Messages posted by: RAJ

Connie;

Does IAN have any statistics on sibling recurrance rates in your data base?

It would be interesting to compare the fraternal twin concordance rates of 31% to sibling recurrance rates.

Thanks

The sibling recurrance risk for autism is reported as between 2 - 8%.

http://www.ncbi.nlm.nih.gov/pubmed/15121991

The IAN twin study reported that 31% of fraternal twins are concordant for any ASD diagnosis.

http://www.ncbi.nlm.nih.gov/pubmed/19805709

If autism is genetically predetermined than concordance rates in fraternal twins should be identical to sibling recurrance rates, but it is not.

If IAN concordance rates for fraternal twins is correct than the risk for autism in fraternal twins is beteen four and ten times greater than the risk for autism in siblings.

The Ian twin study therefore can be interpreted as suggesting that the environmental component in autism is both strongly understated and poorly understood.

Interesting article on your front page. Researchers in Australia have also found that high levels of fetal tetesterone is associated with overgrowth in the developing brain and with language disorders.

One problem is that in all these studies not a single case of ASD has been identified, suggesting that 'autistic-like traits' are not the same as autism.

This is consistent with Rutter's two hit mechanism hypothesis which he explained thusly:

"In other words, what is required for autism 'proper' to develop are the susceptibility genes and some other risk factor that could be either genetic or environmental in origin. The implication, if it is a two hit process is that the genes underlying the broader autism phenotype may not be exactly the same as those involved in the transition to the handicapping disorder." Rutter 2006

While affected and one or more unaffected family members have many normal variation traits in common (autistic-like traits), they differ in enormous ways. Normal variation traits are not associated with mental retardation, seizures or structural and gross anomolies in the brain even in autism with normal or high IQ.

Plomin's group in the UK have reported the incidence of autistic-like traits in a large twin sample (thousands of pairs of twins in the UK) being as high as around 10% with 5% of their sample being described as possessing 'extreme autistic traits'.

The current trend that includes the 'Extreme Male Brain' theory is consistent with the trend towards redefining autism as a dimensional trait condition rather than a developmental disorder, threatens to obscure the boundaries between a debilitating neurological disorder and common normal 'traits'.

A new study has been published and has reported that the association between certain genetic syndromes (Fragile X, Tuberous Sclerosis, Downs, Angelmans, Rhetts) are only superficial associations:

http://www.ncbi.nlm.nih.gov/pubmed/19708861?
While these genetic syndromes share a number of isolated symptoms seen in autism as well as other neurologically impaired populations, including adult stroke patients, there are clear differences that are associated not with autism but rather the severity of cognitive impairment.

A new study just published in the Journal of Pediatrics screened 219 babies who were born in 1995 and were extremely preterm, less than 26 weeks gestation.

At followup 8% of all the babies (16 out of 219)examined met diagnostic criteria for an ASD.

http://www.ncbi.nlm.nih.gov/pubmed/20056232?

Fetal Alcohol Syndrome has been identified as being associated with ASD risk:

http://www.ncbi.nlm.nih.gov/pubmed/9344050?

Classical twin study design assumes an equal prenatal envornment and twin studies in ASD have reported a 60% concordance rate in identical twins and 0% concordance rate in fraternal twins.

http://www.ncbi.nlm.nih.gov/pubmed/7792363?

The prenatal environment in twin pregnancies differs between identical and fraternal twins. 2/3's of identical twins share the same prenatal environment (same placenta) while 1/3 of identical twins and all fraternal twins develop in seperate placentas.

Could concordance rates in ASD classical twin studies be better explained by differences in the prenatal environment?

A new study suggests that the answer is yes. Gerari et al examined the placenta of a pair of fraternal twins who had been heavily exposed prenatally to alcohol. A series of guinea pig littermates who were prenatally exposed to alcohol was included in the study as a control.

The authors found that one fraternal twin had high amounts of alcohol in the placental tissue while the co-twin had no level of alcohol in the placental tissue.

http://www.ncbi.nlm.nih.gov/pubmed/19127948?

Classical twin studies which assume an equal prenatal environment may have overstated the magnitude of the genetic component in ASD.

DSM is an acronym for "The Diagnostic and Statistical Manual of Mental Disorders".

Since when did Normal Variation manage to work its way into possible inclusion as a mental disorder in the next version of DSM. This is described as 'Socially isolated or ?awkward" with some ritualized behaviors and preoccupations but these are NORMAL for developmental stage and cause NO interference" but the proposal, if implemented would place common and normal variations of human characteristics under the umbrella of a 'Mental Disorder'.

What they also are describing is normal behavioral variations of adult stroke patients. Where is the relevance?

If implemented it looks like prevelance rates are headed towards 1/10 and Autism Spectrum Disorder would become an indiscrimantly applied meaningless label.

Here is Simon Baron-Cohen's take on the proposal in an Op-Ed published in the NY Times:

http://www.nytimes.com/2009/11/10/opinion/10baron-cohen.html?_r=1

Now that the APA will be publishing the latest version of DSM (DSM-V) in 2012 how might they define Diagnostic Criteria for 'Autism'.

Current diagnostic tools use cutoff scores, for example DSM-IV contains 12 isolated symptoms of equal weight (none are specific to 'autism'). If a clinician checks off four items, you have autism, if the clinician checks off three items you don't.

Many researchers have argued that cutoff points are abitrary especially in ASD screening tools.

The Wisconsin Twin study has examined whether Chinese menu checklists(one from column, 1 from column b) are arbitrary. The answer apears to be yes.

Using cutoff scores from different diagnostic tools, concordance rates in identical twin pairs compared to fraternal twin pairs varied from a high of 'ADOS-spectrum cut-off = MZ 77% (17/22), DZ 31% (9/29)' to a low of 'A combined criterion of ADOS-spectrum cut-off and SCQ led to a MZ pairwise concordance of 50% (10/20) and a DZ pairwise concordance of 15% (3/21)'

If you can't define a problem how is it possible to solve it?

http://imfar.confex.com/imfar/2009/webprogram/Paper4692.html

In 2007, Sabat and Wigler published a study of the prevalence of Copy Number Variations (CNV's) identified in volunteer families, including ubjects recruited from the IAN data base. They reported that 90% of cases were not inherited from their parents.

http://www.ncbi.nlm.nih.gov/pubmed/17363630?

CNV's and risk for disease has been the hot topic in genetic research and since the publication of the article CNV's have been found to occur more frequently than in healthy controls in many diseaes including mental retardation, schizophrenia and HIV infection susecptability.

Nothing has been proven with respect to what do CNV's do to 'cause' autism.

Since the report, a study has been published to look in depth at the behaviors and phenotypes of patients meeting diagnostic criteria for an ASD and the presence of CNV's:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16840569

Nine case were associated with CNV's. Seven were de novo CNV's (present in the patient but absent in the parents). In two cases the CNV was inherited from an unaffected parent.

The cases were included were patients with what the authors descibe as 'syndromic' ASD, which are patients who have, in addition to meeting diagnostic criteria for an ASD, minor and major congenital anomolies, including dysmorphic features.

The authors reported that in all cases, mental retardation was present (mild to moderate) and all had congenital anomlies.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2563185&rendertype=table&id=T3

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2563185&rendertype=figure&id=F2

It would be an interesting study to examine the presence of de novo or inherted CNV's in non-syndromic ASD (ASD without mental retardation or dysmorphic features.

The first research has been published. The theory is that closely following babies born in families with a child previously diagnosed with autism would shed light on the genetic transmission of autism.

This study examined the infant sibs beginning at six months of age and tracked their subsequent development 18 months later (2 years of age).

None of the infant sibs who showed lower levels of eye contact at six months were autistic at outcome. The study did show that eye contact at six months was not predictive of autism but was predictive of differences in language development.

http://www.ncbi.nlm.nih.gov/pubmed/19702771?

This first study is a blow to the genetic theorists who predicted that autism can be detected as early as six months of age, it cannot.

The study also adds evidence to the gene-environment interaction model. What has been described as autistic-like traits in unaffected family members, traits such as lower eye gaze, a higher rate of reserved personality types, differences in cognitive and language styles are all normal variants of human behavior.

This is evidence for a two hit mechanism operating in an autism subgroup. Affected and unaffected family members may share a clustering of what has been described as 'autistic-like' traits. Traits that are perfectly normal variences of human behavior.

What may seperate affected and unaffected family members is not a shared clustering
of normal trait variances but rather the underlying structual abnormalities in brain development (a two hit mechanism), present in affected family members but absent in unaffected family members.

Autistic-like traits may be highly heritable, but autism per se is not since it is associated with unfavorable events in the pre, peri and neonatal period that are associated with risk for a disruption in early brain devlopment.

http://pediatrics.aappublications.org/cgi/content/full/107/4/e63#T1

The APA's Working Group on autism has published a recommendation for changes to the next DSM manual (DSM-V). If the recommendation is implemented there will be vast changes as follows:

The category of Pervasive Developmental Disorder will be removed and replaced by Autism Spectrum Disorders (ASD).

Under the umbrella of ASD there will be five sub-categories. Autistic Disorder, PDD/NOS and Asperger Syndrome will be removed and replaced by the following with two additional sub-categories added:

1. Severe ASD
2. Moderate ASD
3. Mild ASD
4. Atypical ASD
5. Normal Variation ASD

Normal variation ASD is described as persons who do not have any development problems but who, on a Bell Curve of personality types, tend to fall in the introverted personality type category. Studies of the general population consistently demonstrate that about 25% of the total population fall into the category of introvert personality type with 75% of the total population falling into the extrovert personality type.

If these recommendations are implemented the current 'autism epidemic' will pale in comparison to what the new prevelance rates will eventually report. It is entierly reasonable that the prevelance rates will skyrocket to a possible 1/4 rate for ASD in the general population.

These recommendations points to a major shift in the conceptualization of what autism is, away from a conceptualization of autism as a developmental disorder, to one of a 'trait' or personality disorder.

Comments?

Here is the link:

http://www.psych.org/MainMenu/Research/DSMIV/DSMV/DSMRevisionActivities/DSM-V-Work-Group-Reports/Neurodevelopmental-Disorders-Work-Group-Report.aspx

A great deal of media hysteria (Autism gene discovered!) has followed the breathtaking announcement that 65% of autistic people have a common genetic variant located on chromosome 5.

http://www.chicagotribune.com/health/chi-autism-genetics-29apr29,0,6754959.story

Common genetic variances are defined as genetic variances which occur in more than 5% of the general population. Here are a couple of statements given to the media by the authors:

"If we could remove this variant from the population, just take it away ... as much as 15 percent of autism would disappear, which is highly significant," Hakonarson said.

Another statement questions the importance of this announcement:

"One of the studies released Tuesday found that 65 percent of autistic participants shared a genetic variation between cadherin 10 and cadherin 9, a region of the genome that controls cell-adhesion molecules in the brain. The figure for study participants without autism was 60 percent -- a statistically notable difference."

Since this common genetic variance is found in 60% of the general population it would suggest that 60% of the entire population possess a 'risk' for autism and if we could just eliminate the 60% of the general population that possess this common genetic variant, autism would just disappear.

IAN ought to get in on the 'New autism gene discovered! hysteria. IAN in one of the excellent research papers have identified another common genetic variant that occurs in approximately 50% of the general population that increases the risk for autism by a factor of between 4.2 and 9 times significantly greater than the 1.2 increased risk for autism in the chromosome 5 study.

This common genetic variant is the presence of XY sex chromosomes which significantly increases the risk for autism. The presence of another common genetic variant reported by IAN of XX sex chromosomes also significantly reduces the risk for autism. If we could just remove this common genetic variant (XY sex chromosomes) autism would disappear.

http://www.iancommunity.org/cs/ian_research_reports/ian_research_report_july_2007#Gender_Ratio

"I stand corrected however it still has not been looked at enough in my opinion. You look at some of these medications they are linking to autism, and it seems a lot of autistic people often go on those drugs later in life. So it begs the question are drugs doing something to them, or are their mothers just carrying the autism genes which don't manifest as autism but other stuff perhaps depression, or seizures etc. so they need the medications"

Actually Valproate Acid is contraindicted for use in pregnancy but is still in use.

Animal studies have also shown that prenatal exposure to Valproate Acid is associated with the same brain structural abnormalities reported in autism autopsy cases (Cerebellar pathology) and has been proposed as a useful animal model for autism.

http://www.ncbi.nlm.nih.gov/pubmed/9100317?

The resistance for any explanation for ASD etiology other than genetics accounts for the disinterest in the autism research community. The associations between ASD and any environmental cause have all come from researchers outside the close knit network of autism researchers.

A new study has examined the outcomes of 126 children diagnosed with Cerebral Palsy using universally accepted Gold Standard diasgnotic schemes for the presence of ASD's.

http://www.ncbi.nlm.nih.gov/pubmed/19335564?

Of 126 subjects 15% met diagnostic criteria for either Autistic Disorder or PDD/NOS using DSM-IV diagnostic criteria.

Adult stroke patients have also been consistently been shown, as a group, to be 'socially impaired'.

http://www.ncbi.nlm.nih.gov/pubmed/11796956?

All of these condition are associated with brain structural abnormalities with ASD and CP occuring during brain development and stroke affecting the fully developed brain.

My daughter, was diagnosed with PDD/NOS, and my Mom was diagnosed with stroke at age 73. At the time of diagnosis, the outlook for both was bleak. Remarkeably they both underwent many of the same evidenced based interventions, including speech and language therapy, occupational therapy and physical therapy.. and both had normal outcomes.

'One study proves nothing at all, it only means that we must look in that direction. You see until a study can be replicated then no one can be sure if it the truth or not'.

Actually, there are a dozen papers that have noted the association between prenatal exposure to valproate acid and Fetal Valproate Acid Syndrome, which is associated with poor developmental outcomes, including autism.

You can get a list of the refernces in The 2005 edition of the Handbook of Autism and Pervasive Developmental Disorders edited by Fred Volkmar (page 555 -556) who is also the editor of the Journal of Autism and Developmental Disorders.