Autoimmune Thyroid Disease

An Unfortunate and Lengthy Adventure in Misdiagnosis

Archive for April 2008

Aspirin-like compounds increase insulin secretion in otherwise healthy obese people

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And it’s supposed to be a good thing?

Chris sent me this great press release to deconstruct. If you’re in on the joke, it’s downright hysterical.

Aspirin-like compounds (salicylates) can claim another health benefit: increasing the amount of insulin produced by otherwise healthy obese people. Obesity is associated with insulin resistance, the first step toward type 2 diabetes.

Aspirin and other salicylates are known to reduce blood glucose in diabetic patients. New research accepted for publication in the Journal of Clinical Endocrinology & Metabolism reveals a similar beneficial effect among obese individuals by increasing the amount of insulin secreted into the bloodstream.

“The administration of a salicylate led to the lowering of serum glucose concentrations,” said Jose-Manuel Fernandez-Real of the Institut d’Investigacio Biomedica de Girona and CIBEROBN Fisiopatologia de la Obesidad, Spain, and lead author of the study. “These findings highlight the importance of further research on the possible therapeutic benefit of aspirin in the fight against type 2 diabetes.”

For their study, Fernandez-Real and his colleagues evaluated the effects of triflusal (a derivative of salicylate) on 28 subjects (nine men and 29 women). The average age of the participants was 48 years old and their average Body Mass Index (BMI) was 33.9. A BMI of over 30 is considered obese. During three, four-week treatment periods, the study participants received a 600 mg dose, a 900 mg dose, or a placebo once per day.

The researchers found that administration of triflusal led to decreased fasting serum glucose. Contrary to their expectations, insulin sensitivity did not significantly change during the trial. Insulin secretion, however, significantly increased in relation to the dose size.

In conjunction with the human studies, the researchers also conducted laboratory studies on insulin-producing cells (known as islets of Langerhans) from mice and humans. The researchers observed that triflusal significantly increased the insulin secreted by these cells.

Aspirin therapy has been recognized to improve glucose tolerance and to reduce insulin requirements in diabetic subjects,” said Fernandez-Real. “To our knowledge, this is the first study to show that salicylates lowered serum glucose in non-diabetic obese subjects. We believe that this effect was due to a previously unsuspected increase in insulin secretion rather than enhanced insulin sensitivity.”


The paper “Salicylates increase insulin secretion in healthy obese subjects” will appear in the July issue of JCEM, a publication of The Endocrine Society.”

Other researchers involved in the study include Abel Lobez-Mermejo, Ana-Belen Ropero, Sandra Piquer, Angel Nadal, Judit Bassols, Roser Casamitjana, Roman Gomis, Eva Arnaiz, Inaki Perez, and Wifredo Ricart. Aspirin-like compounds increase insulin secretion in otherwise healthy obese people

Were these scientists born yesterday? Aspirin therapy does not “improve glucose tolerance”. It just lowers blood glucose! If anything, it impairs glucose tolerance by inducing the release of too much insulin, which causes hypoglycaemia.

There are two types of diabetics; Type 1 and Type 2. Type 1 diabetics have an autoimmune condition characterised by low to non-existent insulin levels, high blood sugar, and weight loss. Type 2 diabetics have something called ‘insulin resistance’. They have high levels of insulin, high blood sugar, and weight gain. Insulin lowers blood sugar by pushing glucose into cells. T2 diabetics resist the presence of insulin, so they have both high insulin levels and high blood sugar. When doctors talk about improving insulin sensitivity, they are talking about decreasing the resistance to insulin.

Any endocrinologist (in fact, any diabetic) can tell you that insulin is a weight gain hormone. They will also tell you that the more weight you gain, the more resistant to insulin you will be. So why, why would you want to give a T2 diabetic more insulin?

Because you’re using the wrong criteria to assess their health!

Currently diabetes medicine is labouring under a sad misunderstanding. The misunderstanding is that most of the negative symptoms of diabetes are caused by high blood sugar, and that blood sugar must be kept under control at all costs. Unfortunately some of the negative symptoms of diabetes are actually caused by high insulin levels, not high blood sugar. This means that outdated drugs that actually worsen T2 diabetes over time are still being prescribed to T2 diabetics. In fact, Michael Eades MD posted on this subject not so long ago, describing how the large, well-funded ACCORD study has halted its rigorous blood sugar control trials in diabetics because the diabetics who were controlling their blood sugar the best (by raising their insulin levels even higher), were dying faster than the control group.

There are two main types of drugs that are given to T2 diabetics: drugs that increase insulin output (or actual insulin), and drugs that increase sensitivity to insulin. The first class of drugs includes the sulfonylurea drugs, which work to lower blood sugar by stimulating insulin release. The second class of drugs includes metformin, which works by increasing the body’s sensitivity to the existing insulin – that is, by reducing insulin resistance. Metformin is the drug of choice for T2 diabetics. Not sulfonylureas, whose side effects include weight gain. Duh!

So here we have this bizarre study of triflusal – which appears to be a drug without real a purpose other than to mimic aspirin – and researchers are looking for some use for it. Some bright spark who read a medical book once comes up with this. What’s the betting triflusal also causes weight gain and hypoglycaemia? Just the same as salicylates cause me weight gain and hypoglycaemia by inducing insulin release. I’m willing to put money on it.


Written by alienrobotgirl

30 April, 2008 at 11:28 am

Posted in Quacktitioners

Tagged with

Vasoactive intestinal peptide

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Vasoactive intestinal peptide is a peptide hormone produced in the gut, the pancreas, and the brain. It has a number of different effects on the body:

  • With respect to the digestive system, VIP seems to induce smooth muscle relaxation (lower esophageal sphincter, stomach, gallbladder), stimulate secretion of water into pancreatic juice and bile, and cause inhibition of gastric acid secretion and absorption from the intestinal lumen. Its role in the intestine is to greatly stimulate secretion of water and electrolytes, as well as dilating intestinal smooth muscle, dilating peripheral blood vessels, stimulating pancreatic bicarbonate secretion, and inhibiting gastrin-stimulated gastric acid secretion. These effects work together to increase motility.
  • It also has the function of stimulating pepsinogen secretion by chief cells.
  • It is also found in the brain and some autonomic nerves. One region of the brain includes a specific area of the suprachiasmatic nuclei (SCN), the location of the ‘master circadian pacemaker‘. The SCN coordinates daily timekeeping in the bodyand VIP plays a key role in communication between individual brain cells within this region. Further, VIP is also involved in synchronising the timing of SCN function with the environmental light-dark cycle. Combined, these roles in the SCN make VIP a crucial component of the mammalian circadian timekeeping machinery.
  • VIP helps to regulate prolactin secretion. [Prolactin inhibits the sex drive]
  • It is also found in the heart and has significant effects on the cardiovascular system. It causes coronary vasodilationas well as having a positive inotropic and chronotropic effect. Research is being performed to see if it may have a beneficial role in the treatment of heart failure. VIP Wiki

Vasoactive intestinal peptide has been connected to autism. This is from a 2001 news report:

A new discovery by Nelson, Grether, and colleagues, however, may bring investigators even closer to the origins of autism than the cerebellum has.

They collected blood that had been taken from 246 subjects at birth and stored in a deep freezer. Of the 246 subjects, 69 had autism, 60 mental retardation, 63 cerebral palsy, and 54 were healthy controls. They then analyzed the blood samples for five different brain proteins—nerve growth factor, substance P, brain-derived neurotrophic factor, calcitonin gene–related peptide, and vasoactive intestinal peptide.

They found comparable amounts of nerve growth factor and substance P in blood samples from all four groups of subjects. However, they found much higher levels of the other three proteins in blood taken from subjects with autism and with mental retardation than in blood taken from the cerebral palsy subjects and healthy controls. And what was especially intriguing is that while about a quarter of the autism subjects did not develop symptoms of autism until they were at least 1 year old, they already had large amounts of these three proteins at birth.

Thus the three proteins may well play causative roles in autism, Nelson and her team concluded, and they believe their findings also suggest that autism is already present at birth or maybe even before. Some other evidence, in fact, also implies that this is the case, she pointed out.

For instance, if mouse-embryo brains are exposed to vasoactive intestinal peptide, they flourish; but if the brains are deprived of this protein, they do not grow properly. Vasoactive intestinal peptide is also known to be involved in the sleep-wake cycle, and autism patients often have sleep problems. Vasoactive intestinal peptide is also known to be made in the gut, and autism patients often have gastrointestinal problems. Small Steps Mark Progress in Understanding Autism

Symptoms of too much vasoactive intestinal peptide are likely to correlate with symptoms of VIPoma, which produces too much vasoactive intestinal peptide:

The major clinical features are prolonged watery diarrhea [..] and symptoms of hypokalemia and dehydration. […] Lethargy, muscle weakness, nausea, vomiting and crampy abdominal pain are frequent symptoms. Hyperkalemia and impaired glucose tolerance occur in < 50% of patients. During attacks of diarrhea, flushing similar to the carcinoid syndrome occur rarely. VIPoma Wiki

Okay, hands up if you have autism and also have gastrointestinal problems, sleep problems, a dampened sex drive, acid reflux, and impaired glucose tolerance? If so, Occam’s razor suggests vasoactive intestinal peptide might be involved.

We investigated the vasoactive intestinal peptide receptor type 2 (VIPR2) gene as a candidate gene for autism. We searched for mutations in the VIPR2 gene in autistic individuals, and 10 novel polymorphisms were identified. Three polymorphisms in the upstream region were studied in detail, and there was no significant difference in the frequencies between the autistic group (n = 14) and unrelated controls (n = 52). The distribution of the genotypes in two of the three polymorphisms differed somewhat between autistic subjects with gastrointestinal problems and those without. Moreover, there was a trend showing a correlation between the genotypes for the third polymorphism and the severity of stereotypical behavior as ranked by the Gilliam Autism Rating Scale. These preliminary results suggest that VIPR2 may have a role in gastrointestinal symptoms and stereotypical behaviors in autism, although a larger collection of samples suitable for transmission disequilibrium tests is necessary to validate the results. A Study of Novel Polymorphisms in the Upstream Region of Vasoactive Intestinal Peptide Receptor Type 2 Gene in Autism

The symptoms are so similar to some people’s experience of food chemicals – particularly salicylates, that I suspect salicylates may work to aggravate underlying VIPR2 polymorphisms somehow.

Written by alienrobotgirl

29 April, 2008 at 3:18 pm

Posted in Autism Genetics

Atheism and evolution: policy statement

It is with a sad sort of resignation that I post this knowing that some readers will see the title of this post and experience immediate offense – perhaps some won’t even read it or stop reading this blog. As someone who lives in Britain where, along with the rest of Europe, 80% of people declare a lack of belief in God, and evolution is regarded as a plain fact, I must confess I don’t really understand what all the fuss is about on the other side of the pond.

I believe – like most European commenters on the situation – that the reason that evolution is not fully accepted by our American cousins is because religious fundamentalism has such a strong-hold in the states that evolution has never been taught properly or extensively in American schools.

I am an atheist. I have been since I was about eight years old. I am proud of my atheism. Religion and evolution are non-debates for me. I’m sorry if some people find that offensive. To be quite frank, there are a lot of things I could find offensive if I wanted to, but as I am not a zealot of any kind I respect other people’s right to believe what they want. I don’t much care what other people believe. I have real-life friends who are Catholics, pagans, Muslims, undefined spiritualists, and fellow atheists. I show a slight interest in their religion, only because it helps me to understand the workings of their minds.

Religion is a political and emotional minefield, and I work very hard not to accidentally offend religious friends. Sometimes that is not possible, because one can make totally neutral comments and still be misinterpreted as saying something insulting. Religious people seem to be on a hair-trigger with that respect. But religious people shouldn’t be the only people who are allowed to be offended. Plenty of atheists have borne a significant amount of the brunt of religious bigotry throughout history, sometimes with their lives. If religious people are allowed to take offense so easily, atheists should have the right to be offended too.

For example: I am offended that atheism is regarded by religious people as ‘just another religion’. This shows a fundamental lack of understanding of the nature of atheism and is quite insulting.

Except sometimes I think there is too much of this taking of offense going on. People sometimes use their right to take offense as a political cudgel to beat other people with valid viewpoints into silence. I do not think people who have what are essentially differences in political opinions should be allowed to get away with playing the ‘I’m offended by your criticism of my precious beliefs’ card. In fact it’s an essential aspect of freedom of speech that political and religious ideas should be debated openly and honestly without people being forced to tiptoe around. By contrast, people who have physical attributes that make them a target for discrimination – whether they be black, women, gay, disabled, religious, non-religious or just different – damn well have a right to get offended when ideas start to advocate the wiping out or shutting up of a group of people. Saying a religious idea is wrong is quite different to saying a religious person should be discriminated against. People are not ideas. It is important to get this distinction right. I’ve seen a lot of overstepping the mark on both sides.

People who are religious will frequently cite the argument that ‘atheism is just another form of religion’. This is not true. Atheism is the disbelief in religion. It is a refusal to accept the hypothesis that there is a god. It is the normative scientific starting point. Atheism does not have to provide proof. The burden of proof is on those asserting the hypothesis – it is up to them to prove the existence of god. This simple scientific assertion, an integral feature of atheism, appears to be enough to send some religious people into paroxysms of rage.

People also often confuse atheism and agnosticism. Atheism is characterised by the absence of belief. Atheism is not necessarily saying ‘there is definitely no god’, it is merely saying ‘show me some real proof before I accept your hypothesis of a god’. Not believing that something is true is not the same as believing that it is false. Different forms of atheism exist however, and ‘strong’ or ‘positive’ atheism is a definite assertion that there is no god. In contrast to atheism, an agnostic is someone who says that we cannot know for sure whether god exists or not, a fence-sitter if you will. If you would like to understand atheism here is a good introduction.

With the burden of proof in mind I want to say a few simple, logical words about creationism.

  • A scientific hypothesis must be testable and falsifiable
  • Creationism is not testable or falsifiable
  • Therefore creationism is not science

A debate about creationism and creationist-influenced evolutionary theory does not really have a valid place on a scientific forum, especially when it is conducted purely as an ego-massage to support someone’s personal religious beliefs. In rubbishing fundamental tenants of Darwinian evolution, it then becomes impossible to explain basic questions about genetics from a scientific standpoint. In order to understand why different forms of genes exist, you must first understand and accept evolutionary theory. Otherwise you will just be forced to fall back on making offensive remarks about some people being ‘less perfect’, or ‘defective’, or even ‘more deserving of God’s punishment’ than others.

Here is a run down of exactly why creationism is not science.

By contrast:

  • Evolutionary theory is testable and falsifiable
  • Therefore evolutionary theory is science

Evolutionary theory is not merely ‘a theory’. It is in no way on a level playing field with other ‘religious beliefs’ from which people can pick and choose at will. There is an enormous amount of evidence for evolutionary theory in the fossil record, and in our genes. Not only is evolution the science to creationism’s anti-science, evolution has been proved beyond reasonable doubt.

Written by alienrobotgirl

28 April, 2008 at 8:26 pm

Posted in How to be Scientific

Tagged with

Histamine intolerance review

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Histamine and histamine intolerance is an excellent review.

Diamine oxidase (DAO) is the main enzyme for the metabolism of ingested histamine. It has been proposed that DAO, when functioning as a secretory protein, may be responsible for scavenging extracellular histamine after mediator release. Conversely, histamine N-methyltransferase, the other important enzyme inactivating histamine, is a cytosolic protein that can convert histamine only in the intracellular space of cells.

DAO is more important than HNMT in histamine metabolism.

Ingestion of histamine-rich food (6), alcohol (7-9), or drugs (10-13) that release histamine or block DAO may provoke diarrhea, headache (14), congestion of the nose, asthmatoid wheezing (6, 8, 15), hypotension, arrhythmia, urticaria (16, 17), pruritus, flushing, and other conditions in these patients. Approximately 1% of the population has histamine intolerance, and 80% of those patients are middle-aged (18). Because of the multifaceted symptoms, the existence of histamine intolerance is frequently underestimated, or its symptoms are misinterpreted. Clinical symptoms and their provocation by certain foods and beverages appear similar in different diseases, such as food allergy and intolerance of sulfites, histamine, or other biogenic amines (eg, tyramine).

It’s virtually impossible to tell the difference between different food chemical reactions.

In mammals, DAO expression is restricted to specific tissues; the highest activities are shown for small bowel and colon ascendens (4, 5, 33) and for placenta and kidney (28, 31). Lower DAO activity has been discussed as a potential indicator of intestinal mucosa damage in inflammatory and neoplastic diseases (17, 24, 34) and in persons undergoing chemotherapy (35). HNMT is widely expressed in human tissues; the greatest expression is in kidney and liver, followed by spleen, colon, prostate, ovary, spinal cord cells, bronchi, and trachea (36). HNMT is regarded as the key enzyme for histamine degradation in the bronchial epithelium (37).

When these scientists talk about ‘intestinal mucosa damage’ they are not talking about intestinal dysbiosis. They are talking about Crohn’s disease, ulcerative colitis and coeliac disease, quite serious diseases.

Histamine can be metabolized by extracellular oxidative deamination of the primary amino group by diamine oxidase (DAO) (2) or intracellular methylation of the imidazole ring by histamine-N-methyltransferase (HNMT) (3). Therefore, insufficient enzyme activity caused by enzyme deficiency or inhibition may lead to accumulation of histamine. Both enzymes can be inhibited by their respective reaction products in a negative feedbackloop (4). N-Methylhistamine is oxidatively deaminated to N-methyl-imidazole acetaldehyde by monoamine oxidase B (MAO B) (5) or by DAO (6).

After histamine is methylated by HNMT, it still needs further metabolism by DAO or MAO B.

Recently, a potential genetic background of a reduced histamine metabolism has also been investigated. The human DAO gene spans {approx}10 kbp and is located on chromosome 7q35 (27) Various single-nucleotide polymorphisms (SNPs) in the DAO gene have been shown to be associated with inflammatory and neoplastic gastrointestinal diseases, such as food allergy (44), gluten-sensitive enteropathy, Crohn disease, ulcerative colitis, and colon adenoma (45-47). No significant difference in the distribution of the investigated HNMT alleles could be shown between patients with gastrointestinal diseases and control subjects (45, 47), but a functional relevant polymorphism of the HNMT gene (chromosome 2q22) has been described for white asthma patients (48). Conversely, this association could not be observed in Japanese (49), German pediatric (50), and East Indian (51) populations. Thus, histamine intolerance seems to be acquired mostly through the impairment of DAO activity caused by gastrointestinal diseases or through the inhibition of DAO, but the high interindividual variations in the expression of DAO in the gut and the association of SNPs in the DAO gene with gastrointestinal diseases provide evidence for a genetic predisposition in a subgroup of patients with histamine intolerance (27).

So impairments in DAO activity (whether genetic or acquired) are thought to be the main cause of histamine intolerance. I wonder whether that HNMT polymorphism in white asthma patients is actually interacting with another ‘white’ (i.e disproportionately present in caucasians) gene that causes it to be significant?

Headache can be induced dose-dependently by histamine in healthy persons as well as in patients with migraine (53, 61). Histamine-induced headache is a vascular headache caused mainly by nitrate monoxide (62). Histamine releases endothelial nitrate monoxide upon stimulation of H1R, which is also expressed in the large intracranial arteries (63). In migraine patients, plasma histamine concentrations have been shown to be elevated both during headache attacks and during symptom-free periods.

Everyone is adversely affected by a dose of histamine that exceeds their own personal tolerance levels.

Besides headache, gastrointestinal ailments including diffuse stomach ache, colic, flatulence, and diarrhea are leading symptoms of histamine intolerance. Elevated histamine concentrations and diminished DAO activities have been shown for various inflammatory and neoplastic diseases such as Crohn disease (17), ulcerative colitis (67), allergic enteropathy (39), food allergy (33, 68, 69), and colorectal neoplasmas (24). In the colonic mucosa of patients with food allergy, a concomitant reduced HNMT (70) and an impaired total histamine degradation capacity (THDC) (69) have been found (33), so that the enzymes cannot compensate each other. Therefore, an impaired histamine metabolism has been suggested to play a role in the pathogenesis of these diseases.

During or immediately after the ingestion of histamine-rich food or alcohol, rhinorrea or nasal obstruction may occur in patients with histamine intolerance; in extreme cases, asthma attacks also may occur. Reduced HNMT activity has been shown for patients with food allergy (70) and asthma bronchiale (71).

Possibly a methylation cycle related connection for some but not all individuals.

In addition to histamine-rich food, many foods such as citrus foods are considered to have the capacity to release histamine directly from tissue mast cells, even if they themselves contain only small amounts of histamine (Table 4). In vitro studies of persons with a history of pseudoallergic reactions to food have shown a fragility of duodenal mast cells with massive degranulation in the presence of histamine-releasing substances that is significantly greater than that shown by control subjects (85). However, clinical studies using oral challenge tests to support the hypothesis for the histamine-releasing capacity of foods are required (22).

You don’t need to have a problem with salicylates to have a reaction to citrus fruits!

Alcohol, especially red wine, is rich in histamine and is a potent inhibitor of DAO (9, 86). The relation between the ingestion of wine, an increase in plasma histamine, and the occurrence of sneezing, flushing, headache, asthma attacks, and other anaphylactoid reactions and a reduction of symptoms by antihistamines has been shown in various studies (7, 8, 14, 65, 87, 88). However, among the multitude of substances contained in wine, other biogenic amines such as tyramine (80) and sulfites (89) have been supposed to contribute to symptoms summarized as “wine intolerance” or “red wine asthma” (19, 89, 90).

How about red wine-violently-throwing-up-sickness? I’ve never been able to tolerate more than a small glass.

In the female genital tract, histamine is mainly produced by mast cells, endothelial cells, and epithelial cells in the uterus and ovaries. Histamine-intolerant women often suffer from headache that is dependent on their menstrual cycle and from dysmenorrhea. Besides the conctractile action of histamine, these symptoms may be explained by the interplay of histamine and hormones. Histamine has been shown to stimulate, in a dose-dependent manner, the synthesis of estradiol via H1R; meanwhile, only a moderate effect on progesterone synthesis was observed (117). The painful uterine contractions of primary dysmenorrhea are mainly caused by an increased mucosal production of prostaglandine F2{alpha} stimulated by estradiol and attenuated by progesterone. Thus, histamine may augment dysmenorrhea by increasing estrogen concentrations. And, in reverse, estrogen can influence histamine action. A significant increase in weal and flare size in response to histamine has been observed to correspond to ovulation and peak estrogen concentrations (118). In pregnancy, DAO is produced at very high concentrations by the placenta (119, 120), and its concentration may become 500 times that when the woman is not pregnant (120). This increased DAO production in pregnant women may be the reason why, in women with food intolerance, remissions frequently occur during pregnancy (14).

Interesting, because oestrogen also decreases monoamine oxidase activity. I’ve thought for ages that I have too much oestrogen.

I’ve also noticed that some women who are usually complete crazy bitches seem perfectly sweet and lovely during pregnancy, whilst other women who seem like perfectly lovely people go nuts. Coming from a family who were closely involved in the administration of a fibromyalgia support network, I’m familiar with the anecdotal ‘fibromyalgia sufferers always get better during pregnancy then relapse again’ phenomenon.

Written by alienrobotgirl

27 April, 2008 at 10:21 am

Posted in The Science of FCI

Overview of autism genetics

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An excellent overview of autism genetics:

Identical twin studies put autism’s heritability in a range between 0.36 and 0.957, with concordance for a broader phenotype usually found at the higher end of the range.[1] Autism concordance in siblings and fraternal twins is anywhere between 0 and 23.5%. This is more likely 2–4% for classic autism and 10–20% for a broader spectrum. Assuming a general-population prevalence of 0.1%, the risk of classic autism in siblings is 20- to 40-fold that of the general population. To What Extent Do Genes Cause Autism?

These are the genes that the article runs through:

SERT – rigid compulsive behaviours, social adversity, depression as a result of social adversity, hyperserotonemia.

GABA – GABRA4 through interaction with GABRB1. GABRB3 – savant skills. [Interestingly GABRA1 is associated with Juvenile Myoclonic Epilepsy – the individual I know with JME scores very high-normal on an AQ test.]

Engrailed 2 (EN2) – cerebellar development.

3q25-27 region – autism and asperger’s, function unknown.

7q21-q36 region, REELIN (RELN) – memory formation, neurotransmission, synaptic plasticity.

SLC25A12 – AGC1, mitochondrial aspartate/glutamate carrier.

HOXA1 and HOXB1 – brain stem development. Possibly head circumference. May interact with teratogens like valproic acid. Undermethylation?

PRKCB1 – Protein kinase C beta 1, diverse signalling pathways. Involvement in arachidonic acid cascade?

FOXP2 – Developmental language and speech deficits.

UBE3A – Angelman syndrome, Rett syndrome. Development delay, hand flapping, happy demeanour.

Shank3/ProSAP2, 22q13 and Neuroligins – neuroligins regulate structural organisation of neurotransmitter receptors. SHANK3 – encodes a synaptic scaffolding protein. Interaction between SHANK3 and 22q13 – global development delay, delayed speech, delayed cognitive abilities, high pain tolerance, chewing and mouthing. Neuroligin-3 – poor social skills and increased intelligence.

MET (MET receptor tyrosine kinase) – brain development, regulation of the immune system, repair of GI system. Disrupted neuronal growth in cerebral cortex, smaller cerebellum. MET variants influence cancer metastases – cancer less likely in these autistic children.

Neurexin 1 – CNTNAP2 – communication between nerve cells, regulating chemical transmission, early brain development.

GSTP1 – glutathione s-transferase acting in mother during pregnancy increasing risk of autism in child.

Other candidate loci include the 17q21 region, the 3p24-26 locus, PTEN and 15q11-q13.

Other possibles: SLC6A2 (Social phobia), FMR1 (Fragile-X), 5-HT-1Dbeta (OCD), 7q11.23 (William’s syndrome, language impairment), 4q34-35, 5q35.2-35.3, 17q25 (Tourette syndrome), 2q24.1-31.1 (Intelligence), 6p25.3-22.3 (Verbal IQ), 22q11.2 (Visio-Spatial IQ).

The genes mentioned above aren’t the only genes with suspected involvement in autism – there are methylation genes too:

The metabolic results indicated that plasma methionine and the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), an indicator of methylation capacity, were significantly decreased in the autistic children relative to age-matched controls. In addition, plasma levels of cysteine, glutathione, and the ratio of reduced to oxidized glutathione, an indication of antioxidant capacity and redox homeostasis, were significantly decreased. Differences in allele frequency and/or significant gene-gene interactions were found for relevant genes encoding the reduced folate carrier (RFC 80G > A), transcobalamin II (TCN2 776G > C), catechol-O-methyltransferase (COMT 472G > A), methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A > C), and glutathione-S-transferase (GST M1). Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism

And a number of studies linking low functioning MAO with increased severity.

These comments are from the biggest autism twin study mentioned in the article:

High heritability was found for extreme autistic-like traits (0.64-0.92 for various cutoffs) and autistic-like traits as measured on a continuum (0.78-0.81), with no significant shared environmental influences. All three subscales were highly heritable but showed low covariation. In the genetic modeling, distinct genetic influences were identified for the three components. Genetic heterogeneity between the three components of the autism spectrum: a twin study

As you can see there are a huge number of different genes implicated in the etiology of autism. I’ve often thought of the label ‘autism’ as being a bit like a rubbish bin diagnosis into which many different types of people are put because they fit a few basic criteria. In the past those people would have been put into different criteria – for example they would have been defined as ‘retarded’ or ‘psychotic’ or ‘shy’. Some autistics are mentally retarded, some have increased intelligence. Some have savant skills. Some rock and flap and poo smear. Others write computer programs, design jet planes, or teach astrophysics for a living. Some don’t talk at all. Others never stop talking. I identify closely with some of the autistics whose blogs I read (I find myself thinking she’s got exactly the same symptoms/personality as me right the way down to the fear of having to use a telephone). I think other autistics whose blogs I read are just plain weird (I find myself thinking he’s one of those mad/paranoid/illogical/retarded autistics). It takes many different genes to produce many different aspects of the personality.

Written by alienrobotgirl

26 April, 2008 at 5:02 pm

Posted in Autism Genetics

Tagged with

Autistics: highly evolved

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Following on from the two genetic theories of autism I’ve discussed before, and the questioning of the odds involved in new mutations causing autism, here’s a little more news that slipped under the radar recently.

There is a new wrinkle to the genetic research however. Based on family studies, scientists have long characterized autism-linked genes as “heritable.” But recent research shows a surprisingly large number of mutations tied to autism are “de novo” glitches that arise spontaneously in children whose parents don’t carry them.

Such spontaneous mutations have come to light by studying so-called “structural changes” in the genome, which, if DNA’s chemical letters were arranged in book form, would consist of largish mistakes such as duplicated and missing pages. A recent study that got much less attention than the Poling story showed that 7% of kids with autism carry structural changes not found in their parents, compared with less than 1% of such glitches seen in the general population.

“This is really exciting, and a lot of people haven’t picked up on it yet,” says geneticist Stephen Scherer, a co-author of the study at the Hospital for Sick Children in Toronto.

It’s likely that many more such changes will be linked to ASDs as researchers examine a wider array of cases with new gene-scanning tools. Some researchers even theorize that the majority of autism cases stem from such spontaneous mutations.

Why would genes linked to autism be so mutation-prone?

Consider a mutation on chromosome 16 recently tied to autism. The glitch is in a DNA region containing so-called “morpheus” genes, which changed very rapidly as evolution produced ever brainier apes. The genes may well help shape cognitive capacities specific to apes and humans, including ones affected by autism.

Since fast mutation goes hand in hand with fast evolution, it’s likely that the new autism-linked gene lies in a DNA “hotspot” prone to spontaneous mutation. In short, the same phenomenon that helped to rapidly evolve our braininess may contribute to autism. Tracing autism’s roots

So first off – the ‘surprisingly large number’ of de-novo mutations in autistic children has now fallen from ten percent to seven percent (7%) of autistics versus 1% of the general population. The vast majority of autistics aren’t involved in this process.

And second – try as I might, I can’t find any evidence that mutations in Morpheus genes are affected by DNA methylation, transposons, or anything else. This seems to be an effect entirely independent of dietary folate and blah blah blah during pregnancy. In fact, it appears to be an inbuilt evolutionary mechanism for increasing brain power.

It seems that in this case the far-out New Age beliefs that autistics are ‘crystal children’ who are ‘the next stage in our evolution’ are less far-off the mark than WAPF member’s judgemental beliefs that autistics are ‘Pottenger’s children’ whose DNA has been ‘damaged’ by their parents diets.

Written by alienrobotgirl

26 April, 2008 at 12:59 pm

Posted in Autism Genetics

Tagged with

Are you an altie?

with 2 comments

I’m really pleased to discover that I’m not an altie. I answered no to every question except one.

There was a time when I was still naive enough that I might have said yes to 3-4 of those statements, including:

125. If you think that ancient people using nothing but herbs, witch-doctoring and an outdoor lifestyle lived long, disease-free lives, you might be an altie.

Sorry Weston A. Price Foundation members. I’m not that naive anymore – and I was never totally that naive. Unlike most WAPF members, I’ve actually read Nutrition and Physical Degeneration. What surprised me at the time was that Price barely mentions the diet of the natives he studied, and the only statistics he gathered were the counting of caries. He didn’t give them physical exams. He didn’t find out how long they lived. He just made a general assessment that they ‘looked healthy’. You know, people who have asthma and fibromyalgia look healthy too.

Something I did answer yes to:

64. If you’ve ever grown/brewed your own jar/crock of “Kombucha tea”, yup, you’re an altie.

I tried it, it seemed to do something. I thought it might be helping. It took me several months to figure out that the way I react to kombucha tea is the way I react to any tea. It’s the theanine.

Written by alienrobotgirl

25 April, 2008 at 4:59 pm