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MAKING SENSE OF AUTISM
JOSEPH J. HALLETT, MD, AND VIREN D'SA, MD
Autistic disorder (AD) is a PODs are Rett's disorder, childhood to define with quantitative, objective
disorder of brain development. Its disintegrative disorder, Asperger's diagnostic criteria and to associate the
neuropathogenesis and etiology are disorder and PDD not otherwise phenotype with a biological marker.
thought to be heterogeneous and are specified (PDD NOS). POD NOS At present neither is available although
know in only a small fraction of cases. was included to allow clinicians to the Autistic Diagnostic Observation
Genes have a complex indirect and, indicate that a child had a behavioral Schedule (ADOS) offers a meaningful
to date, undefined role in AD. This phenotype that was similarto one of the advancement. Diagnostic criteria are
chronic neurologic disorder leaves defined PODs but did not meet the full based on a qualitative determination of
affected individuals dependent on their criteria for that disorder. In the next the severity of behavioral impairments,
families for life. revision of the DSM III infantile autism and demonstrating that a child has
was changed to autistic disorder(AD), the DSM IV prescribed number
TERMINOLOGY
the term used in subsequent editions, of impairments. This qualitative
Autism, autistic disorder and including the DSM IV. determination is subject to the
autistic spec'trum disorder need With the explosion of research confounding of observer bias and
definitions. They are best understood in the past 25 years, the concept marked rater-to-rater variance. This
from a historical perspective. has emerged that the behavioral confounding variance has been a
In 1943 Leo Kanner, a child characteristics observed in children recurring source of considerable
psychiatrist, described 11 children, with AD are not unique to AD but disagreement among physicians,
most from prosperous and well- are distributed in lesser forms and in a disagreement that no doubt has
educated parents (several were different combinations throughout a perplexed the PCP who is caring for
physicians) with "autistic disturbances the child and supporting the family.
of affected contact.'" He borrowed the The ADOS offers an observational
"AD AND THE
word autistic from the schizophrenia instrument to reduce the influence of
literature, where it denoted the self- OTHER PDDs ARE these confounding variables.
centered thinking, detached behaviors BEHAVIORALLY
and resulting isolation observed in AUTISTIC DISORDER
schizophrenia. Following his report, DEFINED SYNDROMES AD is a behaviorally defined
the term infantile autism emerged. THAT MEDICINE syndrome characterized by severe
Kanner's report received little impairments in social interaction, the
AND THE SCIENCES
attention in part because the behavioral social components of language and
phenotype was already subsumed ARE STRUGGLING inflexible and restricted behaviors or
under the diagnosis of childhood TO DEFINE WITH interests. A diagnosis is made based
schizophrenia. However, in the 1950s on a behavior phenotype defined in
the psychodynamic theorists resurrected QUANTITATIVE, DSM IV.' Since the diagnosis is based
his work and hypothesized that children OBJECTIVE on behaviors, the AD phenotype can
became autistic because they were not overlap with other disorders. For
DIAGNOSTIC
given appropriate emotional nurturing example, a large percent of children
by their "refrigerator" mothers. 2.3This CRITERIA ..." with tuberous sclerosis have the AD
approach to autism was the antithesis phenotype. Similarly, approximately
of Kanner's speculation that infantile population; AD behaviors represent 1% of children with AD have
autism had a biologic cause. Infantile a portion of this distribution. In the tuberous sclerosis. This overlap of
autism was formalized as a disorder 1990s the descriptive term, autistic phenotype is also seen with congenital
in 1980 when it was included in the spectrum disorder (ASD), was coined brain malformations and untreated
Diagnostic Statistic Manual, third in the experimental literature. The phenylketonuria. However, most cases
edition (DMS 111).4It was categorized term migrated into clinical literature of AD are idiopathic.
as a pervasive developmental disorder where it is often used as a diagnostic
(PPD), a group of behaviorally AUTISTIC SPECTRUM DISORDER
term even though a common clinical
defined syndromes that share the The basic behavioral traits that
definition has not been agreed upon.
characteristic of severe and pervasive comprise autism have not changed
disruption of development in "..social PERVASIVE DEVELOPMENTAL DISORDERS since Kanner reported them. However,
interaction skills, communication skills AD and the other PODs are the interpretation of these traits has
or the presence of stereotyped behavior, behaviorally defined syndromes that changed and so has the type of child
interests and activities."4 The other medicine and the sciences are struggling receiving an autism diagnosis. The
1
VOL. 88 NO.5 MAY 2005
broadest interpretation is represented disorders with shared neuropathological Organic, behavioral and emotional
by the term autistic spectrum disorder parameters is a question awaiting comorbidities are common. (Table 1)
(ASD). It assumes that autism is not clarifYing studies. AD has implications for the
a discreet disorder but should be Although the utility of ASD is debated, entire family. Mild language, social
viewed as a spectrum of conditions it has become a popular clinical term, or psychiatric problems can be present
or behaviors unified by impairments used to define a behavioral phenotype 1
in parents. 14. 5 Siblings have a greater,
in social interactions, communication without reference to pathogenesis or albeit small, risk of AD, language
and restricted behaviors or interests. etiology. An understanding of this disorder, learning disabilities, social
Since ASD is defined by behaviors is important because the use of ASD problems and psychiatric disorders.
and not by pathogenesis or causative must be accompanied by a vigorous
agent, a spectrum can include the diagnostic evaluation for treatable PREVALENCE
Kanner-type AD in which there is disorders. A rise in the prevalence of
severe and profound impairments as children with an autistic diagnosis has
well as mental retardation, to milder EPIDEMIOLOGY been established although a specific
cases such a POD NOS, to atypical The epidemiology of AD has Population
prevalence rate has not.12.16.17
cases such as high functioning AD not changed substantially from the studies in the 1980s and early 1990s
(AD with IQ> 70), to cases with no findings reported in the 1980s and found a prevalence ranging from 2 to
impairment of language development early 1990s. It is most often diagnosed 10 per 10,000 chiidren.13.17After 1994
and only mild impairments in social in males (male to female ratio of 4 to prevalence increased annually with
interaction and inflexibility such 1). Cases do not segregate by race, recent estimates reaching as high as 67
as in Asperger disorder, to children level of education, socioeconomic per 10,000 for ASD and 4 per 10,000
whose impairments in the past were status or geography. Behavioral signs for ADY Since 1994 Rhode Island
considered below diagnostic threshold typically appear before the age of has mirrored this trend in its special
for POD. The dilemma present by three.1o Delays in language (either education population.18 In 2003, 605
this approach is how to distinguish absence or slow progression) are the students with an autistic diagnosis
between ASD behavior and behavior most common presenting complaint. II were educated in Rhode Island schools.
that is eccentric, idiosyncratic or odd A small portion have regression after Understanding the factors behind this
which are in general considered within typical language development. Sixty rise in prevalence is critical to our
the range of normal. to seventy-five percent of the children understanding of AD and ASD.
Support for interpreting autism with AD have mental retardation.12.13 Population-based incidence studies,
as ASD comes from studies that find Cognitive deficits may be more using contemporary diagnostic criteria,
AD behavioral traits, albeit with severe in girls than boys although are believed to more accurately reflect
varying severity, distributed through approximately 40% of boys will have potential changes in the occurrence of
families of children with AD and in severe to profound mental retardation. disorders across time periods. One such
the general population.6. 7.8 Further
support comes from functional brain Table 1. Comorbidities in autistic disorder
imaging studies (fMRI) that found
similar activation patterns in adults Mental retardation (60-75%)
with high functioning autism and Epilepsy (5% in children, 30% in adults)
Asperger syndrome.9 On the other Phenylketonuria if untreated (5%)
hand, the term spectrum is most often Tuberous sclerosis «1 %)
used in the context of disorders that are Neurofibromatosis
clinically distinct and share a common Congenital malformations
etiology while varying in the severity of Cerebral palsy
symptoms. The validity of grouping Down syndrome
behaviorally defined phenotypes of Hearing impairments
potentially different etiologies has been Vision impairments
questioned. AD and the disorders Learning disabilities
subsumed under ASD are postulated Sleep disorder
to have heterogeneous etiologies which Self-injurious behaviors
open the possibility that the autistic Aggressive, angry or combative behaviors
behavioral phenotype may represent Oppositional behavior
a final common pathway for a variety Hyperkinetic behavior
of disorders. Determining whether Depression
an autistic phenotype represents the Anxiety
final common expression of distinct Obsessive compulsive disorder
disorders or represents a spectrum of Tics
DICINE AND HEAL.TH I RHODE ISL.AND
study in Olmsted County Minnesota
(OC) found increases in the incidence Table 2. Examples of disorders associated with
of AD from 0.55 per 10,000 children autistic disorder.
in 1980-1983 to 4.49 per 10,000
children in 1995-1997.17 A rising in utero exposure to rubella, CMV, valproate, thalidomide
incidence among young children was
responsible for most of the increased. neonatal or early infant insults (e.g., hypoxia, infection, trauma,
During the same period the incidence hypothyroidism)
among children older than 10 years of
brain malformations
age remained stable. Several putative
environmental agents, such as mercury
and vaccines, have been intensely chromosomal abnormalities (5%)
stUdied, but to date no environmental
agent has been identified to explain the Gene mutations (1-2%)
rise in incidence. Genetic and genomic 15q11-13 (Prader Willi/Angelman region) most frequent
stUdies have also failed to explain the fragile X mutation
nse. tuberous sclerosis
Prevalence stUdies assessing time phenylketonuria (if untreated)
trends are subject to inaccuracies that
in 1991. If this biased diagnosis, in the past but is now rare. Other causes
result from changes in diagnostic
stUdies ascertaining cases using school of AD include prenatal agents such as
criteria, inability to validate diagnoses
and increased awareness of the disorder data would be expected to identify infection and hypoxia. Although
across time, all of which have occurred a rise in prevalence. Support for several environmental agents have been
this possibility would be evidence of implicated as causative agents (e.g.,
in autism. I? 19.20 The broadening of
diagnosis swapping. Croen20 found mercury), stUdies have not provided
the diagnostic criteria can be seen in
the revisions of the DSM since infantile evidence of diagnosis swapping in supporting evidence.
autism was first included in 1980. The California, a state that has reported Current conceptUalization of the
use of ASD has broadened the criteria a dramatic rise in autism. A period role of genes in AD is that of imparting
of rising prevalence in AD saw a susceptibility but not causing AD.
still further. Public and physician
corresponding drop in the prevalence of Genetic heterogeneity is the operating
awareness has grown substantially. mental retardation without autism. hypothesis in studies with estimates
Validating the AD or ASD is short
The reasons for the disturbing rise of the number of involved genes
coming in many prevalence stUdies. A
in the prevalence of AD andASD do not ranging from 10-15. Four candidate
second stUdy of Minnesota children
suggest a meaningful rise in new cases susceptibility genes are currently under
(MS) illustrates the problems. This
but a rise due to diagnosis swapping, stUdy.22 (Table 3) Linkage stUdies
study found a greater increase in
an increased identification of cases have identified chromosomes 2, 7, 17,
prevalence, to 52 per 10,000, than the
and a broadening of diagnostic criteria 22 and X, but confirming stUdies have
OC stUdywhich measured incidence.21
to include cases that were considered given inconsistent results. Numerous
This difference can be explained in
below the diagnostic threshold in the candidate genes have been identified
part by the method of ascertaining
past. However, the possibility that a including most neurotransmitter
subjects and validation differences
between the two stUdies. In the OC portion of the rising prevalence results receptors and proteins for essential
from a true increased incidence in brain development (e.g., neuroligin,
study, investigators reviewed medical autism has not been excluded.
and school records to determine the reelin), but no candidate gene has
been consistently found in children
diagnosis of each subject using DSM ETIOLOGY with AD. This lack of clarity is
criteria. The MS stUdy used student
AD is categorized as either not inconsistent with overlapping
data reported to the department of
education. Such data do not allow idiopathic or secondary when the cause gene effects. Genes can be epistatic
is known. Approximately 90% of the (several genes influencing a behavior)
diagnostic validation.
cases are idiopathic. A cause of the AS or pleiotrophic (one gene influencing
The possibility that school data
can be identified in approximately 10%. several behaviors).
may be biased towards categorizing (Table 2) Chromosomal abnormalities
students as autistic is suggested by the account for 5% of the secondary INHERITANCE
timing of the initial rise in prevalence The inheritance of idiopathic AD
AD. Duplication in the Prader Willi/
(between 1991 and 1994 in most
Angelman region (15qll-13) is the is complex and non-mendelian. No
stUdies). Coincident with the initial
most frequent gene mutation. Untreated single inheritance pattern has been
rise was the inclusion of autism in the
phenylketonuria was responsible a recognized. Inheritance is thought to be
list of disabilities eligible for federally multifactoral involving the interaction
considerable portion of secondary AD
mandated special education services
VOL. 88 NO.5 MAY2(
neuronal morphology and number,
Table 3. Candidate autism susceptibility genes synaptic abnormalities and dysfunctional
pathways as a consequence.
chromosome locus
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17. Barbaresi W, Katusic S, et al. Arch Pediatr
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that AD had a biological cause. He autistic individuals. 51.
supported his speculation by observing Of particular interest is the serotonin
that severalchildren had largeheads. His system: 30% of children with AD have Joseph H Hallett, MD, is Physician-
observation of macrocephaly has been elevated platelet serotonin. Whether this in-Chief, Department of Pediatrics,
confirmed by anthropomorphic and contributes to the neuropathogenesis of Memorial Hospital of Rhode Island, and
neuroimaging studies. Macrocephaly is AD or is an incidental finding will {Clinical}of Pediatrics,
AssociateProfessor
present in 20% of the children with AD, require further stUdy. Brown Medical School.
appears late in the first year and resolves Studies of the autistic brain have VirenD'Sa, MD, isa Developmental
by five years old in most children. The produced heterogeneous collections Behavioral Pediatric Fellow,
high incidence of seizures and mental of findings most likely the result of Neurodevelopmental Center, Department
retardation provides further evidence its heterogeneous etiologies. The of Pediatrics, Memorial Hospital
for a neuropathogenesis. picture that appears to be emerging is
StUdies to elucidate abnormal disruption of early brain development Correspondence:
brain regions in AD have produced with subsequent abnormalities in Joseph J. Hallett, MD
f6
MEDICINE AND HEAL.TH I RHODE ISL.AND
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