Researcher in Developmental & Behavioral Neuroanatomy
December 25, 2009
A recently published abstract from
researchers at the Children's Hospital of Philadelphia (CHOP) states
that the increased rate of autism-spectrum disorders "might be
attributable to factors such as new administrative classifications,
policy and practice changes, and increased awareness" (1). However,
that the researchers selected and presented that concept and rhetoric
while failing to state the other main option - environmental factors
contributing substantially to the increase - is a form of bias by
choice of rhetoric, especially when presented in an abstract that will
be read far more widely than will the full text of the article.
In the very least, we might take heart in the fact that the CHOP
authors' use of the word "might" implicitly implies "might not". And
fortunately, many researchers are beginning to describe complex
interactions accurately. As examples preferable to the CHOP
researchers' glibness, Pessah & colleagues write, "genetic,
epigenetic, and environmental factors that might act in concert to
influence autism risk, severity and co-morbidities, and immunological
and neurobiological targets as etiologic contributors." (12) While
Geier and colleagues offer, "Emerging evidence supports the theory that
some autism spectrum disorders (ASDs) may result from a combination of
genetic/biochemical susceptibility, specifically a reduced ability to
excrete mercury (Hg), and exposure to Hg at critical developmental
In further contrast to the CHOP researchers' invocation of the
establishmentarian myth that the autism epidemic "Must be better
diagnosis", many of us have heard observations from long-term
elementary-school teachers and from long-term special-education
teachers who report that in prior decades, there weren't nearly so many
affected children. Importantly, a study which evaluated how much of
autism-rate increase derives from increased awareness, diagnostic
changes, etc, versus an actual increase concluded that much of
California's increased rate of precisely categorized autism was real
(2, see also 3).
Another cleverness is noteworthy in the CHOP researchers' abstract's
propagandistic rhetoric. The authors use common phraseology for DSM-IV
autism - "severe deficits in socialisation, communication, and
repetitive or unusual behaviour" (1). With this word usage, the authors
lump a diagnostic summary for DSM-IV autism within the often confusing
category "autism spectrum disorders" [sic] and have thereby slurred
over important differences among DSM-IV autism, Asperger's syndrome,
and DSM-IV PDD/NOS. In contrast, more accurate phraseology is offered
by Nassar et al, who offer "autism spectrum disorders (ASDs), which
include autism, Asperger syndrome and pervasive developmental disorder
not otherwise specified (PDD-NOS)" and also by Bryson et al, who looked
within ASD subgroups, retained clarity of diagnostic categories, and
wrote, "Children with autism were compared to children with other ASDs
- Asperger's disorder, Rett's disorder, and PDD-NOS."
Claiming that the epidemic of autism and other ASDs is merely an
artifice of better diagnosis and increased awareness is to turn
attention away from the real-increase observed by long-term teachers
and by astute researchers (eg, 2) and also turns attention away from
increasing documentation of environmental factors associated with
autism and with increased rates of autism (eg, 6-9, see also reviews in
Blurring important differences between diagnostic
categories (1) hinders the search for subgroup-specific etiologies and
for subgroup-specific treatments (eg, 14-15).
Levy SE, Mandell DS, Schultz RT.
Children's Hospital of Philadelphia
Lancet. 2009 Nov 7;374(9701):1627-38. Epub 2009 Oct 12.
Autism spectrum disorders are characterised by severe deficits in
socialisation, communication, and repetitive or unusual behaviours.
Increases over time in the frequency of these disorders (to present
rates of about 60 cases per 10,000 children) might be attributable to
factors such as new administrative classifications, policy and practice
changes, and increased awareness. Surveillance and screening strategies
for early identification could enable early treatment and improved
outcomes. Autism spectrum disorders are highly genetic and
multifactorial, with many risk factors acting together. Genes that
affect synaptic maturation are implicated, resulting in neurobiological
theories focusing on connectivity and neural effects of gene
expression. Several treatments might address core and comorbid
symptoms. However, not all treatments have been adequately studied.
Improved strategies for early identification with phenotypic
characteristics and biological markers (eg, electrophysiological
changes) might hopefully improve effectiveness of treatment. Further
knowledge about early identification, neurobiology of autism, effective
treatments, and the effect of this disorder on families is needed.
2. The rise in autism and the role of age
Hertz-Picciotto I, Delwiche L.
Epidemiology. 2009 Jan;20(1):84-90.
BACKGROUND: Autism prevalence in California, based on individuals
eligible for state-funded services, rose throughout the 1990s. The
extent to which this trend is explained by changes in age at diagnosis
or inclusion of milder cases has not been previously evaluated.
METHODS: Autism cases were identified from 1990 through 2006 in
databases of the California Department of Developmental Services, which
coordinates services for individuals with specific developmental
disorders. The main outcomes were population incident cases younger
than age 10 years for each quarter, cumulative incidence by age and
birth year, age-specific incidence rates stratified by birth year, and
proportions of diagnoses by age across birth years. RESULTS: Autism
incidence in children rose throughout the period. Cumulative incidence
to 5 years of age per 10,000 births rose consistently from 6.2 for 1990
births to 42.5 for 2001 births. Age-specific incidence rates increased
most steeply for 2- and 3-year olds. The proportion diagnosed by age 5
years increased only slightly, from 54% for 1990 births to 61% for 1996
births. Changing age at diagnosis can explain a 12% increase, and
inclusion of milder cases, a 56% increase. CONCLUSIONS: Autism
incidence in California shows no sign yet of plateauing. Younger ages
at diagnosis, differential migration, changes in diagnostic criteria,
and inclusion of milder cases do not fully explain the observed
increases. Other artifacts have yet to be quantified, and as a result,
the extent to which the continued rise represents a true increase in
the occurrence of autism remains unclear.
3. Prevalence of autism spectrum disorders
--- autism and developmental disabilities monitoring network, United
Autism and Developmental Disabilities Monitoring Network Surveillance
Year 2006 Principal Investigators.
MMWR Surveill Summ. 2009 Dec 18;58(10):1-20.
Problem/Condition: Autism spectrum disorders (ASDs) are a group of
developmental disabilities characterized by atypical development in
socialization, communication, and behavior. ASDs typically are apparent
before age 3 years, with associated impairments affecting multiple
areas of a person's life. Because no biologic marker exists for ASDs,
identification is made by professionals who evaluate a child's
developmental progress to identify the presence of developmental
disorders. Reporting Period: 2006. Methods: Earlier surveillance
efforts indicated that age 8 years is a reasonable index age at which
to monitor peak prevalence. The identified prevalence of ASDs in U.S.
children aged 8 years was estimated through a systematic retrospective
review of evaluation records in multiple sites participating in the
Autism and Developmental Disabilities Monitoring (ADDM) Network. Data
were collected from existing records in 11 ADDM Network sites (areas of
Alabama, Arizona, Colorado, Florida, Georgia, Maryland, Missouri, North
Carolina, Pennsylvania, South Carolina, and Wisconsin) for 2006. To
analyze changes in identified ASD prevalence, CDC compared the 2006
data with data collected from 10 sites (all sites noted above except
Florida) in 2002. Children aged 8 years with a notation of an ASD or
descriptions consistent with an ASD were identified through screening
and abstraction of existing health and education records containing
professional assessments of the child's developmental progress at
health-care or education facilities. Children aged 8 years whose
parent(s) or legal guardian(s) resided in the respective areas in 2006
met the case definition for an ASD if their records documented
behaviors consistent with the Diagnostic and Statistical Manual of
Mental Disorders, 4th edition, text revision (DSM-IV-TR) criteria for
autistic disorder, pervasive developmental disorder--not otherwise
specified (PDD NOS), or Asperger disorder. Presence of an identified
ASD was determined through a review of data abstracted from
developmental evaluation records by trained clinician reviewers.
Results: For the 2006 surveillance year, 2,757 (0.9%) of 307,790
children aged 8 years residing in the 11 ADDM sites were identified as
having an ASD, indicating an overall average prevalence of 9.0 per
1,000 population (95% confidence interval [CI] = 8.6--9.3). ASD
prevalence per 1,000 children aged 8 years ranged from 4.2 in Florida
to 12.1 in Arizona and Missouri, with prevalence for the majority of
sites ranging between 7.6 and 10.4. For 2006, ASD prevalence was
significantly lower in Florida (p<0.001) and Alabama (p<0.05) and
higher in Arizona and Missouri (p<0.05) than in all other sites. The
ratio of males to females ranged from 3.2:1 in Alabama to 7.6:1 in
Florida. ASD prevalence varied by type of ascertainment source, with
higher average prevalence in sites with access to health and education
records (10.0) compared with sites with health records only (7.5).
Although parental or professional concerns regarding development before
age 36 months were noted in the evaluation records of the majority of
children who were identified as having an ASD, the median age of
earliest documented ASD diagnosis was much later (range: 41 months
[Florida]--60 months [Colorado]). Of 10 sites that collected data for
both the 2002 and 2006 surveillance years, nine observed an increase in
ASD prevalence (range: 27%--95% increase; p<0.01), with increases
among males in all sites and among females in four of 11 sites, and
variation among other subgroups. Interpretation: In 2006, on average,
approximately 1% or one child in every 110 in the 11 ADDM sites was
classified as having an ASD (approximate range: 1:80--1:240 children
[males: 1:70; females: 1:315]). The average prevalence of ASDs
identified among children aged 8 years increased 57% in 10 sites from
the 2002 to the 2006 ADDM surveillance year. Although improved
ascertainment accounts for some of the prevalence increases documented
in the ADDM sites, a true increase in the risk for children to develop
ASD symptoms cannot be ruled out. On average, although delays in
identification persisted, ASDs were being diagnosed by community
professionals at earlier ages in 2006 than in 2002. Public Health
Actions: These results indicate an increased prevalence of identified
ASDs among U.S. children aged 8 years and underscore the need to regard
ASDs as an urgent public health concern. Continued monitoring is needed
to document and understand changes over time, including the multiple
ascertainment and potential risk factors likely to be contributing.
Research is needed to ascertain the factors that put certain persons at
risk, and concerted efforts are essential to provide support for
persons with ASDs, their families, and communities to improve long-term
4. Autism spectrum disorders in young
children: effect of changes in diagnostic practices.
Nassar N et al.
Int J Epidemiol. 2009 Oct;38(5):1245-54. Epub 2009 Sep 7.
BACKGROUND: It is unclear whether the increase in autism over the past
two decades is a real increase or due to changes in diagnosis and
ascertainment of autism spectrum disorders (ASDs), which include
autism, Asperger syndrome and pervasive developmental disorder not
otherwise specified (PDD-NOS)... CONCLUSIONS: The rise in incidence of
all types of ASDs by year of diagnosis appears to be related to changes
in diagnostic and service provision practices in WA. In children aged
5. Characteristics of children with autism
spectrum disorders who received services through community mental
Bryson SA, Corrigan SK, McDonald TP, Holmes C.
Autism. 2008 Jan;12(1):65-82.
Despite the presence of significant psychiatric comorbidity among
children with autism spectrum disorders (ASDs), little research exists
on those who receive community-based mental health services. This
project examined one year (2004) of data from the database maintained
by 26 community mental health centers (CMHCs) in the Midwestern US
state of Kansas. Children with autism were compared to children with
other ASDs - Asperger's disorder, Rett's disorder, and PDD-NOS.
Children with autism predictably received more special education
services than children with other ASDs, while the latter were more
likely to have experienced prior psychiatric hospitalization. Children
with ASDs other than autism were also significantly more likely to be
diagnosed with attention deficit hyperactivity disorder, oppositional
defiant disorder, depressive disorders, and bipolar disorder. In 2004,
Kansas CMHCs served less than 15 percent of the children estimated to
have an ASD. Implications of these findings are discussed.
6. Environmental mercury release, special
education rates, and autism disorder: an ecological study of
Palmer RF et al. Health Place. 2006 Jun;12(2):203-9.
The association between environmentally released mercury, special
education and autism rates in Texas was investigated using data from
the Texas Education Department and the United States Environmental
Protection Agency. A Poisson regression analysis adjusted for school
district population size, economic and demographic factors was used.
There was a significant increase in the rates of special education
students and autism rates associated with increases in environmentally
released mercury. On average, for each 1,000 lb of environmentally
released mercury, there was a 43% increase in the rate of special
education services and a 61% increase in the rate of autism. The
association between environmentally released mercury and special
education rates were fully mediated by increased autism rates. This
ecological study suggests the need for further research regarding the
association between environmentally released mercury and developmental
disorders such as autism. These results have implications for policy
planning and cost analysis.
7. Proximity to point sources of
environmental mercury release as a predictor of autism
Palmer RF et al. Health Place. 2009 Mar;15(1):18-24.
The objective of this study was to determine if proximity to sources of
mercury pollution in 1998 were related to autism prevalence in 2002.
Autism count data from the Texas Educational Agency and environmental
mercury release data from the Environmental Protection Agency were
used. We found that for every 1000 pounds of industrial release, there
was a corresponding 2.6% increase in autism rates (p<.05) and a 3.7%
increase associated with power plant emissions(P<.05). Distances to
these sources were independent predictors after adjustment for relevant
covariates. For every 10 miles from industrial or power plant sources,
there was an associated decreased autism Incident Risk of 2.0% and
1.4%, respectively (p<.05). While design limitations preclude
interpretation of individual risk, further investigations of
environmental risks to child development issues are warranted.
8. Autism spectrum disorders in relation to
distribution of hazardous air pollutants in the san francisco bay
Windham GC et al. Environ Health Perspect. 2006 Sep;114(9):1438-44.
OBJECTIVE: To explore possible associations between autism spectrum
disorders (ASD) and environmental exposures, we linked the California
autism surveillance system to estimated hazardous air pollutant (HAP)
concentrations compiled by the U.S. Environmental Protection Agency.
METHODS: Subjects included 284 children with ASD and 657 controls, born
in 1994 in the San Francisco Bay area. We assigned exposure level by
census tract of birth residence for 19 chemicals we identified as
potential neurotoxicants, developmental toxicants, and/or endocrine
disruptors from the 1996 HAPs database. Because concentrations of many
of these were highly correlated, we combined the chemicals into
mechanistic and structural groups, calculating summary index scores. We
calculated ASD risk in the upper quartiles of these group scores or
individual chemical concentrations compared with below the median,
adjusting for demographic factors. RESULTS: The adjusted odds ratios
(AORs) were elevated by 50% in the top quartile of chlorinated solvents
and heavy metals [95% confidence intervals (CIs) , 1.1-2.1], but not
for aromatic solvents. Adjusting for these three groups simultaneously
led to decreased risks for the solvents and increased risk for metals
(AORs for metals: fourth quartile = 1.7 ; 95% CI, 1.0-3.0 ; third
quartile = 1.95 ; 95% CI, 1.2-3.1) . The individual compounds that
contributed most to these associations included mercury, cadmium,
nickel, trichloroethylene, and vinyl chloride. CONCLUSIONS: Our results
suggest a potential association between autism and estimated metal
concentrations, and possibly solvents, in ambient air around the birth
residence, requiring confirmation and more refined exposure assessment
in future studies.
9. Hepatitis B triple series vaccine and
developmental disability in US children aged 1-9
Gallagher C, Goodman M. Toxicol Environ Chem 2008 90(5):997-1008.
This study investigated the association between vaccination with the
Hepatitis B triple series vaccine prior to 2000 and developmental
disability in children aged 1-9 years (n = 1824), proxied by parental
report that their child receives early intervention or special
education services (EIS). National Health and Nutrition Examination
Survey 1999-2000 data were analyzed and adjusted for survey design by
Taylor Linearization using SAS version 9.1 software, with SAS callable
SUDAAN version 9.0.1. The odds of receiving
EIS were approximately nine times as great for vaccinated boys (n = 46)
as for unvaccinated boys (n = 7), after adjustment for
confounders. This study found statistically significant evidence to
suggest that boys in United States who were vaccinated with the triple
series Hepatitis B vaccine, during the time period in which vaccines
were manufactured with thimerosal, were more susceptible to
developmental disability than were unvaccinated boys.
10. Environmental risk factors for autism: Do they help cause de novo
genetic mutations that contribute to the disorder?
Dennis K. Kinney et al.
Med Hypotheses. 2010 Jan;74(1):102-6.
Recent research has discovered that a number of genetic risk factors
for autism are de novo mutations. Advanced parental age at the time of
conception is associated with increased risk for both autism and de
novo mutations. We investigated the hypothesis that other environmental
factors associated with increased risk for autism might also be
mutagenic and contribute to autism by causing de novo mutations. A
survey of the research literature identified 9 environmental factors
for which increased pre-conceptual exposure appears to be associated
with increased risk for autism. Five of these factors--mercury,
cadmium, nickel, trichloroethylene, and vinyl chloride--are established
mutagens. Another four--including residence in regions that are
urbanized, located at higher latitudes, or experience high levels of
precipitation--are associated with decreased sun exposure and increased
risk for vitamin D deficiency. Vitamin D plays important roles in
repairing DNA damage and protecting against oxidative stress--a key
cause of DNA damage. Factors associated with vitamin D deficiency will
thus contribute to higher mutation rates and impaired repair of DNA. We
note how de novo mutations may also help explain why the concordance
rate for autism is so markedly higher in monozygotic than dizygotic
twins. De novo mutations may also explain in part why the prevalence of
autism is so remarkably high, given the evidence for a strong role of
genetic factors and the low fertility of individuals with autism--and
resultant selection pressure against autism susceptibility genes. These
several lines of evidence provide support for the hypothesis, and
warrant new research approaches--which we suggest--to address
limitations in existing studies. The hypothesis has implications for
understanding possible etiologic roles of de novo mutations in autism,
and it suggests possible approaches to primary prevention of the
disorder, such as addressing widespread vitamin D deficiency and
exposure to known mutagens.
11. Similarities in features of autism and
asthma and a possible link to acetaminophen use
Kevin G. Becker, Stephen T. Schultz
Medical Hypotheses 74 (2010) 7–11
Autism and autism spectrum disorders are enigmatic conditions that have
their origins in the interaction of genes and environmental factors. In
this hypothesis, genes statistically associated with autism are
emphasized to be important in inflammation and in innate immune
pathways, including pathways for susceptibility to asthma. The role of
acetaminophen (paracetamol) in an increased risk for asthma is
described and a possible similar link to an increased risk for autism
12. Immunologic and neurodevelopmental
susceptibilities of autism.
Pessah IN et al.
Neurotoxicology. 2008 May;29(3):532-45.
Symposium 5 focused on research approaches that are aimed at
understanding common patterns of immunological and neurological
dysfunction contributing to neurodevelopmental disorders such as autism
and ADHD. The session focused on genetic, epigenetic, and environmental
factors that might act in concert to influence autism risk, severity
and co-morbidities, and immunological and neurobiological targets as
etiologic contributors. The immune system of children at risk of autism
may be therefore especially susceptible to psychological stressors,
exposure to chemical triggers, and infectious agents. Identifying early
biomarkers of risk provides tangible approaches toward designing
studies in animals and humans that yield a better understanding of
environmental risk factors, and can help identify rational intervention
strategies to mitigate these risks.
13. A comprehensive review of mercury
Geier DA et al.
Indian J Med Res. 2008 Oct;128(4):383-411.
Emerging evidence supports the theory that some autism spectrum
disorders (ASDs) may result from a combination of genetic/biochemical
susceptibility, specifically a reduced ability to excrete mercury (Hg),
and exposure to Hg at critical developmental periods.
Elemental/inorganic Hg is released into the air/water where it becomes
methylated and accumulates in animal tissues. The US population is
primarily exposed to methyl-Hg by fish consumption. In addition, many
pharmaceuticals have been, and some continue to be, a ubiquitous source
of danger because they contain mercurials. Mercurials may be found in
drugs for the eye, ear, nose, throat, and skin; in bleaching creams; as
preservatives in cosmetics, tooth pastes, lens solutions, vaccines,
allergy test and immunotherapy solutions; in antiseptics,
disinfectants, and contraceptives; in fungicides and herbicides; in
dental fillings and thermometers; and many other products. Hg has been
found to cause immune, sensory, neurological, motor, and behavioural
dysfunctions similar to traits defining/associated with ASDs, and that
these similarities extend to neuroanatomy, neurotransmitters, and
biochemistry. Furthermore, a review of molecular mechanisms indicates
that Hg exposure can induce death, disorganization and/or damage to
selected neurons in the brain similar to that seen in recent ASD brain
pathology studies, and this alteration may likely produce the symptoms
by which ASDs are diagnosed. Finally, a review of treatments suggests
that ASD patients who undergo protocols to reduce Hg and/or its effects
show significant clinical improvements in some cases. In conclusion,
the overwhelming preponderance of the evidence favours acceptance that
Hg exposure is capable of causing some ASDs.
14. Novel clustering of items from the
Autism Diagnostic Interview-Revised to define phenotypes within autism
Hu VW, Steinberg ME.
Autism Res. 2009 Apr;2(2):67-77.
Heterogeneity in phenotypic presentation of Autism spectrum disorders
has been cited as one explanation for the difficulty in pinpointing
specific genes involved in autism. Recent studies have attempted to
reduce the "noise" in genetic and other biological data by reducing the
phenotypic heterogeneity of the sample population. The current study
employs multiple clustering algorithms on 123 item scores from the
Autism Diagnostic Interview-Revised (ADI-R) diagnostic instrument of
nearly 2,000 autistic individuals to identify subgroups of autistic
probands with clinically relevant behavioral phenotypes in order to
isolate more homogeneous groups of subjects for gene expression
analyses. Our combined cluster analyses suggest optimal division of the
autistic probands into four phenotypic clusters based on similarity of
symptom severity across the 123 selected item scores. One cluster is
characterized by severe language deficits, while another exhibits
milder symptoms across the domains. A third group possesses a higher
frequency of savant skills while the fourth group exhibited
intermediate severity across all domains. Grouping autistic individuals
by multivariate cluster analysis of ADI-R scores reveals meaningful
phenotypes of subgroups within the autistic spectrum, which we show, in
a related (accompanying) study, to be associated with distinct gene
15. Gene expression profiling
differentiates autism case-controls and phenotypic variants of autism
spectrum disorders: evidence for circadian rhythm dysfunction in severe
Hu VW et al.
The George Washington University Medical Center
Autism Res. 2009 Apr;2(2):78-97.
Autism spectrum disorders (ASD) are neurodevelopmental disorders
characterized by delayed/abnormal language development, deficits in
social interaction, repetitive behaviors and restricted interests. The
heterogeneity in clinical presentation of ASD, likely due to different
etiologies, complicates genetic/biological analyses of these disorders.
DNA microarray analyses were conducted on 116 lymphoblastoid cell lines
(LCL) from individuals with idiopathic autism who are divided into
three phenotypic subgroups according to severity scores from the
commonly used Autism Diagnostic Interview-Revised questionnaire and
age-matched, nonautistic controls. Statistical analyses of gene
expression data from control LCL against that of LCL from ASD probands
identify genes for which expression levels are either quantitatively or
qualitatively associated with phenotypic severity. Comparison of the
significant differentially expressed genes from each subgroup relative
to the control group reveals differentially expressed genes unique to
each subgroup as well as genes in common across subgroups. Among the
findings unique to the most severely affected ASD group are 15 genes
that regulate circadian rhythm, which has been shown to have multiple
effects on neurological as well as metabolic functions commonly
dysregulated in autism. Among the genes common to all three subgroups
of ASD are 20 novel genes mostly in putative noncoding regions, which
appear to associate with androgen sensitivity and which may underlie
the strong 4:1 bias toward affected males.
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