July 2011; doi:10.1056/NEJMoa1104017

Additional source: NIH.

World Hepatitis Day: Call To Action

Yesterday, Thursday 28 July, is World Hepatitis Day, marking the need to increase awareness of viral hepatitis and the diseases it causes, and prompting calls for action urging people to get tested and immunized and help stop new infections.

Thelma King Thiel, the CEO and chairman of Hepatitis Foundation International, said in a statement issued from the organization's US headquarters in Silver Spring, Maryland, earlier today that: "We have the power to prevent new hepatitis infections and we need people to take action."

Ways to prevent hepatitis infection include immunization, avoiding risky behaviors such as sharing needles, toothbrushes and razors, and encouraging people at risk to get infected, said Thiel.

Hepatitis means inflammation of the liver, and there are several causes, including drugs, alcohol, autoimmune disorders, and viruses. There are many viruses that result in liver inflammation, but the term viral hepatitis refers primarily to viruses that attack the liver directly, such as the most common types, A, B, and C.

The burden of hepatitis worldwide that is attributable to these three types of virus is huge. Estimates from Hepatitis Foundation International suggest:

· Every year, 1.4 million people find out they have hepatitis A.

· 2 billion people worldwide are infected with hepatitis B.

· 130 million people worldwide are chronically infected with hepatitis C.

In the US, thanks to increased awareness and improved hygiene, cases of hepatitis A have reduced dramatically, but chronic hepatitis C and hepatitis B infections continue to persist.

Also, because it can take many years, decades even, for symptoms to emerge, it is estimated that up to 75% of Americans that are infected don't realize it, and therefore are not receiving the care and treatment they need, according to a statement made recently by the US Department of Health and Human Services (DHHS).

Two months ago, in May 2011, the DHHS, issued its action plan "Combating the Silent Epidemic: US Department of Health and Human Services Action Plan for the Prevention, Care and Treatment of Viral Hepatitis", to address what it describes as a "silent epidemic" affecting between 3.5 and 5.3 million Americans.

The DHHS says that the problem of many infected people not realizing they are infected is made worse by the fact that health care providers, through lack of training, don't have the skills or tools to assess the risks, offer prevention counselling, or diagnose and treat viral hepatitis. Assistant Secretary for Health, Howard K Koh, said the action plan, which he describes as "unprecendented", is a call to action for better education, treatment and prevention.

Dr Thomas R Frieden, Director of the US Centers for Disease Control and Prevention (CDC), said the action needed can't be accomplished by one government agency alone, it needs everyone across government to work together to take "prevention efforts to the next level".

"Far too many Americans are unaware of the serious impact of viral hepatitis and the devastating consequences that can result from leaving it untreated. The time for action is now," he urged.

In their message earlier today, Hepatitis Foundation International reinforced the urgency of this message, and especially the need to "identify the large at-risk population of Baby Boomers, who are likely unaware of their infection". They urge people to take the following steps to prevent hepatitis and save their liver:

1. Get tested: contact your local public health department or your doctor to find out how.

2. Get vaccinated: hepatitis A and hepatitis B vaccines are available.

3. Get educated: learn the value of your liver, how it is key to health, avoid drugs and alcohol and limit intake of fatty and unhealthy foods.

Sources: HFI, DHHS.

Human Brain Shrinks With Age, While Chimp Brain Does Not

Unlike the brain of our closest living relatives, the chimpanzees, particular parts of our human brain shrink in volume as we age, probably as an evolutionary consequence of our longer lifespan, suggest US researchers who report how they used MRI scans of chimps' brains to arrive at their findings in an early online issue of the Proceedings of the National Academy of Sciences published on 25 July 2011.

First author Dr Chet C. Sherwood, associate professor of anthropology at George Washington University's Columbian College of Arts and Sciences, told the press that:

"Although other animals experience some cognitive impairment and brain atrophy as they age, it appears that human aging is marked by more dramatic degeneration."

To investigate how this might relate to brain size, they set out, in the first study of its kind in this field, to compare total and regional brain volume of chimps at different ages with that of humans.

But as there appears to be a gap in data available on chimps' brains, the researchers used magnetic resonance imaging (MRI) to measure brain volumes in a cross-sectional sample of 99 adult chimpanzee brains aged from 10 to 51 years.

The researchers measured total brain volume and the volume of certain regions, including: total neocortical gray matter, total neocortical white matter, frontal lobe gray matter, frontal lobe white matter, and the hippocampus.

They then compared these measurements with brain structure volumes measured in 87 adult humans aged from 22 to 88 years.

They found that while the volume of brain structures in chimpanzees did not change much as they aged, there was a decline in the sizes of all the brain structures measured in humans.

Further analysis ("using an iterative age-range reduction procedure") showed that the strongest effects in humans came from those individuals who were older than the maximum longevity of chimpanzees (in the wild, few chimps live past their 45th birthday).

"Thus, we conclude that the increased magnitude of brain structure shrinkage in human aging is evolutionarily novel and the result of an extended lifespan," write the researchers.

The team were particulary interested in the hippocampus, because this is particularly vulnerable to age-related degeneration in humans. Among other things, the hippocampus encodes new memories and helps with spatial navigation. It is an area of the human brain that suffers the most damage in Alzheimer's disease (AD).

Affecting mostly older people, Alzheimer's is the result of gradual loss of the structure and function, and also death, of brain cells or neurons. Chimps don't get the disease.

Perhaps humans are vulnerable to Alzheimer's disease because we have more pronounced brain atrophy than other species, including our close relatives, even when we age normally and healthily, said the researchers.

Humans have evolved to possess a large brain and a very long lifespan:

"While there are certainly benefits to both of these adaptations, it seems that more intense decline in brain volume in the elderly of our species is a cost," commented Sherwood.

"Aging of the cerebral cortex differs between humans and chimpanzees."
Chet C. Sherwood, Adam D. Gordon, John S. Allen, Kimberley A. Phillips, Joseph M. Erwin, Patrick R. Hof, and William D. Hopkins.
PNAS published ahead of print July 25, 2011, doi:10.1073/pnas.1016709108
Link to Abstract.

Additional sources: George Washington University.

Hope For Duchenne Muscular Dystrophy Patients Using A Targeted Antisense Therapy

AVI-4658, a targeted antisense therapy to restore expression of dystrophin, a key protein which patients with Duchenne muscular dystrophy lack, shows promise, researchers from the Neuromuscular Centre, UCL Institute of Child Health, London, UK, wrote in the journal The Lancet.

Professor Francesco Muntoni and team wrote that approximately 1 in every 3,500 British males has Duchenne muscular dystrophy (DMD). The patient's muscle cells break down and are lost, leading to progressive muscle weakness. By the time the boy is between the age of 8 and 12 years he can no longer walk. By the time they reach late adolescence or early adulthood their condition has deteriorated so much that many die.

AVI-4658 might be an effective treatment for a considerable number of patients.

This open-label, phase 2, dose-escalation study with 19 patients was carried out at three centers - Great Ormond Street Hospital, or Children NHS Trust (GOSH), both in London, and the Royal Victoria Infirmary, Newcastle, England.

When treatment was completed, a muscle biopsy was taken from each child. The team discovered that the patients' ability to produce functional mRNA through "exon skipping' was repaired with the use of AVI-4658 - eventually allowing them to manufacture functional dystrophin protein.

The researchers said:

"Seven patients had a significant dose response, six of whom were in the two high-dose cohorts, showing restoration of dystrophin protein expression up to 18% of normal levels."

They concluded:

"On the basis of our data and recent preclinical data, we expect that extended administration of AVI-4658 at doses of 10 mg/kg or higher will result in sufficient dystrophin expression to have a positive effect on the prevention of muscle degeneration in Duchenne muscular dystrophy... AVI-4658 has the potential to ameliorate the progressive natural history of Duchenne muscular dystrophy and now needs to be investigated in clinical efficacy trials." Comment in the same journal Dr Akinori Nakamura, Shinshu University School of Medicine, Matsumoto, Japan, and Dr Shin'ichi Takeda, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan, wrote:

"The regulatory and practical (ie, scaling up) barriers to clinical use of exon-skipping therapy are much less daunting than those for gene therapy with viral vectors or cell transplantation therapy. Therefore, successful clinical trials of exon skipping therapy in patients with Duchenne muscular dystrophy could have a great effect on development of treatments for other intractable hereditary neuromuscular disorders."

"Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study"
Sebahattin Cirak*, Virginia Arechavala-Gomeza*, Michela Guglieri, Lucy Feng, Silvia Torelli, Karen Anthony, Stephen Abbs, Maria Elena Garralda, John Bourke, Dominic J Wells, George Dickson, Matthew J A Wood, Steve D Wilton, Volker Straub, Ryszard Kole, Stephen B Shrewsbury, Caroline Sewry, Jennifer E Morgan, Kate Bushby, Francesco Muntoni
The Lancet July 25, 2011. DOI:10.1016/S0140-6736(11)60756-3

Asthma Risk Lower In Breastfed Babies

Babies fed only on breast milk up to the age of six months have a lower risk of developing asthma-related symptoms in early childhood, and this appears to be independent of infectious and allergic diseases, according to a study by researchers at the Erasmus Medical Center in Rotterdam in The Netherlands that was published early online recently in the European Respiratory Journal. The researchers said their findings add support to the idea that babies in industrialized countries should be given only breast milk up to the age of six months. The research is part of the Generation R Study, which is following thousands of multi-ethnic urban children from before birth until early adulthood, to identify early environmental and genetic causes of normal and abnormal growth, development and health. Although other studies have already linked breastfeeding to asthma risk, the researchers said their findings are the first to show a link between duration of breastfeeding and number of wheezing periods. They also found that asthma-related symptoms appear earlier in children who are breastfed for fewer months or who are also given other milk or solids earlier (in the first four months). The researchers used questionnaire-gathered data to look at the effect of breastfeeding duration and the introduction of other liquid and solid food on 5,368 children. The data told them whether the children had been breastfed in their first 12 months of life, when they stopped having breast milk, and whether they were given any other milk or solids, and if so, when. Another set of data came from questionnaires filled in later, when the children reached 1, 2, 3 and 4 years of age. This told them about diseases and illnesses, including asthma-related symptoms such as wheezing, shortness of breath, dry cough and persistent phlegm. The results showed that: Compared to children who were breastfed for 6 months or more, children who had never received breast milk had an increased risk of wheezing, shortness of breath, dry cough and persistent phlegm in their first 4 years. The strongest associations were with persistent phlegm (children who were never breastfed had 1.5 times higher risk of this symptom), and wheezing (1.4 times higher risk if never breastfed).
Being fed solids or other milk as well as breast milk during the first four months were linked to higher risk of wheezing, shortness of breath, dry cough and persistent phlegm in preschool years compared to having only breast milk in the first four months.
Adjusting for potential influencers, the links between breastfeeding and asthma-related symptoms could not be explained by eczema, but partly by lower respiratory tract infections. The researchers concluded that: "Shorter duration and non-exclusivity of breastfeeding were associated with increased risks of asthma-related symptoms in preschool children. These associations seemed at least partly explained by infectious but not by atopic mechanisms." Lead author Dr Agnes Sonnenschein-van der Voort, who also works in the Department of Paediatrics in the Division of Respiratory Medicine at the Erasmus Center, told the press that although more studies should be done to look at whether breastfeeding protects against asthma later in life: "These results support current health policy strategies that promote exclusive breastfeeding for 6 months in industrialised countries." "Duration and exclusiveness of breastfeeding and childhood asthma-related symptoms." A.M.M. Sonnenschein-van der Voort, V.V.W. Jaddoe, R.J.P. van der Valk, S.P. Willemsen, A. Hofman, H.A. Moll, J.C. de Jongste, and L. Duijts Eur Respir J erj01781-2010; published ahead of print 20 July 2011: doi:10.1183/09031936.00178110 Additional source: European Lung Foundation.

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