Handbook of Clinical Neurology, Vol.

174 (3rd series)

Neurocognitive Development: Disorders and Disabilities
A. Gallagher, C. Bulteau, D. Cohen and J.L. Michaud, Editors
https://doi.org/10.1016/B978-0-444-64148-9.00010-7
Copyright © 2020 Elsevier B.V. All rights reserved

Chapter 10

Autism spectrum disorder

LAURENT MOTTRON*

Department of Psychiatry and Addictology, University of Montreal, Montreal, QC, Canada

Abstract
Autism is a frequent, precocious behavioral constellation of social and communicative atypicalities asso-
ciated with apparently restricted interests and repetitive behavior and paired with an uneven ability profile.
Its definition has constantly broadened in the past 75 years, introducing phenotypes increasingly distant
from its initial description, heterogeneous in intelligence and speech level, and associated conditions.
When it is unassociated with other conditions, its origin is mostly genetic, transmissible, and favored
by frequent polymorphisms with small effects present in the general population. Identified de novo rare
mutations with large deleterious effects produce phenotypes only loosely related to nonsyndromic autism.
Autism is associated with brain reorganization at multiple levels, and with a variant of typical information
processing, i.e., the way humans perceive, memorize, manipulate, and attribute emotional value to avail-
able information. Its phenotype evolves over the span of life, with an overall reduction of autistic signs, but
it still requires some level of support. There is no treatment for this condition; however, it is compatible
with high levels of integration into society.

described and then elaborated on in Kanner’s follow-

DEFINITION
Autism is a precocious behavioral constellation of
social and communicative atypicalities associated with
apparently restricted interests and repetitive behavior
(RIRB) and paired with an uneven ability profile. It is
still considered a behavioral syndrome 75 years after
its initial recognition by Kanner (1943) and under
a different form by Asperger (1944). Kanner’s and
Asperger’s views on autism were relatively clear-cut;
their initial definition summarized the particularities
presented in 11 children (4 for Asperger) who were
clearly distinguishable from their peers. None of the
children described by Kanner and Asperger had a recog-
nizable neurologic genetic syndrome in addition to
autism. All had strong speech atypicalities and/or delay.
None of these children were considered to be intellectu-
ally disabled, but their intelligence manifested itself in
an atypical way. Autism was stable over time, though
some developmental transformations were originally
up papers. Although the autism category is historically
centered on an easily recognizable clinical presentation,
its extension, following accepted definitions, now
encompasses a spectrum of presentations that vary in
adaptive level, neurogenetic alterations, and similarity
with the initial clinical image described by both Kanner
and Asperger in the middle of the 20th century. We still
ignore if the current autism category represents one, sev-
eral, or an indefinite number of “natural categories”
(Hollin, 2017).
The definition of autism is grounded on clusters of
positive and negative clinical traits related to the social
character and variety of overt behavior (symptoms), a
situation that requires agreement among experts. In the
DSM-5 (2013) categorical definition of “autism spec-
trum disorder,” sociocommunicative symptoms should
include quantitative or qualitative alteration in social
communication and social interaction across multiple
contexts, as manifested by deficits in social–emotional

*Correspondence to: Laurent Mottron, M.D., Ph.D., MACSS/FCAHS, Department of Psychiatry and Addictology, University
of Montreal, H^opital en sante mentale Rivière-des-Prairies 7070, boul. Perras, 3rd floor, Montreal, QC, Canada H1E 1A4.
Tel: +1-514-972-4841, E-mail: laurent.mottron@gmail.com
128 L. MOTTRON
reciprocity and nonverbal communicative behaviors
used for social interaction, as well as developing, main-
taining, and understanding relationships. Furthermore,
two symptoms of restricted, repetitive patterns of behav-
ior, interests, or activities should be present, among a
list of four: stereotypical or repetitive motor movements,
use of objects, or speech; insistence on sameness, inflex-
ible adherence to routines, or ritualized patterns or verbal
nonverbal behavior; highly restricted, fixated interests
that are abnormal in intensity or focus; and hyper- or
hyporeactivity to sensory input or unusual interests in
sensory aspects of the environment. It encompasses the
previous DSM-IV (1994) definition of autistic disorder,
Asperger syndrome, and pervasive developmental disor-
ders not otherwise specified. Symptoms must be present
in the early developmental period and cause clinically
significant impairment in present functioning. Intellec-
tual disability is the only differential diagnosis when it
can by itself explain the major part of the clinical pre-
sentation. The heterogeneity of the autism spectrum is
intrinsic in its current definition, which reciprocally con-
tributes to maintaining it (Mottron & Bzdock, 2020).
While no autism subtypes are identified in DSM-5
(as Asperger syndrome was in DSM-IV, a form of autism
without speech delay or impairment and excluding
measured intellectual disability), four clinical specifiers
are proposed: level of cognitive functioning, associated
comorbid neurogenetic or psychiatric conditions, lan-
guage level, and severity, identified as the level of assis-
tance required for functioning. Each of these specifiers
can be considered a quasidimensional variable, which
results in extreme phenotypic variations, theoretically
not interfering with the categorical diagnosis. Intelli-
gence can vary from the lowest levels, where a clinically
significant distinction between autism and intellectual
disability can be made, conventionally around 18 months
of mental age, to the highest levels, where clinical
distinction between atypicality resulting from giftedness
and autism may be challenging. Language level is a
major factor of heterogeneity and characterized two
subgroups in DSM-IV, with (autism) and without
(Asperger) structural and/or developmental language
atypicalities (Mottron, 2020). Autism is probably the
only neurodevelopmental condition where speech can
vary from being inexistent to being perfect. The comor-
bidity specifier comprises conditions associated with
neurogenetics and psychiatry. The recognition of an
inventory of diagnosable conditions associated with an
autistic-like phenotype has resulted in the addition of
another 10%–15% of individuals now described as
showing syndromic, etiologic, or secondary autism, in
contrast with idiopathic or primary autism where there
are no identifiable syndromes apart from autism, or
only mutations that cannot be causally related to
autism. Autistic people, particularly adults, also present
identifiable psychiatric conditions that extend from call-
ing the same condition another name (for instance, most
autistic people being positive for the current criteria of
avoidant personality disorder or speech disorder) to an
actual, independent condition such as anxiety or mood
disorder. Last the severity specifier indicates that, besides
the mandatory presence of a significant impairment, the
level of adaptation may vary dramatically but must be at
least “clinically significant.”
PREVALENCE
Autism was thought to be rare: the first attempt at
epidemiology revealed a prevalence of only 4/10,000.
It is now common and composed of a spectrum of clinical
presentations, with considerable variability. Clinicians
and researchers now must conciliate this variability with
demands for categorical diagnosis required by the devel-
opment of research and the pressure of social recognition
and service allocation. Variation in prevalence of autism
has not been dramatic per se (reported as 2/1000 in
numerous studies published starting in the mid-1990s),
given deliberate increases in public awareness, planned
increases in availability of services (including diagnostic
services), and a purposeful improvement in case finding
(Gernsbacher et al., 2005). Within the same study sam-
ple, using the same standardized diagnostic instruments
(SDIs), the same diagnosing clinicians, and so on, differ-
ences in diagnostic definition, some of them very subtle,
can be responsible for a fourfold difference in prevalence
estimates (Baird et al., 2006).
Several characteristics of the autistic phenotype
relevant for epidemiological studies reveal by their var-
iability the extent to which the current delineation of
the autistic spectrum phenotype is malleable. Sex ratio
ranges from a quasibalance between boys and girls in
the case of children with secondary autism who are con-
sidered intellectually disabled, to as many as 10 boys for
one girl in the case of children with Asperger syndrome.
As a sex ratio in favor of males is accepted as an impor-
tant component of the autistic phenotype, this suggests
that primary and secondary autism are of a different
nature, or that syndromic autism is a phenocopy of
primary autism. However, this sex ratio is measured on
a population detected using diagnostic criteria identical
for both sexes, assuming that autism is expressed
identically in males and females. Questioning this
assumption has resulted in the diminishing of the
male dominance in the sex ratio to two to three males
for one female (Loomes et al., 2017) but does not
completely suppress it. It also resulted in the emergence
of a large number of self-diagnosed women, based on
the notion of invisible autism, which is questionable
(Halladay et al., 2015). The proportion of autistics
 AUTISM SPECTRUM DISORDER
regarded as intellectually disabled has fluctuated greatly
through the decades, depending on how autism has
been defined and intelligence measured. The recognition
of the partial overlap between Asperger syndrome and
Kanner’s autism had the effect of adding to the initial
autism category a group with nondelayed speech
development but showing signs in the social and RIRB
areas similar to those encountered in autism.
The current reported prevalence of epilepsy ranges
from 5% to 40% in autistic individuals. Like sex
ratio and intellectual disability, it differs considerably
according to whether autism is etiologic or idiopathic.
Currently, there are no studies on the prevalence of
epilepsy in samples with measured intelligence in the
normal range and from which secondary autism has
been excluded. Clinical evidence is in the direction
of a prevalence of epilepsy in this population that is
not much higher than in the nonautistic population.
The often-repeated figure of 20%–30% is clearly an
overestimate, and would, if anything, characterize
only secondary autism, where epilepsy is considerably
more frequent, as well as microcephaly and intellectual
disability (Amiet et al., 2008). This aggregation, along
with the aforementioned gender balance, points again
toward a separate status for primary and secondary
autism. In sum, uncertainty about the prevalence of
autism and its major neurologic and demographic corre-
lations is a consequence of current standards of clinical
phenotype delineation, the absence of exclusion criteria
toward other neurodevelopmental conditions, and the
arbitrary nature of any categorical delimitation in the
distribution of continuous behavioral phenotypic traits.
The heterogeneity of individuals currently encompassed
under the DSM-5 autism spectrum disorder (ASD) cri-
teria should not be considered as a fact informative on
the neurobiologic mechanisms producing autism, but
as the result of a checklist identification strategy based
on consensual criteria, rather than on the recognition of
one or several prototypes.
POSITIVE DIAGNOSIS
Autism tends to be suspected first by parents or some-
times by others such as daycare staff. General physicians,
pediatricians, child psychiatrists, and increasingly
specialized autism clinics confirm the diagnosis. Any
reference channel that results in half of the referred
individual being diagnosed at the end of the process
is reliable, if the people not diagnosed are properly
oriented, and screening should not try to combine spec-
ificity and sensitivity. The diagnosis and assessment of
ASDs requires about 2 days of multidisciplinary investi-
gations. It involves the combined use of standardized
instruments, clinical expertise, neurocognitive, speech,
129
and motor assessment, observation in natural settings,
and neurogenetic and neuropediatric investigations when
required. SDIs consist of a parent interview autism diag-
nostic interview (ADI) and observation scale autism
diagnostic observation schedule (ADOS) providing stan-
dardized and fine-tuned symptom definition, assessment
procedures, and scoring, which correspond to DSM-IV
or ICD 10 diagnostic criteria. The use of SDIs should
be limited to autism specialized clinics, as they require
a high level of expertise in autism and their adminis-
tration to avoid misinterpretations. Referrals to neurolo-
gists, geneticist, or third-line pediatricians are limited
to complex or unclear clinical situations, including
epilepsy, as well as medical and genetic conditions with
a neurologic expression and a greater-than-chance asso-
ciation with autism or a partial clinical overlap with
its criteria. While a combined expertise is required for
the entire range of level of functioning, clinical presen-
tations, and child and adult differential diagnoses,
clinical teams for adults and children should be relatively
autonomous. Adult assessment is more difficult and less
reliable, due to developmental transformations, and
alteration of the original presentation due to the social
positive or negative value of differential diagnoses.
The use of the cutoff provided by checklist diagnostic
instruments (DSM or SDIs) encompasses more individ-
uals than the recognition of a prototypical autistic
pattern by clinical experts. Their sensitivity is good to
very good, but their specificity is low, since they
overinclude most child psychiatric and neurodevelop-
mental conditions. Accordingly the specificity of SDIs
has been demonstrated toward specific groups of
idiopathic intellectual disabilities or language/learning
disorders, but not toward other neurodevelopmental
conditions, for which the autism score may range
from marginal to strongly positive based on these
criteria. These instruments also miss some very
intelligent individuals (especially after puberty, and
women), who nevertheless test positive for autism cri-
teria according to expert judgment. In addition, diagnos-
tic cutoffs on the SDIs have the damaging effect of
likening autism to a behaviorally unidimensional cate-
gory, despite genetic independence of some of its overt
behavioral traits. A diagnostic threshold can be reached
by an enormous number of different combinations
of phenotypic dimensions, some of them extremely dis-
tant from prototypical autism. “Dimensional” scales
as Social Responsiveness Scale have been developed,
but they are largely contaminated by variations in
psychologic states. However, SDIs are indispensable
to pinpoint a prototypical category in which both clini-
cal and research purposes are grounded. In particular,
SDIs have contributed decisively to ascertaining the
distinction between autism with or without intellectual
disability and intellectual disability without autism.
130 L. MOTTRON
DIFFERENTIAL DIAGNOSIS
Differential diagnoses of autism with typical speech
level and neurodevelopmental conditions with limited
or no impact on measured intelligence, such as Tourette
syndrome or some presentations of ADHD, are specially
challenging as these conditions frequently meet SDI
cutoffs, especially during preschool years. Meeting
ADOS or ADI cut-off scores are inversely but quasili-
nearly dependent on measured intelligence, with system-
atic reaching of cutoffs for children whose measured
mental age is under 15–18 months. Therefore, the most
difficult diagnostic issue consists in differentiating the
apparent decrease in sociocompetence inherent to any
neurodevelopmental diagnosis, as well as the restriction
in the variety of interests resulting from any develop-
mental delay, from their autism equivalent. A full psychi-
atric investigation of differential diagnosis is justified
in the presence of major autistic traits, whether or not a
neuropsychiatric co-occurring condition is suspected.
The main neurodevelopmental conditions of psychiatric
relevance whose phenotype overlaps with the autistic
spectrum include Tourette syndrome, ADHD, and devel-
opmental dysphasia in their strongest forms, attachment
disorders, childhood depression and social phobia,
especially in its selective mutism form. Early-onset
schizophrenia in its prototypical form is not a diagnostic
issue, but schizoid personality is currently one of the
differential diagnoses of Asperger syndrome. ADHD is
not an exclusion criterion anymore, but cautious assess-
ment should distinguish hyperexploratory behaviors,
frequently in search of perceptually relevant material,
sometimes associated with autism, from distributed
motor and ideational activity resulting from pure ADHD.
Last the newly defined pragmatic communication disor-
der in DSM-5 is supposed to encompass individuals with
similar sociocommunicative alterations to autism, but
without restricted interest and repetitive behavior. Poorly
defined, it is practically not studied and of limited clinical
utility as most neurodevelopmental conditions could
satisfy its criteria.
In the presence of incontestable psychiatric diagnosis
anterior or alternative to autism, we suggest applying
an economy principle, i.e., answering the following
question: Can the sociocommunicative atypicalities or
limitation in the variety of activities be explained in a
more straightforward manner by autism or an alternative
diagnosis? For example, an individual presenting with
strong Tourette syndrome will display poor social adap-
tation due to attention deficit, irascibility, and side effects
of their temper, with the result of limiting the variety of
their activities according to what they successfully pro-
cess. This will lead them to score positively for autism
criteria in DSM-5 in addition to satisfying the criteria
for Tourette syndrome. However, this second diagnosis
will neither provide information relevant to intervention
nor contribute to a better understanding of their adaptive
difficulties, which will still have to be addressed in a
Tourette syndrome framework. A similar position is
recommended in the presence of major ADHD or attach-
ment disorders.
Conversely, some conditions are so frequent in autism
that they should lead to a systematic examination of
autism when they are the entry point for neurologic
examination. Whereas “pure” developmental dysphasia
(or specific language impairment), despite definitional
limitations in communicative abilities, does not have
an impact on nonverbal social interaction, this syndrome
is inherent in a large fraction of autistic individuals
(Boucher, 2012). One-third of autistic individuals may
fall under this additional diagnosis, which nevertheless
needs to be distinguished from transient delayed echo-
lalia and stereotyped speech intrinsic to the autism
diagnosis. Therefore in the presence of other autism
diagnostic criteria in the two major behavioral areas,
developmental dysphasia should not exclude the search
for autism. In addition, positive scoring for ADHD
criteria is the rule in most children with Asperger syn-
drome, and, consequently, it should not be considered
an exclusion criterion for this diagnosis. Most persistent
forms of childhood epilepsy, especially precocious
ones and regardless of their cause, produce complex
behavioral regressions overlapping with autism criteria,
but with disastrous effects on nonverbal intelligence.
Regression with epilepsy is more dramatic than the loss
of first words and counting of numbers less than 10,
which signal autism in one-quarter of autistic children.
It also occurs at an earlier age (West syndrome) or later
age (Landau–Kleffner syndrome) than is the case with
apparent loss of speech in autism. Partial seizures, which
are difficult to detect clinically in an autistic child, still
have to be investigated in the presence of dramatic
changes or discontinuity in cognitive performance.
The diagnosis can be challenging as each DSM crite-
rion may have a considerably different expression across
development, from toddlers to adolescents. Narrowly
defined autism is usually not reliably discernible before
the middle of the second year of life. In secondary autism,
manifestations of the first diagnosis and especially
waking age delays often precede or mask autistic signs.
A decrease in peer-oriented initiatives and reactions,
including joint attention, orientation toward a parent’s
voice as well as smile, babbling, and gestures coupling
during interactions with parents and peers, is generally
the first observed manifestation. Atypically prolonged
or unusually angled visual fixation on objects may be
present at that time but is less obvious or salient to
observers. A period of quasi absence of oral verbal
 AUTISM SPECTRUM DISORDER
expression typically follows until 3–5 years of age, when
echolalia and then stereotyped speech appear. In less
than 10% of autistic children, speech will not develop,
but in the majority of cases, speech will flourish, still
varying considerably in terms of functional value
(Wodka et al., 2013). The maximum number of recogniz-
able signs is observed around the ages of 3 and 6–7, due
to the presence by this age of language signs that are
characteristic, if not definitive. Retrospective assessment
with SDIs therefore take the 4–5 years of age period as
the time frame during which targeted signs have to be
present, whatever developmental transformation occurs
afterwards. The variability of outcomes seems to be
directly dependent on how early the diagnosis was made
(the later the diagnosis, the more stable it is) and how
close to prototypical autism the child was at this age
(the greater the distance from the prototype, the less
stable the diagnosis). The developmental trend of strictly
defined autism with speech onset delay contrasts with
that of Asperger syndrome, which may involve preco-
cious and spectacular speech abilities (Pickles et al.,
2014). The adaptive prognosis as adults is overall poor
in terms of autonomy and intimate and familial relation-
ships, with less than one-fourth of diagnosed autistic
adults living independently and/or on their own income.
With few exceptions, they will benefit from some kind
of lifelong support as their life remains hampered by
multiple practical and psychologic issues, including
mood and anxiety disorders. The notion that autism is
a lifelong condition must be tempered by the absence
of predictors of adaptive outcome at toddler age.
Critically the outcome cannot be predicted (in both direc-
tions) for the apparent severity or nonseverity of the
presentation in childhood (Baghdadli et al., 2018).
ASSESSMENT
Rather than etiologically oriented and related to autism,
clinical investigations should be conducted according to
medical or neurogenetic symptoms presented in a child.
Individuals should be examined for medical signs.
Medical assessments should investigate the effect on
physical health of being autistic: food selectivity is the
rule, with consequences ranging from specific metabolic
deprivation to obesity. Gastrointestinal symptoms should
be investigated for themselves and not as potentially
causative. Sleep disorders are not constant, but have
major consequences on familial well-being, and can
be alleviated by medical and psychoeducational care.
Health issues are relevant as autistics do not or cannot
complain, the major effect being a shorter life expec-
tancy. The most frequent medical condition that mimics
an autistic profile in childhood is sensorial impairment,
specifically congenital or early blindness and congenital
131
Leber amaurosis. Rare reported medical conditions are
mitochondrial syndrome and prenatal exposure to
valproic acid, but routine metabolic testing is not
recommended.
Investigating the familial history of an autistic person
for neurodevelopmental conditions, learning disabilities,
and psychiatric syndromes is mandatory, leading to stan-
dard genetic explorations (CGH) in the case of minor
morphological dimorphism, any sign of a neurodeve-
lopmental syndrome, recognizable or not, and learning
or intellectual disability. The list of genetic conditions
whose phenotypes may present some overlap with
autism is open, but the most frequently cited, with a
reported prevalence rate of less than 5% in autism
cohorts, are tuberous sclerosis and Fragile X syndrome
(FrX). Tuberous sclerosis (TS) is found in 8%–14% of
individuals displaying autism with epilepsy (but excep-
tional in those without) and is thereby 100 times more
frequent among autistic people than in the general
population. TS is also one of the most important causes
of West syndrome, which is associated with dramatic
behavioral and cognitive regression. This results in a
clinical image scoring positive on autism criteria but
also with a measured age under the threshold from
where distinctions between autism and intellectual
disability becomes possible. FrX is associated with an
autistic phenotype in around one-fifth of cases and
should be searched for only in the presence of lowered
nonverbal IQ and physical characteristics. Other com-
monly mentioned conditions, with a prevalence rate
of less than 1%, include the following syndromes: Down
(3x21), Turner (X0), XYY, Klinefelter (XXY), Rett,
Angelman, and Prader-Willi (15q11–q13), DiGeorge
(22q11), Cornelia de Lange, Lesch–Nyhan, Smith–
Lemli–Opitz, San Philippo, Williams (7q11.23), Cohen,
Ito, Joubert, FG, ARX, PKU, 1q21.1, 3q29, 16p11.2,
neurofibromatosis, Moebius and Smith Magenis
(17p11.2), and an indefinite number of copy number
variations that can also exist without an autism or
autism-like presentation (Richards et al., 2015).
Neuropsychologic language/communication and
motor characterization are required for diagnosis as well
as education and support at all ages and developmental
levels. For a nonverbal child or a child who has not yet
reached the age of language development, psychologic
testing may be impossible due to lack of compliance or
comprehension of task instructions. This may mean
adapting test administration procedures, the modeling
of answers, or modifying the way information is col-
lected. For instance, activities could take place in natural
settings and information gathering could be limited to
an in-depth interview with caregivers. When passing for-
mal tests is impossible, estimating the complexity and
rapidity of the tasks realized spontaneously by the child
132 L. MOTTRON
may represent the best proxy for nonverbal intelligence.
The three major questions to be answered should be: is
the average level of cognitive performance at the normal
or the intellectually disabled level? Is the cognitive and
communication profile consistent with an autism sub-
type? What is the communication channel allowing the
exchange of information?
Neuropsychologic and communication assessment
should search for and reveal successful channels of
communication and specific areas of ability and transmit
this information to caregivers. The interpretation of intel-
ligence level in autism is challenging since some tests
underestimate cognitive levels and display an isolated,
low level of performance, lower than that associated with
the majority of tasks representing the child’s baseline
level (Courchesne et al., 2015). In contrast, other tasks
are performed at a level markedly superior to this base-
line. In the first years, language-mediated tasks requiring
the understanding of verbal instructions are typically the
most difficult to perform, especially those measuring the
ability to face a new social situation presented by means
of a verbal answer. However, vocabulary tasks requiring
the child to point to answers or to decode words may be
performed at a typical or even superior level. The highest
performance is found in the “block design” subtest and in
nonverbal fluid intelligence tasks (Raven’s progressive
matrices) (Nader et al., 2015). Whereas low scores in
an individual’s profile may predict an overall in adapta-
tion to daily demands without accommodation, high
scores predict abilities and intelligence level in adapted
conditions. This pattern of performance diverges mark-
edly from that observed in autistic people without speech
onset delay (the previous Asperger subgroup), where
some verbal tasks such as similarities and information
often present a level of performance superior to what
is expected at the child’s chronological age. In contrast,
coding and digit span subtests are usually associated with
the lowest levels of performance due to attention diffi-
culties. Asperger children do not display visual–spatial
peaks. They also present motor clumsiness, not found
in autism, shown by major difficulties in writing, cycling,
and catching balls.
ETIOLOGY AND MECHANISMS
Autism is, in its prototypical form, a genetic condition
(Gaugler et al., 2014). All medical hypotheses about
large-scale causes of autism can be firmly discarded.
The putative role of vaccines, exposure to lead or mer-
cury, gluten or diary allergies as widespread causes of
autism is no longer a scientific issue. Knowledge about
genetic influence on autism combines strong scientific
evidence of high heritability with limited actual determi-
nation of genes and modes of transmission involved, as
well as clinical applications restricted to a small subgroup
of the phenotype. Differences in concordance between
homozygotic twins (60% and above) vs dizygotic twins
(around 5%) is considerable, although phenotypic differ-
ences between twins may be observed. Concordance
between siblings ranges from 15% to 40% according to
the gender of the child, with larger concordance when
the first child is a girl and the second a boy, and for fam-
ilies who have more than one autistic child (Ozonoff et al.,
2011). There is a substantial drop in aggregation between
first- and second-degree relatives. Familial aggregation
extends beyond narrow autism: concordance for autism
increases considerably when including the “broad autism
phenotype” ensemble of cognitive and behavioral traits
parent to autism but subthreshold for an autism diagnosis.
Familial aggregation is greater for probands with higher
measured intelligence, which can be explained by the
inability to differentiate autism from intellectual disability
(whose heritability is overall lower than that of autism) in
very low mental-age equivalents.
The repeated finding that genetic factors cannot account
for the entire prevalence of autism, and mostly, of its
supposed exponential increase, leaves some space for
environmental factors. The most studied (food allergies,
vaccines) have been thoroughly discarded and were ini-
tially associated with one of the most important scientific
frauds of the 20th century (Fombonne and Cook Jr, 2003).
Other environmental factors, such as prematurity, pre- and
perinatal events, SSRIs, and an undefined list of others
causes, may be associated with a minimal portion of autism
prevalence, which plausibly coincides with the partial
phonotypical overlap between any neurodevelopmental
condition and the current definition of autism.
The understanding of the mechanisms involved in an
autistic clinical presentation is hampered by the uncer-
tainty regarding the extension of the autistic phenotype.
The decision of DSM-5 to consider any identified neuro-
developmental condition as compatible with an autism
diagnosis validates interpreting these associations as
potentially causative and therefore building “autism
animal models” for these conditions. However, the level
of similarity between syndromic and nonsyndromic
autism is low and sometimes trivial, which casts doubt
on the external validity of syndromic autism for nonsyn-
dromic autism (Bishop et al., 2017). Moreover, most
identified associated conditions and pathogenic copy
number variations are de novo, whereas some evidence
of familial clustering is dominant for nonsyndromic
autism. Therefore there are antagonistic views of the dis-
tinction between primary and secondary autism. One is
that if an additional condition is present in only a small
percentage of the autistic spectrum, then this condition
has in fact produced a phenocopy of primary autism,
that is, it mimics a phenotype characterizing a certain
 AUTISM SPECTRUM DISORDER
condition via a completely different mechanism. In
contrast, autism may represent the final common path-
way to an indefinite number of mechanisms (some
known in syndromic autism and unknown in primary
autism), thereby making syndromic autism an oppor-
tunity to understand idiopathic autism and in effect
creating a “human model” of autism. In our opinion
the latter position neglects the large phenotypical differ-
ences between “autism” and “autism with …” Accord-
ingly, there is also the possibility of little or no
informative similarity between primary autism and sec-
ondary autism phenocopies (Harris, 2016). In terms of
neurobiologic mechanisms, autism is associated with
multiple but heterogeneous genetic, cognitive, func-
tional, and structural variations whose established links
with an autistic behavioral and cognitive phenotype are
minimal yet highly dependent on a definition of uncer-
tain boundaries (Rane et al., 2015; O’Reilly et al.,
2017; Pereira et al., 2018). Consequently, the search
for a unique and common neurocognitive mechanism
for all individuals sharing autism criteria should not
be a research objective. Informative similarity between
two autistic phenotypes ranges from maximal (e.g.,
between two idiopathic autistic children sharing the same
cognitive profile) to minimal (e.g., between two individ-
uals with secondary autism differing in their related neu-
rodevelopmental condition). Therefore we will limit our
presentation of current models to idiopathic autism, as
each type of secondary autism requires a specific model
of the relationship between the two diagnoses involved.
Autism is now considered a variant of typical
information processing, i.e., the way humans perceive,
memorize, manipulate, and attribute emotional value
to available information. Compared with nonautistic
people, this variation consists in the less automatic
or mandatory, higher-order processing of incoming
information (categorization, purposive integration, and
attribution of emotional value). Autistic information pro-
cessing differences are domain general, encompassing
information regarded as social (e.g., facial expression
and language pragmatics) and nonsocial (e.g., visuospa-
tial processing) (Mottron et al., 2006). A more optional,
but not in any way absent, relation among cognitive
processes allows for a greater than typical role of
perception, including in domains not considered to be
perceptual in nonautistics. For typical individuals, a
major way to attribute value to incoming information
consists in automatically indexing it with a social value
(personal benefit, social adequacy, consistency with
collective interests). While nonautistic cognition is
dominated by an early, automatic, and exclusive bias
toward social information, the predominance of per-
ception in autistic cognition allows for enhanced
processing of environmental regularities in visual and
133
auditory information (Palmer et al., 2017). Enhanced
perceptual abilities, or peaks of ability, are solidly
demonstrated in prototypical autism, but their preva-
lence in the entire AS group depends on how specific
the diagnosis is. They extend from enhanced discrimi-
nation of low-level psychophysical auditory and visual
information to pattern detection (e.g., visual search) and
manipulation (e.g., mental rotation, visuospatial con-
struction). Apparently, positive emotions might be less
related to social information, although not impaired
per se, than with strong, focused interests and the shar-
ing of these. In contrast, once the effect of measured
intelligence has been removed, no cognitive deficit
has unequivocally been found in cases of autism.
Understanding of human intention in autism, an overt
indicator of social cognition, has been shown in multi-
ple studies to be at least at the typical level. Numerous
findings related to complex purposive actions, problem-
solving, and executive functions yield apparent advan-
tages and disadvantages, depending on experimental
design and task demands, but no overall image of a
deficit. Long-term memory performance follows mea-
sured intelligence, but it is also less influenced by
semantic or emotional properties of the memorized
material than is the case with nonautistics.
The presence of a significant, and probably dominant,
fraction of idiopathic autism with a typical level of
measured intelligence indicates that intellectual disability
is not a mandatory component of autism (Charman et al.,
2011). Another percentage of apparently intellectually
disabled individuals actually displays a normal nonverbal
IQ level, indicating that difficulties with speech or
language, whatever their cause, play a strong role in
how the abilities of some autistic people are judged
(Courchesne et al., 2015). Yet another fraction of autistic
individuals with low measured intelligence probably cor-
responds to the long-term effects of impoverished input
due to unavailability of material that they would be able
to process well. This mechanism can be inferred from
analogous situations involving deaf adults who were
exposed neither to oral nor to sign language, as autistic
people seem more dependent than typical individuals
on access to specific kinds, amounts, and arrangements
of information that may not be easily available or
completely unavailable. Last, in many cases, intellectual
disability in autism coincides with secondary autism and
follows the same explanations as those used for intellec-
tual disability per se (e.g., reduced dendritic spines).
Second-generation brain-based models now deem-
phasize the putative action of single cognitive deficits
with cascading effects, such as amygdala or cerebellum
deficits, in favor of distributed reorganization among
brain functions and levels (Nunes et al., 2018). Most
structural studies find smaller cells and atypical
134 L. MOTTRON
minicolumnar organization in gray matter, but no evident
neurochemical modifications. Functional MRI studies
demonstrate diminished activity in frontal and temporal
regions but enhanced activity in the visual cortex
(Samson et al., 2012). Therefore some reallocation of
regional brain functions must take place. For example,
typical or superior performance in working memory
or problem-solving tasks is obtained in the presence
of an inverted balance of frontal-occipital activation.
Decreased inter- and intrahemispheric connectivity has
been supported by most diffusion tensor imaging studies.
Such reduced functional crosstalk between brain regions
is also consistent with the diminished section of the
corpus callosum, a situation that is consistently found
in autism subgroups. An increase in brain size consis-
tently spares frontal lobes but affects gray and white
matter to a similar extent. Autistic macrocephaly coin-
cides with the first behavioral autistic signs occurring
around the end of the first year of age. Some, but not
all, studies report its normalization at an adult age, while
others found macrocephaly in 30% of adult autistic indi-
viduals compared with 2% of controls. Other cerebral
structures present inconsistent variations that cannot be
interpreted even in a research context.
TREATMENT AND SUPPORT
There is no medical treatment for autism: a distributed
difference in neuronal organization and functional
allocation of brain resources is yet out of reach of phar-
maceutical agents (Lord et al., 2018). Parental guidance
and adaptive measures at home, school, and workplaces,
combined with cognitive-behavioral therapy for asso-
ciated conditions taking communication difficulties
into account, remain the logical way to address most
challenges (Green and Garg, 2018). Early intensive inter-
ventions based on applied behavior analysis, involving
one-on-one training for at least 20, and up to 40 or more,
hours per week, are not supported by randomized
controlled trials. Their cost is unbearable by any health
system, their short- and long-term benefits and harms
have not been sufficiently established, and the associated
ethical issues remain unaddressed. In contrast, enriching
synchrony in parent–child interaction through noninten-
sive parental guidance has a small but measurable benefit
on the entire range of autistic features up to 6 years later
(Pickles et al., 2016).
Parents should be informed about the cognitive and
behavioral peculiarities of their child, autism-based gen-
eral knowledge, combined with the specific profile of
signs and competences and interests detected at the time
of diagnosis. Early intervention targets should be timely,
feasible, and ethically acceptable. The developmental
level of the didactic or play material offered to the child
should be adapted to his nonverbal apparent intelligence,
as estimated through its most complex spontaneous
accomplishments. Printed material, tablets, cell phones,
and screens in general are a profitable entry channel for
speech and nonverbal abilities, and their access should
possible, but reasonably regulated.
Behaviors that are intrinsically linked to autism, such
as unarming repetitive movements and focused interests,
should not be targeted, since they do not represent a
burden to the autistic child himself. One should not try
to suppress in an autistic child what is tolerated in a
typical child, for example, sporadic tantrums. In most
cases of primary autism, self-injurious behavior can be
considered a typical autistic expression of extreme con-
fusion and negative emotions. Since most self-injurious
behaviors is sporadic and without damaging physical
consequences, it should be addressed as a crisis
situation and dealt with as such. On the other hand,
life-threatening self-injuring behavior is part of the
phenotype of a number of genetic conditions asso-
ciated with secondary autism (e.g., Smith–Lemli–Opitz
syndrome).
However, some co-occurring features of the autistic
spectrum may be successfully targeted. Developmental
dysphasia may be addressed with speech therapy, or
alternative communication channels (e.g., keyboards),
but the majority of efforts should concentrate on manag-
ing communication with the child in family and class-
room situations. Moreover, usual targets in speech
intervention should be adapted to the autistic child’s
speech development. For instance, it is of poor use to
attempt to train speech during the “mute” and the echo-
lalic periods of autistic speech development. Support for
sensory-motor difficulties, including desensitization but
also training of underdeveloped motor sectors, is usually
provided by an occupational therapist. Adapted psycho-
logic support, possibly combined with pharmacotherapy,
is required for associated psychiatric conditions. How-
ever, the use of medication with autistic people should
always follow an in-depth, but unsuccessful investiga-
tion of the role of contextual cues in producing a crisis
situation, as well as rational attempts to address the crisis
in that way (NICE, 2013). For example, most apparent
temper tantrums in autistic preschoolers can be alleviated
by teaching parents how to decode the communicative
attempts of their child, how to provide him with informa-
tion and materials that he can process well, and how
to address him in a way that he can understand. Similarly,
depressive mood states in school-age autistic children are
often related to bullying, in which case it is the behavior
of bullies that needs to be addressed. Rare co-occurring
obsessive-compulsive disorder or Tourette syndrome,
 AUTISM SPECTRUM DISORDER
once distinguished from the repertoire of repetitive
autistic movements, can be medicated, if necessary. This
also applies to attention deficit, damaging levels of activ-
ity (especially verbal), anxiety disorder, and depressive
mood in verbal autistic adults. Heavy behavioral prob-
lems, such as aggressive behavior or tantrums, intracta-
ble wandering or the socially damaging pursuit of
restricted interests, are possible but rare. They justify a
combined systemic, cognitive-behavioral and pharmaco-
logic approach. Existing studies have shown that the ben-
efit of atypical antipsychotics in this case is very limited
and may be even lesser than that associated with a pla-
cebo effect. In contrast, melatonin has a demonstrated
effect on sleep delay and length. The access to medical
and dental care for general health issues is a priority as
most health providers are uninformed or unwilling to
physically examine an autistic person. Discouraging
the use of alternative treatment that is costly, damaging,
or simply useless is a necessary step in every situation.
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