Autoimmune Thyroid Disease

An Unfortunate and Lengthy Adventure in Misdiagnosis

MAO variant genes

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WHETHER boys with autism suffer a severe form or just a mild version might depend on which version of a brain gene they inherit. And it is possible that the same gene variants influence the language and social skills of people generally.

Studies on twins and families have shown that heredity plays a big part in autism, but there seem to be many genes involved, and pinning down the ones responsible for autism is proving difficult. Instead, Ira Cohen, a psychologist at NYS Institute for Basic Research in New York, decided to look for gene variants that affect the severity of the condition.

Some people with autism have higher levels of the neurotransmitter serotonin in their blood, but no genes involved in serotonin synthesis have been directly linked to autism. So Cohen’s team looked at the gene coding for monoamine oxidase A (MAOA), an enzyme that inactivates serotonin.

A variation in the length of a control region at the start of the MAOA gene determines how much of the enzyme is produced. Men have only one copy of the gene, since it is found on the X chromosome, and approximately a third of them have the form that results in lower MAOA production.

The team tested 41 autistic boys to see which variant of the MAOA gene they had. They found a clear link with the children’s language and social skills. “Boys with less enzyme are not doing as well, not keeping up with their peers,” says Cohen. “Whereas boys with the high activity form show better progress in language and other skills.”

One previous study failed to find a link between autism and the MAOA gene, but that study looked only at whether one of the gene variants triggered autism. Cohen’s finding might make it possible to identify boys most likely to develop severe autism earlier on. But, Cohen says, a larger study is needed to check the result.

Although the team looked at only autistic children, it is possible the gene affects everyone’s language and social skills, says Tom Wassink, a psychiatrist at the University of Iowa. “Either way it’s interesting.” Brain chemical could be the key to autism severity

Well this explains why boys are more likely to develop autism and Asperger’s syndrome than girls. It also explains why I happen to have what I often describe as a “male” brain. LOL.

PEOPLE with a gene variant known to be linked to aggression may have been born with key brain differences that could make them more likely to snap under pressure.

The gene, called MAOA, produces the enzyme monoamine oxidase-A. Complete absence of this gene, though rare in humans, has been linked to aggressive behaviour in men, and mice engineered to lack MAOA are also unusually aggressive.

Many more people, however, carry a low-activity variant of the gene, known as MAOA-L. A study in 2002 found that men with MAOA-L who had been maltreated as children were more likely to exhibit antisocial behaviour than those with a similar background who had the normal MAOA gene.

Now psychiatrist Andreas Meyer-Lindenberg and colleagues from the US National Institute of Mental Health in Bethesda, Maryland, have discovered differences in brain structure and function that might underlie this link. They looked at the genes of 142 healthy men and women with no history of criminality, violence or abuse, and found that 57 had the MAOA-L variant. Brain scans of the same group revealed that the amygdala and cingulate cortex, which are involved in the perception and regulation of emotion, were on average significantly smaller in men and women with the L variant.

There were some differences in brain activity too. When the researchers showed the volunteers frightening images, the amygdala appeared to overreact in those people who had the L variant. And in the men with MAOA-L, regions that normally regulate the amygdala response, including the cingulate cortex and parts of the prefrontal cortex, were underactive (Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.0511311103). Thus while both sexes may have heightened emotional responses, men with MAOA-L “are less able to inhibit their responses”, says Meyer-Lindenberg.

To some extent, the differences between the sexes may arise because the MAOA gene lies on the X chromosome, so men have only one copy. Women have two copies of the gene, and so are likely to have higher levels of the enzyme monoamine oxidase-A.

The differences in brain structure may become established before birth. Low levels of the enzyme have been linked to high levels of brain signalling chemicals in the fetus, including serotonin, which might affect developing brain circuits.

However, Meyer-Lindenberg is careful to warn against using MAOA-L as a predictor of whether someone is likely to become violent. Many other genes may be involved, not to mention social and environmental factors. “There is certainly not enough evidence to feel that a person who has a combination of risks should be weighed differently in a legal sense,” he says.

Knowing whether someone is less likely to be able to control their emotional responses could, however, have enormous potential for tailoring drug or behavioural treatments for people who suffer trauma at an early age, says Essi Viding of University College London, a psychologist who studies psychopathic violence. A brain primed for violence?

One in 2.5 people have this gene. I suggest it has a developmental impact on the brain and is more inclined to produce specialisation/obsession traits. But, before all of us amine sensitive people panic that we are a slave to our emotions:

Good mothering can abolish the impact of a “bad” gene for aggression, suggests a new study, adding spice to the “nature-versus-nurture” controversy.

The findings come at a time when governments in Britain and Australia are seeking ways to crack down on antisocial behaviour, and refocus attention on the impacts of parenting.

The new work, on rhesus monkeys, backs an earlier study in people which gave the same result. “We think the findings are striking in parallel with the human studies,” says Stephen Suomi of the US National Institute of Child Health and Human Development in Bethesda, Maryland.

Speaking on Monday at a press conference in London to mark the opening of a conference on genes and aggression, Suomi said that his results strongly mirror those of a study in 2002 co-led by Terrie Moffitt of the Institute of Psychiatry at King’s College London (Science, vol 297, p851).

For 26 years, she and her colleagues followed the fate of 1037 children born in 1972 in Dunedin, New Zealand. They found that children were much more likely to grow up to be aggressive and antisocial if they had inherited a “short” version of a gene called MAOA. It makes monoamine oxidase A, an enzyme which helps to break down neurotransmitters such as serotonin, and was less efficient in the individuals with the “short” version.

But carriers only went off the rails if they had had an awful, abusive upbringing. Carriers with good mothering were usually completely normal, showed the New Zealand study. Now, Suomi has replicated the finding in the monkeys, showing that carriers of the “short” MAOA gene only turned bad when denied good mothering. “Good mothering has a buffering effect,” he says.

Suomi was reluctant to say what his findings might mean in humans. “Making cross-species analyses is always a dangerous thing,” he says. But an obvious implication is that a “bad” gene in humans could potentially be kept in check by good parenting.

“The general principle of parenting is important and can have impacts not only at the level of behaviour, but also in hormonal activities, brain chemistry, structure and function, and at the level of gene expression,” he says.

Failure to provide the correct mothering may reset the brain’s circuitry irreversibly to patterns of antisocial behaviour, aggression and self-destruction, possibly to enable sheer survival in the absence of motherly protection during infanthood.

Although the complex genetics and biochemistry have yet to be worked out, the research could ultimately lead to drugs which compensate for the “bad” genes, or prenatal screening tests which ensure that infants at risk receive optimal mothering in their first two years of life.

Suomi’s latest results have been accepted for publication in Biological Psychiatry. Good mothers stop monkeys going bad

Anyone who is sensitive to amines knows they still have control over their actions, even though they are manically happy, seething with anger or are deeply depressed, this doesn’t mean they have to carry out what their biology is telling them to do. And conversely:

BY ANY objective measure, comedian Billy Connolly is a towering success. Yet as a child he was sexually abused. Samantha Morton, Tom Cruise’s co-star in the film Minority Report, also suffered as a child, neglected after the messy break-up of her parents’ marriage and consigned to a series of children’s homes. But like Connolly she has turned out just fine.

What makes some maltreated kids triumph over their early problems while others turn antisocial or violent? A supportive school, caring friends, perhaps the right social worker or a loving relative – any or all of these may ride to the rescue in particular cases. But if you’re looking for a more reliable factor, try a brain enzyme called monoamine oxidase.

At least, that’s the message of a remarkable genetic study published last week in the journal Science(Vol 297, p 851). The research suggests that people endowed with an abundance of the enzyme are more likely to tough-out an unhappy or abusive childhood and lead a normal adult life than those born with lacklustre levels. And by no small margin: male victims of child abuse in the study were nine times as likely to turn thuggish and mean themselves if they were born with a sluggish version of the gene for the enzyme instead of a more active one.

So opens another chapter in the long-running and often rancorous debate about genes and criminality. Even before last week’s study was published, theologians and ethicists were press-releasing their concerns about its implications for our understanding of free will and moral responsibility, with one religious commentator, bizarrely, appearing to link the gene to original sin. Many critics will look at the study and think it proves only that science is still in thrall to its eugenics past, determined to put genetic makeup at the centre of complex social issues where it has no place. Others will think just the opposite – that science has at last proved there really is a gene for violence, and that a piece of wayward DNA is the real culprit for the psychological damage wrought by child abuse. Neither view makes any sense.

Until now, most research in this area simply looked at violent people or criminals and asked what was different about their biology, be it chromosomes, hormones or, in the 19th century, sloping foreheads. But of course our personalities are never going to be shaped entirely by genes when so much of who we are comes from mother nurture.

The new study is more sophisticated. It looks at nature and nurture together and asks whether the two might combine disastrously in some people and families to create cycles of violent behaviour – and claims the answer is an emphatic yes. While boys carrying the sluggish version of the gene were no more likely than others to go off the rails if their childhood was untroubled, a staggering 85 per cent turned into antisocial adults if their childhood was troubled.

This research is an improvement on old-style eugenics, but where does it take us? Nowhere, until a second team replicates the findings in a separate population. But let’s assume these researchers have hit on something. There can be no doubt that if it’s confirmed, this genetic link will help to explain why some children end up more damaged than others by childhood maltreatment. It might even throw light on why violence and antisocial behaviour are more common in men than women. The gene for the enzyme is on the X chromosome, so while boys must make do with a measly single copy, girls enjoy the luxury of always inheriting two.

Yet, being true doesn’t make a scientific explanation useful in practical terms. For example, the study seems to raise the prospect of the authorities one day genetically screening boys so they can offer extra support – perhaps a drug – to those with the sluggish gene. This is a non-starter. First you’d have to be sure that interfering with the enzyme didn’t affect other aspects of a child’s personality (it probably would). Even then this approach would be doomed. One in three males carries this sluggish gene. Even if you could medicate them all, you’d be fixing something that isn’t really broken. These boys are not victims of a toxic brain chemistry. They are victims of a toxic childhood. Take away the latter and you don’t have a problem.

In fact, any attempt to base social policy on this science would not just be impractical. It could be dangerous, fuelling complacency about those with the active gene. Monoamine oxidase is not like some sort of Star Trek force field, offering complete protection against all forms of wickedness. Plenty of boys with the active gene in the study became antisocial adults. And you don’t have to be a thug to be unhappy and unfulfilled. Were the kids who didn’t turn violent as content in life as they might have been? We can never know.

No doubt the finding will encourage lawyers to invoke the “genetic defence”. But judges should be cautious of this: there’s no evidence that the gene wipes out a person’s sense of right and wrong.

Child abuse and neglect are always wrong and always to be rooted out. It does not become any less wicked or deserving of vigilance because the victim has a gene that protects them from some of the consequences. There’s no pill for curing a hellish upbringing

These lucky people with an abundance of monoamine oxidase can probably eat chocolate and cheese until their heart’s content. They probably also bounce right back to their equilibrium from situations that make them angry, depressed, or happy.

The more research I do the more evidence I find that what we are dealing with is genetic. I suspect as they continue to study individuals with this gene variant they will find that as well as exhibiting more emotional responses, these individuals are more likely to be creatively or mathematically driven, more obsessive, and are more likely to be defined as geeks and nerds. Violence is the least of the issues involved!

The biology involved is far more complex than just this one version of the gene. There are many other genes involved and factors that can influence the expression of those genes. The result is the Gaussian curve we see in graphs of amine tolerance, and the massive natural variation in our society.

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Written by alienrobotgirl

5 December, 2006 at 8:13 pm

Posted in Autism Genetics

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8 Responses

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  1. Interesting article, I have Asperger’s syndrome myself. However I think people use genetics as an excuse too much, I’ve heard plenty of people explain seemingly every possible disease away as genetic, heart disease, obesity, etc., and while it’s true there are certainly genetic factors, genetics alone can’t explain why suddenly there are all these degenerative diseases out there. Take celiac disease for example, although you need the gene to get the disease, not all people with the celiac gene develop the disease. So we have evidence that people with certain genes are more likely to be sensitive, that’s far from saying it’s fully genetic. How could that explain experiences of people such as myself whose sensitivity lessens. And about the theory you mentioned about it being caused by “yeast and bacteria”, I do think that’s a part of the issue, the dysbiosis, last summer I used grapefruit seed extract and got a pretty dramatic effect of my sensitivities lessening (as well as my health in general getting better).

    snowman

    6 December, 2006 at 8:08 pm

  2. 1. Because there is more than one gene involved.2. Because the vastly increased quantities of salicylates and amines in the modern diet cause build-up-and-break reactions in the most vulnerable. They actively cause damage to the liver and kidneys which takes time to heal.Grapefruit seed extracts are limonoids. They stimulate the Phase II enzymes required to detoxify salicylates and amines and increase glutathione levels. “Yeast” does not have to be involved.

    Alien Robot Girl

    6 December, 2006 at 9:15 pm

  3. Very interesting stuff, thanks for sharing. Did you read Russell Blaylock on autism and chonical microglial activation? I posted about his article in my blog, since it deals with immunology and nutritional issues as well..

    Anonymous

    8 December, 2006 at 3:45 pm

  4. Hi Detox! That’s an interesting article. He’s picked up on glutamates and heavy metals and the role of prostaglandins, but it’s a shame he doesn’t know more about the effects of amines – also excitatory brain neurotransmitters – and salicylates, which cause changes in prostaglandin production and chronic inflammation, and several additives which do the same. I think if he knew about those too it would pull the whole thing together for him.Detox, I wonder if you have considered trying failsafe for your own problems? I mentioned it before, but from your symptoms you do sound like a serious candidate for food chemical intolerance.

    Alien Robot Girl

    10 December, 2006 at 8:32 pm

  5. […] responses to monoamine oxidase inhibitors than men do? Why would that be? After all, it’s men who only have one copy of the MAO gene – which resides on the X chromosome. Estrogen replacement treatment in menopausal women has been […]

  6. […] acts to mask some of the more extreme differences of asperger’s. The only gene I know of that is sex linked is monoamine oxidase. Males only have one copy, so if they get an inefficient version they become more vulnerable to […]

  7. […] reach high statistical significance within autistic populations, along with COMT and GST. MAO-A has been linked to autism severity, with sex-linked differences connected to the fact that MAO-A resides on the female X chromosome so […]

  8. […] And a number of studies linking low functioning MAO with increased severity. […]


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