Meet Millie, 7, who still smiles despite disease so rare it affects just FOUR people worldwide

By Daily Mail Reporter

Brave Millie Smith can still break into a beaming smile despite suffering from a medical condition which is so rare that it has no name and affects just four people in the world.

She was diagnosed at 16 months when tests revealed she had strands missing from her eighth chromosome.

The condition has left the seven-year-old with severe learning difficulties, low muscle tone and visual problems.

Unique: Millie Smith has a lust for life, despite suffering from a rare genetic disorder that affects just four people in the world

But there is little chance of experts finding a cure as there are too few sufferers to justify wide-scale research.

Her mother Alex Smith, 37, who cares for her full-time at the family home in Linden, Gloucestershire, said it was not easy for her daughter but she was 'always smiling'.

'She's a lovely girl but it's quite hard for children like her because even though she enjoys talking to people sometimes they feel very awkward with her.

Play time: Millie has no trouble amusing herself with one of her baby dolls

'She can't dress herself or do a lot of things we take for granted and because she doesn't look disabled people often don't understand why she can't respond.

'Unfortunately, there's not enough money to make it worth researching such a rare disorder. Hopefully it will be given a name when more sufferers are found.'

There are less than 100 people in the world who have problems with their number eight chromosome but only four with similar breaks and symptoms to Millie.

Still smiling: Millie, pictured aged three, has always been a happy little girl

She has to be cared for full-time by her mother, but window-fitter father Andrew Smith, 37, and her brother Aaron, 13, also help out.

Millie's rare condition means she will require constant care for the rest of her life and doctors say she may never advance beyond the emotional age of a three-year-old.

Human cells normally contain 23 pairs of chromosomes and genetic problems such as Down's Syndrome - which occurs when there is an extra pair - are relatively common.

Millie's precise disorder is an 'inverted duplication with a partial deletion in the smaller half of her number eight chromosome, or inv dup del 8p'.

Beverly Searle, chief executive of Unique, an international charity for people suffering from rare chromosome disorders, said the problem is so rare it does not 'warrant a name'.

She said: 'All chromosome disorders can cause huge problems to those affected by them and even a tiny genetic change can lead to many different medical conditions.

'In this case the inverted duplication with a deletion of the number eight chromosome is an extremely rare condition.

'Our purpose as an organisation is to collate information on specific disorders and as more research is undertaken rare disorders like this will be named.

'But because there are so few children with this condition there is too little material to warrant doctors naming it like the more common Down's syndrome.'

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Pig organs: Ready for humans at last?

Double lung transplant surgery, carried out in 2007
 at the Department of thoracic surgery, Foch hospital, Suresnes, France (Image: Foch/Phanie/Rex Features)

by Andy Coghlan

IN THE not too distant future, a person in need of a heart transplant could be offered a pig's organ. That's the hope of a group that met in China last week to agree global guidelines for the first clinical trials of "xenotransplants".

The meeting of clinicians, researchers and regulators in Changsha, Hunan province, which was organised by the World Health Organization, resulted in the so-called Changsha Communiqué - a document that should eventually guide global regulation of xenotransplants.

It sets out principles for research, recommends how the WHO and individual countries should monitor such research, and includes guidelines for trials (see "Trials and transplants"). Perhaps most importantly, with human organs in desperately short supply, it reflects how far research has come since a decade ago, when some of the problems associated with xenotransplants seemed insurmountable.

For example, one big concern related to porcine endogenous retroviruses (PERVs). These are dormant viral DNA present in the pig genome that researchers feared would reawaken in an organ transplanted into humans, who, unlike pigs, might not be able to keep the viruses dormant. Pigs have now been genetically engineered either to lack PERVs entirely or to carry RNA interference molecules primed to sabotage any that become active. "Most of us now agree the risk is quite manageable," says Megan Sykes of Massachusetts General Hospital in Boston, who attended the meeting.

The first pig tissue to find its way into humans probably won't be an organ, but insulin-producing islet cells from the pancreas, to treat people with diabetes. Two years ago, Bernard Hering's team at the University of Minnesota in Minneapolis reported injecting unaltered pig islet cells into the livers of diabetic monkeys, along with immunosuppressive drugs. The monkeys were able to go without insulin injections for the duration of the 100-day experiment (Nature Medicine, vol 12, p 301). Hering is now in discussions with the US Food and Drug Administration (FDA) about how to proceed with a human trial.

David White and his colleagues at the Robarts Institute in London, Ontario, Canada, are also talking to the FDA about a possible trial next year. To make islet cells less likely to be rejected, White mixes them with Sertoli cells from pig testes, which contain a molecule that seems to damp down attacks by human T-cells. White explains that Sertoli cells are equipped with the cellular machinery to protect sperm, which would otherwise be vulnerable to attack by the immune system because they have half the chromosomes of other cells.

Rafael Valdés-González of the Children's Hospital of Mexico in Mexico City, who first pioneered the Sertoli cell technique, has already tested it in a small number of people and claims that one patient is still insulin-independent as a result (Clinical Transplantation, DOI: 10.1111/j.1399-0012.2007.00648.x).

Also some grounds for optimism come from a handful of trials of pig islet cells in countries where regulation is less tight. In Russia, the New Zealand company LCT claims to have had some success treating five patients with pig islet cells, which they disguised from the immune system by encapsulating them in alginate, a substance from seaweed that allows nutrients and hormones to diffuse in and out but prevents contact with immune cells. Last month, LCT won authorisation to begin a trial in New Zealand.

Sykes hopes that success with initial islet trials will bring greater public acceptance of xenotransplantation, leading to the really exciting prospect of transplanting full organs. These naturally pose greater problems, though, mainly because they must be hooked up to a blood supply and so face the full force of the immune system.

In 2002, researchers at Revivicor, a company based in Blacksburg, Virginia, found a possible way around this. Their "knockout" pigs lacked the gene for the alpha-gal protein - the molecule that indicates the presence of foreign cells to the human immune system. Other Revivicor researchers have inserted "complement regulator" genes into pig organs, which prevented monkey antibodies from attacking them.

One problem that is proving more difficult to solve is clotting. "We think antibodies bind to blood vessels of the pig graft, and these activate coagulation factors," says David Cooper, a pioneer of xenotransplantation at the University of Pittsburgh Medical Center in Pennsylvania who collaborates with Revivicor.

To deal with this, two groups have produced pigs carrying human genes for anti-clotting substances. Revivicor has inserted a gene for a protein called tissue factor pathway inhibitor, which neutralises tissue factor, a key trigger of clot formation. And at the University of Melbourne in Australia, Anthony d'Apice and his colleagues have bred pigs that make human CD39, a protein that stops platelets from aggregating into clots. The hope is that these substances will only be produced locally, preventing clots in the transplanted organ but not disrupting vital clotting elsewhere (Transplant Immunology, DOI: 10.1016/j.trim.2008.10.003).

Even with these interventions, powerful immunosuppressant drugs would still be needed, weakening the body to other invaders, including cancer. To minimise this problem another idea is taking shape: engineer the organ to make its own immunosuppressant. CTLA-4 Ig, for example, prevents T-cells being switched on, and is already used as an immunosuppressant for transplant patients.

One company is engineering pigs to produce an immunosuppressant in specific organs

Revivicor is now combining all these ideas in one animal by engineering pigs that make CTLA-4 Ig and an anticoagulant in specific organs, have the alpha-gal knockout and make the complement regulator throughout their bodies. D'Apice also claims to have created a pig with four added genes.

Because of the potential success of such experiments, guidelines are essential now. Peter Doyle, a delegate at the meeting and former secretary of the now-defunct UK Xenotransplantion Interim Regulatory Authority says: "Xenotransplantation has the potential to treat millions of people, but the threatened dangers are worrying unless it's properly regulated globally."

Trials and transplants

Global regulation of trials needed to monitor for dangers such as viruses

Trials banned in all countries incapable of effective regulation

All trials and recipients must be registered

Trial regulation must include scientific and ethical assessment, and "involve the public"

First recipients of xeno-organs must be carefully selected to ensure they and their families accept lifelong vigilance for any signs of novel disease

All source animals should be kept in closed colonies free from pathogens

"Compelling justification" needed for trials, including adequate evidence of safety and efficacy from animal studies

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Spotting a sociopath

Mark Easton

How could anyone do those unimaginably cruel, inhuman things?

That is the question that, to most people, immediately flows from hearing the ghastly details of both the Sheffield man who fathered nine children by raping his two daughters and, of course, the tragic story of Baby P.

We seem to have any number of inquiries and investigations now under way into trying to find what went wrong, but I wonder whether the real answer lies buried in that initial question.

The 56-year-old Sheffield businessman who raped his children and the woman and two men who tortured a baby in Haringey would all appear to fit the definition of sociopaths: individuals with a deficit or absence of the social emotions (love, shame, guilt, empathy and remorse), but with a clear facility to deceive and manipulate others.

Mr X, as the rapist was known, refused to attend court to hear his sentence but in a letter to his brother said: "I haven't got any regret over what has happened. It's too late for that. It shouldn't have happened."

Also referred to as "anti-social personality disorder", the behaviour of such people is beyond comprehension to most people because it does not equate with our understanding of what makes us human.

Academics calculate that sociopaths account for about 3-4% of the male population and less than 1% of the female population. Professor Robert Hare from the University of British Columbia is one the world's experts on sociopaths and psychopaths. He writes of people "completely lacking in conscience and in feelings for others".

He describes how "they selfishly take what they want and do as they please, violating social norms and expectations without the slightest sense of guilt or regret".

Such people are, however, very difficult to spot.

In her book The Sociopath Next Door: The Ruthless vs. the Rest of Us, American clinical psychologist Dr Martha Stout explains why she thinks this is:

Since everyone simply assumes that conscience is universal among human beings, hiding the fact that you are conscience-free is nearly effortless. You are not held back from any of your desires by guilt or shame, and you are never confronted by others for your cold-bloodedness. The ice water in your veins is so bizarre, so completely outside of their personal experience that they seldom even guess at your condition.

The individuals that society puts in the front line to try and spot the threat from sociopaths could hardly be more different. Social workers, doctors and teachers are, usually, natural carers - people who empathise easily with others. They are wired to see the best in people, to develop trust.

And most of the time, that is exactly what we want such professionals to do - to support and to help people through their difficulties. But we also demand that they retain a deep cynicism about the individuals they work with - constantly questioning and imagining the very worst.

Sometimes they must make professional judgments about people who are wired completely differently to themselves - people who do not share the basic qualities that define humanity as they understand it.

In his report [pdf] into the death of Victoria Climbie in Haringey in 2000, Lord Laming wrote of the need for "respectful uncertainty" when dealing with a child's family and of "critical evaluation" of what professionals are told. He has spoken of the "over optimism" he encountered, the way in which social workers tend to "travel with hope".

When one reads the appalling details of 25 years of abuse and suffering in the Sheffield case, it does seem incredible that it went on for so long and without anyone in authority noticing.

But perhaps it is the very incredibility that explains why.

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