Archive for the ‘Autism Genetics’ Category
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.
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. 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.
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.
About 30% of autistics have elevated serotonin levels, and autism has been linked to polymorphisms in SERT – a serotonin transporter. Chris sent me this great link the other day:
Many children with autism have elevated blood levels of serotonin – a chemical with strong links to mood and anxiety. But what relevance this “hyperserotonemia” has for autism has remained a mystery.
New research by Vanderbilt University Medical Center investigators provides a physical basis for this phenomenon, which may have profound implications for the origin of some autism-associated deficits.
In an advance online publication in the Journal of Clinical Investigation, Ana Carneiro, Ph.D., and colleagues report that a well-known protein found in blood platelets, integrin beta3, physically associates with and regulates the serotonin transporter (SERT), a protein that controls serotonin availability.
Autism, a prevalent childhood disorder, involves deficits in language, social communication and prominent rigid-compulsive traits. Serotonin has long been suspected to play a role in autism since elevated blood serotonin and genetic variations in the SERT have been linked to autism. Sticky blood protein yields clues to autism
I love the way the science reporter thinks the link between elevated serotonin and autism is a mystery. He doesn’t know that serotonin has a powerful influence on shyness versus sociability.
The relationship of SERT with integrin beta3 is a good demonstration of how the same effects (in this case high serotonin) can be caused by several different genes.
Wait – wait… nope… still nothing to do with mercury.
This is another one for the ‘autism is all about glutamate’ file.
Fragile X syndrome is an X-linked syndrome with physical characteristics, mental retardation and autism.
Boys with the syndrome may have large testicles (macroorchidism), prognathism, hypotonia and autism, and a characteristic but variable face with large ears, long face, high-arched palate, gynecomastia, and malocclusion. Additional abnormalities may include lordosis, heart defect, pectus excavatum, flat feet, shortening of the tubular bones of the hands, and joint laxity. Females who have one fragile chromosome and one normal X chromosome may range from normal to mild manifestations of the fragile X syndrome.
The genetics of Fragile X are quite straightforward:
The fragile X syndrome is a genetic disorder caused by mutation of the FMR1 gene on the X chromosome. Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 259 females. (Incidence of the disease itself is about 1 in every 4000 females.)
Normally, the (FMR1 gene contains between 6 and 55 repeats of the CGG codontrinucleotide repeats). In people with the fragile X syndrome, the FMR1 allele has over 230 repeats of this codon.
Expansion of the CGG repeating codon to such a degree results in a methylation of that portion of the DNA, effectively silencing the expression of the FMR1 protein.
This methylation of the FMR1 locus in chromosome band Xq27.3 is believed to result in constriction of the X chromosome which appears ‘fragile’ under the microscope at that point, a phenomenon that gave the syndrome its name.
Mutation of the FMR1 gene leads to the transcriptional silencing of the fragile X-mental retardation protein, FMRP. In normal individuals, FMRP binds and facilitates the translation of a number of essential neuronal RNAs. In fragile X patients, however, these RNAs are not translated into proteins. Fragile X Wiki
Today Grey Matter/White Matter linked to a press release reporting new progress in fragile X research.
ATLANTA, March 10 (UPI) — A U.S. team of scientists has identified several drugs and small molecules that reverse features of fragile X syndrome — a form of mental retardation.
The scientists, led by Stephen Warren of Emory University, made their discoveries using a new drug screening method in Drosophila (fruit flies), setting the stage for development of new treatments for the syndrome, one of the leading known causes of autism.
Warren led a group of scientists that discovered in 1991 that the FMR1 gene is responsible for fragile X syndrome.
In the current experiment, scientists discovered when FMR1-deficient fly embryos were fed food containing increased levels of glutamate, they died during development.
The scientists placed the FMR1-deficient fly embryos in thousands of tiny wells containing food with glutamate. In addition, each well contained one compound from a library of 2,000 drugs and small molecules. Using that screening method, the scientists uncovered nine molecules that reversed the lethal effects of glutamate.
The study that included Shuang Chang, Steven Bray and Peng Jin of Emory, Zigang Li of the University of Chicago and Daniela Zarnescu from the University of Arizona appears online in the journal Nature Chemical Biology. Progress reported in fragile X research
In a longer news article we find:
A variety of scientific evidence suggests that increasing glutamate neuronal transmission may be beneficial in autism and in fragile X syndrome. Imaging studies demonstrate that areas of the brain that are extremely rich in glutamate transmission are less active in autistic patients. Molecular studies suggest that although genes involved in the AMPA-type glutamate receptor are more active in autistic patients, the density of AMPA-type glutamate receptors is decreased. Drugs that reduce glutamatergic transmission induce symptoms similar to those seen in autistic patients. Taken together, these facts suggest that enhancing AMPA receptor activity may be beneficial in autistic patients. New Drug That Enhances Glutamate Transmission In The Brain Being Evaluated For Fragile X
Wikipedia also mentions:
One hypothesis is that many symptoms are caused by unchecked activation of mGluR5, a metabotropic glutamate receptor, which was found in a 2007 study to contribute significantly to the pathogenesis of the disease; this suggests that mGluR5 blockers could be used to treat fragile X syndrome.
I do not have fragile X syndrome. But dietary free glutamate makes me very withdrawn and inhibited and later incredibly sleepy, so there is clearly something going on with the way I process and use glutamate. Glutamate is also implicated in autism through the gene for neurexin 1.
Wake up folks! It’s still not mercury.
The “new mutations” genetic theory of autism is one pioneered by scientists such as Professors Michael Wigler and Jonathan Sebat at the Cold Spring Harbor Laboratory on Long Island, New York. This short piece from the New Scientist explains their theory:
Duplications or deletions of portions of the genome may cause many – if not most – cases of autism.
Such errors can alter the number of copies of particular genes in the regions affected. These copy-number variations are 10 times as common in autistic children as in other children.
A team led by Jonathan Sebat of Cold Spring Harbor Laboratory on Long Island, New York, examined 118 families that have one autistic child and 99 families with children who are not autistic. Ten per cent of the autistic children, but only 1 per cent of the other children, had copy-number variants in their genomes that didn’t appear in their parents (Science, DOI: 10.1126/science.1138659).
The copy-number variants tend to affect different genes in each autistic child. This suggests that autism is not caused by a single genetic defect. Clues to autism revealed in copied genes
I’ve spent most of my time recently talking about single nucleotide polymorphisms – where one letter of a gene is substituted for another letter. Here, the scientists studied deletions and duplications of genes. Deletions and duplications and variants of genes are normal, very common, and widely found in the genetic code of all human beings. What the scientists have found here is that new deletions and duplications are present in a small but significant minority of autistic children – ten percent of autistic children to be exact, whereas they are normally present in about one percent of births. This is not at all surprising, considering the correlation of low-functioning DNA methylation genes with autism.
What we have to be cautious about is concluding causation from this – deletions/duplications rarely cause any observable changes in people, and they can occur anywhere in our genome – which consists of tens of thousands of different genes. For deletions/duplications to actually have some effect on the likelihood of being born with autism, they need to occur in genes that affect personality or the brain and nervous system.
What does the rest of the scientific community think?
Much of the autism research community believes there may be roughly six major genes involved in autism, and maybe 30 others that may confer some risk. A combination of mutations in any of these genes could contribute to the likelihood of being born with autism. Largest Ever Autism Study Identifies Two Genetic Culprits
Even if we included all of the personality and nervous system genes, that’s still a pretty narrow selection of genes that would have to be deleted or duplicated in order to produce changes in the child’s personality, let alone changes that cause autism.
One of the regular genes identified in autism by the Autism Genome Project is CNTNAP2. CNTNAP2 encodes neurexins – synaptic cell surface proteins – which are involved in glutamate functioning in the nervous system and brain. According to Entrez Gene, “This gene encompasses almost 1.5% of chromosome 7 and is one of the largest genes in the human genome.” That’s a lot of room for variation isn’t it?
Wow. Donna Williams’ family history sounds just like mine!
I was born into a very challenged and challenging household of unusual, eccentric, personalities. Various combinations of mood, anxiety, compulsive disorders, addiction, rage, dyslexia, ADHD, Asperger’s, autism, suicide, Crohn’s, Colitis, Coeliac, Diabetes, eczema, asthma, croup, hives and allergy rashes all run in various side of my family, going back generations on my father’s side.
Not all people with autism have my physical, sensory-perceptual, language processing, neurological integration or co-morbid mood, anxiety or compulsive disorders. Most of these issues run on one or both sides of my family. I feel that what I inherited was the combined impact of the challenges of both my parent’s sides of the family and that under certain environmental conditions, these things expressed themselves in early infancy, causing the developmental breakdown that presented as a ‘psychotic infant’, disturbed child, autistic adult. Autism; it ain’t all physical
I was going to say I can’t think of a case of suicide – but I can – my dad’s cousin was a millionaire who lived in a stately hall in Bakewell, and he killed himself.
No Crohn’s/colitis/coeliac as far as I know – just plenty of garden-variety IBS. Also some kidney stones and gallstones.
Like me, Williams seems to have inherited most of her autie personality from her father. My father is a boffin, crazy inventor, tinkerer, collector, and all-round know-it-all.
I even have something in my family history that Williams doesn’t – my maternal grandfather’s sister had intractable epilepsy and was locked up in a sanitarium until she died.
I would have loved to have met my great grandfather Beau Pré. He was an African missionary – a very angry man by most accounts – an alcoholic, who died in the African jungle of an asthma attack.
I am so repeating myself here. Do you think if I keep saying “IT’S GENETIC” some of the chelators and the gut bacteria folks and the vitamin deficiency zealots will eventually stop and listen?
Or am I talking to a brick wall here?
The autism genome project have been running scans on the whole of the human genome using gene chips:
The consortium leveraged the unprecedented statistical power generated by its unique sample set by using “gene chip” technology to look for genetic commonality in autistic individuals culled from almost 1,200 families. One third of the DNA and clinical data was provided by the Autism Genetic Resource Exchange (AGRE). The AGP also scanned DNA from these families for copy number variations (CNV), or sub-microscopic genomic insertions and deletions that scientists believe might be involved with this and other common diseases. The innovative combination of these two approaches implicates a previously unidentified region of chromosome 11, and neurexin 1, a member of a family of genes believed to be important in neuronal contact and communication, among other regions and genes in the genome. The neurexin finding in particular highlights a special group of neurons, called glutamate neurons, and the genes affecting their development and function, suggesting they play a critical role in autism spectrum disorders. AGP results
I’ve been searching for some kind of explanation of these findings, and Chris very kindly sent me this article last weekend:
DALLAS – Sept. 7, 2007 – Mice containing a mutated human gene implicated in autism exhibit the poor social skills but increased intelligence akin to the title character’s traits in the movie “Rain Man,” researchers at UT Southwestern Medical Center have found.
The researchers’ study also shows how the mutation affects nerve function and provides an animal model that might allow further study of the debilitating condition.
“It’s an attempt to replicate, as best we can, a complicated disease that has as a symptom an inability to use language effectively,” said Dr. Thomas Südhof, chairman of neuroscience and senior author of the study, which appears online in Science Express and will be published later in Science.
“Any model we make will only be an approximation of the human condition,” he cautioned.
Autism spectrum disorders cover a wide span of conditions and symptoms, from severe mental retardation to mild social impairment. In general, people with autism have problems with social interactions, such as maintaining eye contact or reading body language. They may also exhibit stereotypical behavior, such as being obsessed with lining up objects. In the movie “Rain Man,” the title character was unable to form social bonds and became distressed when his normal routine was disrupted, yet he could perform exceptional mental mathematics.
About 1.5 million people in the United States have autism spectrum disorders, with boys affected more often than girls.
Some cases of autism are genetically linked and have been associated with mutations that affect molecules called neuroligins, which link nerve cells together.
In the latest study, the researchers introduced a mutated human form of the neuroligin-3 molecule into mice. They then tested the animals’ social interactions by exposing them to an unknown mouse in a cage. The genetically engineered mice spent less time near the strange mouse than their normal littermates and preferred to spend time with inanimate objects.
The engineered mice were significantly better than normal, though, at learning a water maze, in which they had to find and learn the location of an underwater platform. They were also better at relearning a new position of the platform after it was moved.
“When you manipulate a brain, you usually don’t improve it,” Dr. Südhof said. “The fact that we get an improvement is very good. It shows we’re changing something specific; we’re affecting how the brain processes information.”
Other tests of coordination, anxiety and motor ability showed normal results, indicating that the changes in brain activity were specific, Dr. Südhof said.
The researchers also studied the patterns of electrical activity in the brain. Normally, some nerve cells halt, or inhibit, other nerve cells from firing, while others excite action in their neighbors. An imbalance in the normal pattern is thought to be involved in autism.
Nerve cells from the genetically engineered mice showed a significantly greater inhibitory action than their normal littermates, even though only about 10 percent of the normal amount of neuroligin-3 was present. This finding was a surprise, as other studies have indicated that a loss of inhibitory action might be involved in autism spectrum disorders, the researchers said.
The results indicate that focusing on inhibitory action might be a way to treat autistic behaviors, said Dr. Südhof, director of the Gill Center for Research on Brain Cell Communication and the C. Vincent Prothro Center for Research in Basic Neuroscience. He is a Howard Hughes Medical Institute investigator at UT Southwestern. ‘Rain Man’ mice provide model for autism
I’m surprised that researchers are surprised that there are inhibitory effects happening in autism! My brain feels like it’s in constant INHIBIT gear. My brain is always trying to tell me to stop talking and not make friends.
If you’ve had a chance to read and digest The Times article I posted yesterday, I’d like to elaborate.
I posted this article because it is a pretty good overview of where modern mainstream medicine is at the moment. Genes aren’t specifically named in the article, but the subtext of ‘many common polymorphisms’ seems to be there.
Autism is thought to be caused by polymorphisms and mutations in various different neurotransmitter receptor/signalling/transport genes – such as the dopamine receptor genes I mentioned. In addition scientists have been looking at alterations in glutamate signalling/function as well as serotonin signalling/function.
The article lays out the two main genetic theories of autism:
- Autism is caused by a ‘cocktail’ of different single nucleotide polymorphisms that have different effects on the personality, and when a particular combination appears together, this produces an extreme result as in autism.
- Autism is caused by ‘random new mutations’ that change the function of the brain, because many new mutations have been found in autistic children.
In my opinion, it is the first theory which produces the second effect.
In other words, the ‘cocktail’ of different genes are the naturally occurring, heritable polymorphisms. These polymorphisms are not new and have existed for millions of years. Similar polymorphisms occur in most other species and are not restricted to Homo Sapiens Sapiens.
There’s little substance and much belief among some members of WAPF at the moment that autism must be caused by DNA undermethylation – that autistics are Pottenger’s children because of the bad diet of their parents, and what you need to avoid autism is lots of folate during pregancy. In fact what is suggested by the science is that only a ten percent minority of autistics have ‘random new mutations’, and these may or may not be influenced by folate consumption.
It is unclear how much epigenetics has to do with autism. Just as poor DNA methylation and other non-nutritional factors produce spontaneous mutations, methylation also has the effect of reprogramming or turning on and off existing ‘transposon’ genes – the small percentage of junk genetic code added to our DNA by viruses. There is no evidence that autism is an epigenetic condition or not an epigenetic condition, but there is plenty of existing evidence that it is a regular genetic cocktail effect based on normal genes. We seem to have a perfectly plausible and fully working understanding of autism spectrum without adding epigenetics into the mix. However, certain named and well understood forms of autism like Rett syndrome (missing X chromosome) and Fragile X have been connected to possible undermethylation of DNA in already risky genotypes.
People with polymorphisms in their methylation genes (like MTHFR variants) are known to have higher rates of neural tube defects and spontaneous genetic mutations than the rest of the population – a problem that is not always fixable with folate, particularly when an inefficient enzyme is already working to capacity. MTHFR polymorphisms in and of themselves 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 boys only have one copy. Only MTHFR is directly related to DNA methylation. Further, there is a survival advantage in MTHFR variants, it’s a classic example of ‘the selfish gene’ at work – the more and faster you mutate, the quicker you can adapt to new environments, and the faster you will outpace other members of your species. The disproportionate number of new mutations found in the genes of autistic children could well be as a result of a crunched up methylation cycle in the parents that is perfectly natural. I prefer this theory to the over-simplistic parental-blame-apportioning theory from holier-than-thou WAPF members.
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:
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?