Autoimmune Thyroid Disease

An Unfortunate and Lengthy Adventure in Misdiagnosis

Autism genome project

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This is an article I read today in The Times:

Parents and scientists are hoping that a new detailed analysis based on human genome will bring a big breakthrough within a year

It has become one of the most controversial and feared medical diagnoses of modern times. Autism was barely spoken of a generation ago but it has been forced into public consciousness by the row over the MMR vaccine and the growing realisation that it is much more common than doctors had imagined.

The suggestion that the developmental disorder can be triggered by the MMR vaccine has been shown to be scientifically unfounded, but it prompted thousands of parents to agonise over the cruel condition that seems to leave children walled off in a social and emotional world of their own, apparently beyond their love.

Their concerns have also been fed by reports of an autism epidemic. A disorder that was once rare has become alarmingly common, with as many as one in 100 children now thought to be affected in some way.

Even if much of this is explained by better diagnosis, the condition retains a brutal mystery. What is it that makes children who seem normal at birth regress suddenly a year or two into life? Now a change in science’s ability to decipher how genes influence health is promising to pin down what autism owes to inheritance.

Within the next year a new study is expected to identify many of the genes that underlie autism for the first time. At the same time, two new theories are challenging established thinking about autism genetics in ways that could ultimately transform diagnosis and treatment.

“The medics tell me we are at a tipping point,” said Dame Stephanie Shirley, the millionaire computer entrepreneur and philanthropist, who is the chairman of the research charity Autism Speaks and the mother of an autistic son.

That genetics are the chief cause of autism has been known for three decades. It was in 1977 that Professor Michael Rutter, of the Institute of Psychiatry at King’s College London, published a twin study that transformed the understanding of its origins.

Twin studies are one of the mainstays of genetics. Because identical twins share all of their genes while fraternal twins share only half, and both share broadly similar environments, comparisons can tease out the relative contributions of nature and nurture.

Professor Rutter found that if an identical twin was autistic, it was highly likely that the other twin was autistic too. Fraternal twins, however, were no more likely to share the diagnosis than ordinary siblings. This made it certain that genes played a large role and it is now thought that autism is among the most heritable of all psychiatric disorders. Genetics account for most of the variance and, although environmental factors matter too, they are less important.

The condition, however, has remained a genetic paradox. For all the certainty that genes are heavily involved, it has proved impossible to discover which ones are guilty. In the 30 years since Professor Rutter’s study, hundreds of genetic mutations that affect health have been found. Most are single-gene disorders, where inheriting a rogue gene invariably means developing a disease such as Hunting-ton’s, which affects the central nervous system. Most of the others have involved very high risks: women with abnormal variants of the BRCA1 gene, for example, have an 80 per cent risk of developing breast cancer.

Autism does not work like that: the search for genes with such large effects has failed. It might be influenced by dozens of genes, each of which raises the risk by amounts too small to have been detected. Or it could be the result of spontaneous mutations instead of more easily tracked defects that are passed from generation to generation. Science does not yet know.

The scientific success story of 2007 has been the coming of age of a new method of gene-hunting that can find the sort of genes with weak effects that are thought to influence autism. These genome-wide association studies compare the DNA of thousands of people who have a disease with healthy controls, using tools called “gene chips” to screen the entire human genome for hundreds of thousands of tiny genetic variations that differ between the two groups.

In recent months, the technique has revealed scores of genes that subtly influence common conditions such as diabetes, heart disease, breast cancer and multiple sclerosis, often raising the risk by as little as 10 per cent.

Autism is the next target. The Autism Genome Project (AGP), an international consortium that studies more than 1,000 families with at least two autistic members, is about to apply the tool to its database.

“We have been waiting ten years for the technology to do this,” said Antho-ny Monaco, of the University of Oxford, one of the project’s leaders. “We were never likely to understand until we were able to screen very large numbers. The probability has always been that autism is highly genetic, but highly heterogeneous – that lots of different genes are involved. We now have a great chance of picking them up.”

The AGP’s genome-wide association study is a classic example of win-win science. Even if it draws a blank, it will still shed new light on the genetic origins of the condition. No results would mean one of two things. It could be that the effects of the genes responsible are even tinier than suspected and bigger samples are needed. Or it could be that a radical new theory of autism genetics is correct.

Professor Michael Wigler, of Cold Spring Harbour Laboratory in New York state, believes that autism might be the result of single genes with big effects after all. These mutations, however, are not quite the same as the inherited ones that cause diseases such as Huntington’s.

According to his model, most cases of autism are caused by random, spontaneous mutations in the sperm or eggs of parents that are passed on to individual children. Most of these then develop the condition but some, particularly girls, do not. They are somehow resistant and, although they carry a potentially harmful mutation, they do not suffer its consequences.

This may explain why autism is an overwhelmingly male disorder, four times more common among boys than girls. It fits with data showing that the children of older parents are at higher risk: sporadic mutations of this sort increase with age. It also points towards an intriguing explanation for the existence of high-risk families with more than one autistic child. Professor Wigler’s research suggests that in these families, a mutation first occurred in one of the parents, usually the mother. While she was immune, probably because of her gender, her sons were not so lucky: half of them would be autistic, depending on whether they inherited the rogue gene.

“Sporadic autism is the more common form of the disease and even the inherited form might derive from a mutation that occurred in a parent or grandparent,” the professor said.

If mutations of this sort are responsible, they would not show up in the AGP: they are new and unique to individuals and families, so will not surface from large comparisons of DNA.

“That is one of the exciting things about our work,” Professor Monaco said. “If we find genes, it is interesting and if we don’t find genes, it is interesting too.”

What Professor Wigler’s theory does not account for is another aspect of new thinking about autism: that it may not be a single disorder.

For autism to be diagnosed, children must meet three criteria: they must show social impairment, communication difficulties and nonsocial problems such as repetitive and restricted behaviour. Yet there is an emerging consensus that these traits do not always go together and that there are people who meet the criteria for one or two characteristics but who do not receive any diagnosis. Autism, in short, may be the confluence of three separate developmental conditions. Only when they occur together is the result devastating.

Research by Angelica Ronald, Franc-esca Happé and Robert Plomin, of the Institute of Psychiatry, has suggested that each of these three problems is influenced by different sets of genes. The twin studies have shown that while each trait is highly heritable, they do not often overlap.

“The label autism is something that was applied to a set of behaviours that were first described in the 1940s,” said Dr Ronald, who is funded by Autism Speaks. “It’s not necessarily a label for a clear biological entity and in research it may be a misnomer to assume it’s one thing.”

This has important implications for gene-hunting. It could be that genes have not been found because scientists have been treating autism as a whole. If different genes affect the communication and social elements of the disorder, finding them might involve looking at people who are not autistic, but who have mild versions of one of the problems. “We need to tackle whether we should look at autism as a single phenomenon, or whether it would be better to look, for example, just at autistic social problems,” Dr Ronald said.

Such an approach would also be valuable by shedding immediate light on what any genes that are found actually do.

Dr Ronald added: “If we split up the symptoms, we can know that these genes are going to be involved in social problems and those ones in nonsocial problems. That is obviously going to be valuable when we look towards diagnosis and treatment.”

An understanding of which genes are involved in which parts of autism should help doctors to spot the condition earlier. It would also prepare parents for the way their child is likely to develop and it could help with the design of therapies.

Dame Stephanie is excited by the pace of change. “It is quite possible that in five to ten years, we will have a real understanding of this disorder,” she said. “That’s a timescale that means today’s children may be helped.” Hunting the gene that traps children in their own world


Difficulties – and above-average intelligence

— Autism is a developmental disorder that first becomes apparent by the age of 3

— It is part of a group of disorders known as the autistic spectrum, which include Asperger’s syndrome, a milder form of the condition

— 1 in 150 children is given a diagnosis of autism

— Boys are four times more likely than girls to have autism

— Autism is defined by three main impairments:

Social interaction

This ranges from a lack of intuition of social stimuli to the inability to form attachments to carers


Autistic children show impairments such as delays in language development and a reduced ability to initiate and sustain conversations

Restricted, stereotyped repetitive behaviour

These include obsessively arranging objects or following very specific routines

— Other problems include phobias, sleeping and eating disturbances, tantrums and self-directed aggression

— Many autistic children show above average intelligence

— There are no current effective means to prevent, treat or cure autism

Sources: Autism Speaks, World Health Organisation, Institute of Psychiatry


A better understanding of the genetics of autism would be of huge value to parents such as Julia Young, who struggled for years to establish the cause of her young son Alex’s behavioural problems.

While Alex, now 12, was apparently normal at birth, his development began to regress around the age of 14 months, soon after his sister, Jess, was born.

“The more the baby crawled and babbled, the less Alex spoke and the more he withdrew,” said Mrs Young, of Bognor Regis, West Sussex.

At Alex’s nursery school, the staff soon began to wonder whether he was deaf. “When you called his name he would not listen to you, he would just carry on doing what he was doing,” Mrs Young said. “If he was painting he would stay painting, and if you asked him to come out of the sandpit he would stay there.”

She took Alex to speech therapy, with no results, and nothing could be found wrong with his hearing. At his first school, his odd and inexplicable behaviour continued.

“He would not sit with the other children – he would sit with his back to the class, but still answering questions. He would not line up when told to, and he would just leave the classroom to go to the toilet without asking.

“His behaviour at home became more and more erratic. He would cross the road in front of cars. He would suddenly turn the hot water on and almost scalded himself. He had no sense of danger.”

At the age of 5, Alex was finally referred to a child psychiatrist. “We had been there for five minutes when he told us that Alex had high-functioning autism.”

Alex’s symptoms are at the less extreme end of the autistic spectrum, but he shows many of its classic signs. “He gets a word in his head and keeps repeating it, trying to get me or his sister to say it,” Mrs Young said.

“He gets obsessions that can last for a year. At one point he was obsessed with Thomas the Tank Engine, and wouldn’t do anything unless we could link it to trains.

“Now he is obsessed with his Play-Station, and with the band Muse. Every time we go in the car, he wants to hear Muse records, and he knows all the words.”

Family history suggests that genetics could be involved. Mrs Young herself has had attention deficit disorder diagnosed recently and her niece’s son has attention deficit hyperactivity disorder. Both often coexist with autism. Alex also has two uncles who have suffered from epilepsy.

Mrs Young said she would welcome genetic insights that help diagnosis, but also worries about where genetic screening could lead.

“It took an age to get Alex the help he needed,” she said. “The earlier you know, the better, and if this could help us identify autism as young as possible it would be wonderful.

“But I would not want a situation like Down’s syndrome, where you tell parents while the child’s in the womb and you have to make a decision.

“We also ask ourselves how much of Alex’s personality is Alex, and how much is the autism. Can we even separate the two?

“If you asked us could we have prevented it, we would have to think. Obviously in some ways it would be better for him, but he is happy in himself.” We ask ourselves, can we separate Alex and autism?


Written by alienrobotgirl

27 August, 2007 at 7:59 pm

Posted in Autism Genetics

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  1. […] is to follow on from previous posts I’ve made about the Autism Genome Project and the two genetic theories of […]

  2. […] Posted in Autism Genetics by the witch on August 28th, 2007 If you’ve had a chance to read and digest The Times article I posted yesterday, I’d like to […]

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