Original Article

Journal of Child Neurology

1-9
Early Infant Development and Intervention ª The Author(s) 2015
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for Autism Spectrum Disorder DOI: 10.1177/0883073815601500
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Lori-Ann R. Sacrey, PhD1,2, Jeffrey A. Bennett, MSc1,

and Lonnie Zwaigenbaum, MD, MSc1,2

Abstract
Objective: The objective is to overview recent findings on early detection/diagnosis of autism spectrum disorders, as well as
clinical trials of early interventions for toddlers at risk for/diagnosed with autism spectrum disorder. Findings: Prospective studies
of infants at high risk of autism spectrum disorder have yielded significant advances in understanding early development in autism
spectrum disorder. Findings from prospective studies indicate that abnormalities in social communication and repetitive behaviors
emerge during the second year, whereas additional ‘‘prodromal features’’ (motor and sensory abnormalities) emerge in the first
year. Subsequently, exciting progress has been made in establishing the efficacy of autism spectrum disorder–specific interventions
for toddlers as young as 15 months. Finally, efforts occur to characterize autism spectrum disorder–specific characteristics in
genetic syndromes with concurrent autism spectrum disorder symptomatology. Conclusion: Substantial progress in char-
acterizing early developmental trajectories as well as the identification of specific behavioral markers has aided early detection.
Work remains to ensure that research findings are translated into clinical practice for uptake in the health care system.

Keywords
early identification, infant siblings, early intervention, autism spectrum disorder, review

Received July 21, 2015. Accepted for publication July 25, 2015.

The heterogeneity of autism spectrum disorders, both clinically
and etiologically, creates challenges in identifying a set of early
risk markers that would be informative across the continuum of
severity and complexity of affected children. However, despite
these challenges, there are many reasons to continue to strive
toward earlier detection and diagnosis of the disorder. First,
there is an unacceptable delay between parents’ first concerns
and confirmation of a diagnosis of autism spectrum disorder,1,2
which creates added stress for families and may adversely
impact on subsequent engagement with health care providers.3
Second, earlier diagnosis creates opportunities for children
with autism spectrum disorder to benefit more fully from ear-
lier initiation of intervention, which benefits both the child and
the community.4,5 There is also broader scientific relevance to
delineating the earliest expression of the autism spectrum dis-
order phenotype in terms of understanding underlying mechan-
isms, and in particular, to be able to study the neurological
features of autism spectrum disorder early in development.
Early detection efforts have benefitted from recent advances
in research, including broad implementation of prospective
study designs involving high-risk infants6 and technological
advances in assessing early brain structure and function.7-9
Indeed substantial progress has been made in characterizing
early behavioral and neurobiological markers of autism spec-
trum disorder in high-risk infant cohorts.10,11 In addition, there
is exciting progress in establishing the efficacy of autism spec-
trum disorder–specific interventions for toddlers as young as
18 months.4,12 Finally, efforts have been made to characterize
autism spectrum disorder–specific characteristics in genetic
syndromes with concurrent autism spectrum disorder sympto-
matology.13-15 These efforts together bring us closer to the core
mechanisms underlying autism spectrum disorder. The authors
summarize advances in each of these areas in this review.
Prospective Design: Application to Studies of
Early Development of Autism Spectrum
Disorder
Prospective studies of high-risk infant cohorts (generally,
younger siblings of children diagnosed with autism spectrum
disorder) are well suited to understand early development in
1
Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
2
Autism Research Centre, Glenrose Rehabilitation Hospital, Edmonton,
Alberta, Canada
Corresponding Author:
Lori-Ann R. Sacrey, PhD, Autism Research Centre—E209, Glenrose Rehabilitation
Hospital, 10230 111 Ave, Edmonton, Alberta, Canada T5G 0B7.
Email: sacrey@ualberta.ca

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2 Journal of Child Neurology
autism spectrum disorder. The prospective, high-risk design
has been used to study other disorders, such as schizophrenia,16
but the advantage of utilizing this method in autism spectrum
disorder is the early onset of the disorder. The prospective
design offers additional advantages. First, infants can be fol-
lowed from a very early age, allowing examination of early
systems, such as motor development and visual attention.
Second, behaviors can be studied longitudinally to age at diag-
nosis, which may help address questions regarding develop-
mental trajectories of autism spectrum disorder. Third,
clinical assessments can be correlated with neurobiological
phenomena, such as underlying EEG measurement. Fourth,
early behavioral signs of autism spectrum disorder can be mea-
sured under standardized conditions, allowing greater compar-
ability both within and between individuals over time. Finally,
interventions can be implemented at an earlier age in infants
and toddlers who show behavioral signs of autism spectrum
disorder.
To what degree can younger siblings be considered ‘‘high
risk’’; that is, what is the recurrence risk of autism spectrum
disorder (ie, the likelihood of autism spectrum disorder for each
later-born sibling) compared to general population risk? One of
the first epidemiological studies of recurrence risk in autism
spectrum disorder was completed in the 1980s at the University
of Utah.17 The recurrence risk was estimated at 8.6%. More
recently, a multisite international network, the Baby Siblings
Research Consortium reported on 664 infant siblings of chil-
dren with autism spectrum disorder followed to age 3, when
they were classified as having or not having autism spectrum
disorder. Overall, the recurrence rate was 18.7%.18 However,
3 recent large population-based studies have reported lower
recurrence rate estimates. A Danish birth cohort study involv-
ing 1.5 million children born between 1980 and 2004, esti-
mated recurrence rate for autism spectrum disorder at only
6.9%.19 Similarly, recurrence rate was 10.1% among younger
siblings of individuals with autism spectrum disorder in a
1990-2003 California birth cohort (n ¼ 6616),20 and 12.9%
in a population-based cohort of Swedish children born between
1982 and 2006 (n ¼ 2 049 973).21 Despite this broad range of
recurrence risk estimates (roughly 8-18%), it is clear that the
rate of autism spectrum disorder among younger siblings is
higher than that in the general population, most recently esti-
mated at 1.5% (or 1 in 68 children) by the US Centers for Dis-
ease Control and Prevention (CDC).22
Prospective Studies of Infants at Risk of
Autism Spectrum Disorder: Key Findings
Converging findings from prospective studies of infants at risk
of autism spectrum disorder (younger siblings) suggest that
‘‘diagnostic’’ symptoms (that is, behavioral features that
related to diagnostic criteria defined by current frameworks
such as the fifth edition of the Diagnostic and Statistical Man-
ual of Mental Disorders)23 are expressed by 12-18 months in
many children with autism spectrum disorder. However, ‘‘pro-
dromal’’ (ie, earlier) symptoms, such as sensory and motor
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impairments, emerge during the first 12 months, and atypical
brain development and function are apparent in the first 12
months and may precede behavioral symptoms. Each set of
findings will be discussed in turn.
Diagnostic Symptomatology
Abnormalities in social communication include deficits in
social reciprocity, nonverbal communication, developing rela-
tionships, and verbal communication. By 12 months of age,
high-risk infants show reduced orienting to name,24,25 gazing
to faces, and directed vocalizations,26 and by 18 months of age,
showed reduced social smiling and social engagement.26,27 In
addition, deficits in responding to referential cues during joint
attention occur early in the second year of life for children who
later are diagnosed with autism spectrum disorder.28,29 Other
nonverbal skills, such as the use of gestures, also show early
impairments. High-risk infants later diagnosed with autism
spectrum disorder are less likely to show an object or use
directed pointing at 12 months of age,30 and have a smaller
inventory of gestures.29,31 High-risk infants who are later diag-
nosed with autism spectrum disorder also show reduced atten-
tiveness to their mother during naturalistic interactions, as well
as reduced dyadic mutuality.32,33 Several studies have reported
delays in receptive language by 12 months of age in infants
who are later diagnosed with autism spectrum disorder. These
siblings understood fewer phrases between 12 to 14 months, as
reported by parents on the Communicative Developmental
Inventories,31 as well as understanding fewer phrases with or
without accompanying gestures on the Mullen Scales of Early
Learning.25,34 In addition to receptive problems, language pro-
duction is also impaired in children who are later diagnosed
with autism spectrum disorder. Parents of these children report
fewer words on the Communicative Developmental Invento-
ries at 18 months of age,25,31 and these children score lower
on the expressive language component of the Mullen Scales
of Early Learning.34
Abnormalities in restricted interests or repetitive behaviors
include repetitive motor movements, atypical use of objects,
and atypical sensory interests. Reports of repetitive movements
suggest that they lack early specificity in autism spectrum dis-
order. Loh and colleagues35 analyzed repetitive movements
during a semistructured assessment and identified the fre-
quency of arm waving as the only item that distinguished 12-
and 18-month-old siblings who were later diagnosed with aut-
ism spectrum disorder from other high-risk and low-risk sam-
ples. In contrast, for use of objects, 12-month-olds often used
play materials in stereotyped, self-stimulatory ways (eg, an
infant might wave a string of beads in front of his/her eyes).36
Similarly, Ozonoff and colleagues37 noted that 12-month-old
high-risk infants later diagnosed with autism spectrum disorder
showed more atypical uses of objects, particularly unusual
visual exploration of objects, rotating, and spinning, but did not
differ on throwing or mouthing of objects. High-risk children
later diagnosed with autism spectrum disorder also show addi-
tional reactivity and sensory issues. Parents of these infant
Sacrey et al
siblings later diagnosed with autism spectrum disorder reported
atypical auditory processing and lower sensory registration on
the Infant-Toddler Sensory Profile at 24 months of age.38
Prodromal Symptoms
A growing literature suggests that early sensory and motor dif-
ferences, and possible emotional regulation differences, form a
prodrome of autism spectrum disorder that manifests in the lat-
ter half of the first year of life,39-42 before the appearance of
social-communication and restrictive behavioral differences
more directly related to autism spectrum disorder diagnostic
criteria (reviewed in Zwaigenbaum et al11).
Motor. Prospective studies of high-risk siblings who are later
diagnosed with autism spectrum disorder identify delays in
gross and fine motor skills on the Mullen Scales of Early
Learning at 14 and 24 months of age, but not at 6 months.26,34,43
Zwaigenbaum and colleagues25 also report lower fine and gross
motor scores on the Mullen Scales of Early Learning compared
with nondiagnosed high-risk infants and controls at 12 and
18 months, but not at 6 months.27
Rather than looking at scale scores, Libertus and col-
leagues42 assessed toy play during the Mullen Scales of Early
Learning and found that high-risk infants exhibited less mature
object manipulation and reduced grasping activity than infants
with no family history of autism spectrum disorder at 6 months,
with grasping activity increasing in high-risk infants between 6
and 10 months. Additional evidence of atypical motor develop-
ment include reduced motor maturity at 3 and 6 months in high-
risk infants versus low-risk infants (without outcome informa-
tion) using the Alberta Infant Motor Scales,44 and pronounced
head lag during pull-to-sit at 6 months, delayed independent
sitting, reduced postural stability, and reduced rhythmic arm
movements in high-risk infant siblings.45,46 Further clarifica-
tion is needed on whether abnormalities in high-risk infants are
specific to those who later are diagnosed with autism spectrum
disorder or are shared by a broader group of high-risk infants
who show later social-communication impairments.44
Sensory. Coding of home videos of children who are diagnosed
with autism spectrum disorder show differences in sensory
behaviors at 9 and 12 months of age, particularly visual explo-
ration of their visual environment, differentiated infants with
autism spectrum disorder from those who had developmental
disabilities or who were typically developing.39 Similar find-
ings come from prospective studies of high-risk infant siblings
of children with autism spectrum disorder. Ozonoff and col-
leagues37 reported that 12-month-old high infants who were
later diagnosed with autism spectrum disorder were different
from children with developmental disability and typically
developing infants in atypical uses of objects, such as rotating,
spinning and unusual visual exploration. Atypical sensory-
oriented behaviors at 12 months (including intense visual
inspection) were also identified as an early risk marker of
autism spectrum disorder in high-risk infants assessed by
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3
Zwaigenbaum and colleagues25 using a semistructured play
assessment. Similar findings are seen in computer based visual
assessments.36,47 Elsabbagh et al8 reported that high-risk
infants who were diagnosed with autism spectrum disorder at
24-36 months showed increases in their latency to disengage
when looking at objects between 7 and 14 months, whereas dis-
engagement latencies in typically developing children and
high-risk infants without autism spectrum disorder decreased
or remained the same. In addition, Elison et al9 found longer
latencies to disengage attention from objects in 7-month-old
infants with high Autism Diagnostic Observation Schedule
scores at 24 months. In addition to prolonged disengagement
from objects, autism spectrum disorder is associated with
diminished attention to faces (no relative difference in eyes
versus mouth) in videotaped social scenes at 6 months of age
in high-risk infants who are later diagnosed with autism spec-
trum disorder.48 Similarly, a prospective longitudinal study of
infants later diagnosed with autism spectrum disorder show
declines in percentage of time gazed at eyes versus mouth on
a face shown on a video during early infancy. In fact, the sever-
ity of decline between 2 and 6 months of age was informative
for autism spectrum disorder risk.49
Temperament. Prospective studies have shown evidence of
reduced positive affect in high-risk infants who are later diag-
nosed with autism spectrum disorder by the first birthday when
compared to nondiagnosed siblings and low-risk controls.29,50
Zwaigenbaum and colleagues25 reported fewer observed posi-
tive affective responses and increased distress in high-risk
infants with autism spectrum disorder at 12 months, as coded
from the Autism Observation Scale for Infants, compared to
those with typical development, consistent with concurrently
collected parental reports of temperament. In a subsequent
analysis of high-risk infant siblings (n ¼ 138) and low-risk
infants (n ¼ 73), Garon et al51 examined the relationship
between temperament at 24 months and 3-year outcomes.
Using discriminant function analysis, they identified profiles
that were informative for general differences between high-
risk siblings and low-risk comparison infants, and that were
specific to siblings subsequently diagnosed with autism spec-
trum disorder. A profile that included poor regulation of nega-
tive emotions, and difficulty with attention control (increased
attention shifting) distinguished the high-risk sibling group
(as a whole) from comparison infants, whereas a second profile
that included low positive affect and increased duration of
attention, was associated specifically with autism spectrum dis-
order. Similarly, Clifford and colleagues52 noted that parents of
high-risk infants later diagnosed with autism spectrum disorder
reported reduced positive affect, but not increased negative
affect, as characterizing beginning at 7 months. As well, Feld-
man and colleagues53 noted that community diagnosed chil-
dren with autism spectrum disorder were rated by the parents
as more difficult when waiting to have their needs met at 9,
12, and 18 months of age. These results suggest that emotional
regulation differences may precede the core symptomatology
of autism spectrum disorder.
4 Journal of Child Neurology
Neurobiological Markers
Atypical brain development and function are evident in the first
12 months in high-risk infants who are later diagnosed with
autism spectrum disorder using magnetic resonance imaging
(MRI) and electroencephalogram (EEG).
MRI. Hazlett and colleagues54 compared brain volumes at 2 and
4 years of age in children at high risk of autism spectrum dis-
order and without familial risk of autism spectrum disorder.
They reported generalized cortical enlargement in children
with autism spectrum disorder at both 2 and 4 years of age, and
after controlling for total brain volume, children with autism
spectrum disorder had disproportionate enlargement of tem-
poral lobe white matter. The authors note that there was no sig-
nificant difference from controls in the rate of brain growth at
this age interval, suggesting that the brain enlargement took
place prior to 2 years of age.54 Investigation of white matter
tract organization from 6 to 24 months of age in children at
high risk of autism spectrum disorder showed higher fractional
anisotropy values at 6 months, followed by slower changes
over time in comparison to infants without autism spectrum
disorder. In a related investigation, measuring visual orienting
latencies in 7-month-old infants at high risk for autism spec-
trum disorder and associating outcomes with the microstructure
of the corpus callosum, Elison and colleagues9 found that high-
risk infants who were later diagnosed with autism spectrum
disorder showed longer disengagement latencies than both
high-risk negative infants and control infants. Furthermore, the
disengagement latencies were associated with the microstruc-
ture organization of the splenium of the corpus callosum in the
control infants, but this association was not apparent in high-
risk infants later diagnosed with autism spectrum disorder,
suggesting early atypical development in autism spectrum dis-
order. Finally, Lewis and colleagues55 measured differences in
brain connectivity in autism spectrum disorder at 24 months of
age, an age at which the diagnostic features of autism spectrum
disorder become clear. Network efficiency was analyzed by
measuring the length and strength of connections between ana-
tomical regions, resulting in significantly decreased local and
global efficiency over the temporal, parietal, and occipital
lobes in high-risk infants classified as autism spectrum disor-
der. The authors suggest that delays or deficits in network effi-
ciency are associated with the impairments in audition, visual
processing, language, and nonlinguistic social stimuli.
EEG. A prospective longitudinal study of infants at high risk of
autism spectrum disorder examined whether neural responses
to eye gaze at 6-10 months of age was associated with autism
spectrum disorder symptomatology.7,56 Event-related poten-
tials were recorded in response to infants viewing faces with
the eye gaze either directed toward or away from the infant and
noted that changes to the characteristic of the event-related
potential response, specifically the P400 response, was associ-
ated with an outcome of autism spectrum disorder. In a subse-
quent study, the authors measured the P400 response to
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directed or averted eye gaze in 7-month-olds and compared it
to infants’ overt behavior during a caregiver-child dyadic free
play session.57 The results suggested that infants with more
positive affect exhibited stronger differentiation to gaze stimuli
in respect to P400 responses to directed gaze versus averted
gaze. These results suggest the integrity of the neural response
is associated with overt, observed behavioral phenomenon.
Other. Increased head circumference in children with autism
spectrum disorder is one of the most consistent findings in aut-
ism spectrum disorder. Yet, this association is now in question
due to problems in interpretation related to using CDC norms
for comparison. A systematic review by Raznahan et al58 iden-
tified 5 independent longitudinal cohorts of typically developing
children that demonstrate trajectories in head circumference
z scores that deviate from CDC norms.59 To understand whether
head growth in the first 3 years differed between high-risk
infants later diagnosed with autism spectrum disorder versus
high-risk infants who were not diagnosed with autism spectrum
disorder and community controls, Zwaigenbaum and col-
leagues60 obtained prospective and growth-records of head cir-
cumference from 492 high-risk infants (77 of whom were later
diagnosed with autism spectrum disorder) and 333 low-risk
community controls. Overall, there were no significant differ-
ences comparing head growth between high-risk infants (regard-
less of outcome) and low-risk controls in the first 3 years of life.
Furthermore, there were no differences in head growth related to
clinical outcome within the high-risk group (when subtyping
based on autism spectrum disorder, developmental disability,
and typical outcomes). The authors concluded that head growth
was largely uninformative as a risk-marker for autism spectrum
disorder, at least within the reported high-risk cohort.
Early Intervention for Autism Spectrum Disorder
As detailed above, prospective studies of high-risk infants who
are later diagnosed with autism spectrum disorder indicate
impairments appear early in development for sensory and
motor ability, visual attention, social-emotional regulation, and
communication. The atypical development of these domains
may lead to disruptions in early interactions with the environ-
ment, resulting in cascading effects during the first 3 years of
life. Moving forward, it becomes necessary to develop earlier
interventions to coincide with earlier identification of autism
spectrum disorder and improve lifelong outcomes for these
children. For a recent review of potential treatment targets for
interventions, see Brian et al,12 and for a recent review article
that summarizes key feature shared in common across recently
reported interventions for infants and toddlers with autism
spectrum disorder or at risk of autism spectrum disorder, see
Schreibman et al.5
Clinical Trials
Dawson and colleagues61 provided the first randomized con-
trolled trial to demonstrate efficacy for a behavioral
Sacrey et al
intervention for toddlers with autism spectrum disorder. Chil-
dren diagnosed with autism spectrum disorder between 18 and
30 months (n ¼ 48) were enrolled in a randomized, controlled
trial to evaluate the efficacy of the early start Denver model, a
comprehensive developmental behavioral intervention for
improving outcomes of toddlers diagnosed with autism spec-
trum disorder. Following random assignment in 1 of 2 groups
(Early Start Denver model for 2 years versus ‘treatment as
usual’ [typical community intervention]), those children who
received Early Start Denver model showed significant
improvements in IQ, adaptive behavior, and autism spectrum
disorder diagnosis (showing fewer autism spectrum disorder
symptoms) compared to the treatment as usual group. Carter
et al62 reported a randomized controlled trial comparing
Hanen’s ‘More Than Words’, a parent-implemented interven-
tion for 3.5 months, to a ‘treatment as usual’ group in 20-
month-old children diagnosed with autism spectrum disorder
(n ¼ 62). Overall, there were no main effects of the More Than
Words intervention on parental responsivity or children’s com-
munication ability compared to the treatment as usual group
receiving community intervention, but the More Than Words
intervention showed differential effects on child
communication depending on their baseline performance.
Wetherby et al63 completed a randomized control trial of the
‘Early Social Interaction’ Project for 16- to 20-month-old tod-
dlers diagnosed with autism spectrum disorder. Children were
matched on nonverbal developmental level and were randomly
assigned to an individualized Early Social Interaction treatment
(1-on-1 parent coaching 2-3 times per week) or group Early
Social Interaction treatment (group parent coaching offered
once per week) conditions for 9 months. The children enrolled
in the individualized Early Social Interaction treatment showed
improvements on observational measures of social communi-
cation and receptive language skills, parent-reported measures
of communication, daily living, social skills, and stability over-
time. In contrast, children enrolled in the group Early Social
Interaction treatment showed worsening or no changes to these
skills, highlighting the importance of parent coaching in an
individualized environment. Similarly, Kasari et al64 per-
formed a randomized control trial on a parent-mediated inter-
vention for 15- to 21-month-old toddlers at high risk of
autism spectrum disorder. Parents were enrolled in 12 ses-
sions of individualized parent education intervention or to
a control group involving 4 sessions of behavioral support
for 3 months. Parental responsiveness improved signifi-
cantly in the individualized treatment group compared to the
control group over the 3-month period, however it had
declined in the 12-month follow-up. Although children in
both groups made gains in cognitive and language ability
over the 12 months, there were no treatment effects on joint
attention for the individualized treatment group. Finally,
Brian and colleagues12 completed a clinical trial on a
parent-mediated intervention, the ‘Social ABCs’, based on
adapted pivotal response treatment principles and strategies.
The intervention relied on in-home, parent-mediated strate-
gies with in-vivo coaching by a trained interventionist.
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5
Parents completed 12 weeks of in-home training and chil-
dren were followed up 24 weeks later to examine communi-
cation ability and shared positive affect. Overall, children
showed improved language performance and functional ver-
balizations, with increases in responsivity, initiations, social
orienting, and shared smiling.
Other Intervention Studies
Pivotal response treatment is an evidence-based, manualized
intervention for individuals with autism spectrum disorder with
empirical support for use with preschool children with autism
spectrum disorder.65 Steiner and colleagues66 developed an
adaptation of pivotal response treatment and piloted, via a brief
parent-training model, the intervention with 12-month-old
infants at risk for autism (n ¼ 3). The results provided prelim-
inary support for the feasibility and utility of pivotal response
treatment for very young children at risk for autism spectrum
disorder. That is, utilizing a multiple baseline design, the
introduction of pivotal response treatment resulted in
increases in the infants’ frequency of functional communica-
tion and parents’ fidelity of implementation of pivotal
response treatment procedures. Landa et al67 reported on a
sample of 2- and 3-year-old children with autism spectrum
disorder (n ¼ 48) who participated in a research-based, 6-
month comprehensive intervention at 10 hours per week
within a nursery classroom. Parents received weekly on-site
education and monthly home-based coaching on teaching
strategies. From pre- to postintervention, significant gains
were made in IQ and communication scores on the Vineland,
as well as a reduction in autism spectrum disorder severity
scores. Measurements completed at 6-month and long-term
follow up after intervention found that IQ and communication
stabilized, but autism spectrum disorder severity scores
increased. Pre- to post-follow-up trajectories showed that
robust gains were observed for both IQ and communication
scores, with no changes in autism spectrum disorder symp-
tom severity. Recently, Rogers et al4 developed and piloted
the feasibility of a manualized, parent-delivered intervention
for infants aged 6-15 months who were highly symptomatic
for autism spectrum disorder (n ¼ 7 high risk and n ¼ 7 low
risk for autism spectrum disorder). The intervention aimed
at 6 target symptoms (visual fixation, repetitive behaviors,
communicative acts, turn taking, phonemic development,
and gaze) and consisted of 12 weekly, 1-hour sessions.
Follow-up at 36 months showed that the treatment group
had lower rates of autism spectrum disorder symptomatol-
ogy and fewer developmental quotients under 70 on the
Mullen Scales of Early Learning than high-risk infants with
autism spectrum disorder who were not enrolled in the treat-
ment intervention. Overall, the results of the intervention
studies reviewed above underscore the importance of early
detection of autism spectrum disorder, noting promising
outcomes of short and long-term intervention in toddlers
with autism spectrum disorder.
6 Journal of Child Neurology
Genetic Disorders and Autism Spectrum
Disorder
Specific genetic syndromes associated with autism spectrum
disorder represent other potential high-risk groups that can be
studied prospectively beginning in infancy. However, the ques-
tion of co-occurring autism spectrum disorder in genetic syn-
dromes can be complex, as reported prevalence rates vary
widely,14,15 and may be driven by particular behavioral symp-
toms. One possible reason for variability in reported prevalence
could be the use of different assessment tools, including autism
spectrum disorder screening questionnaires68-70 and gold stan-
dard autism spectrum disorder diagnostic tools,71-73 as well as
parent report surveys.74,75 Although a complete review of
genetic syndromes associated with autism spectrum disorder
is beyond the scope of this article, for illustration, the following
section reports on 3 syndromes with elevated incidence of aut-
ism spectrum disorder: fragile-X syndrome, Down syndrome,
and Prader-Willi syndrome.
Fragile-X Syndrome
On a national parent survey in the United States, more than
1000 parents of children with fragile-X syndrome were asked
about co-occurring conditions. In total, parents reported that
40% (46% of males and 16% of females) had a diagnosis of aut-
ism spectrum disorder,74 consistent with a recent review citing
a range of 21-50% of autism spectrum disorder in genetic dis-
orders.14 The results from the national parent survey also found
that fragile-X syndrome and autism spectrum disorder were
rarely reported in isolation; rather, they frequently coincided
with attention problems, anxiety, and hyperactivity.74 Asses-
sing the clinical utility of using the CHAT to identify autism
spectrum disorder in young children with fragile-X
syndrome, Scambler et al76 noted that using the Denver
Criteria,77 the CHAT showed high levels of sensitivity (75%)
and specificity (92%) in identifying those children with
fragile-X syndrome who also had concurrent autism spectrum
disorder prior to age 3. Similarly, Rogers et al78 compared chil-
dren with autism spectrum disorder, developmental delays, and
fragile-X syndrome on two gold-standard autism spectrum dis-
order instruments and noted that the subgroup of children with
fragile-X syndrome but without autism spectrum disorder per-
formed similarly to the children with developmental delays,
whereas the subgroup of children with fragile-X syndrome and
autism spectrum disorder were virtually identical to the chil-
dren with autism spectrum disorder. Overall, children with
fragile-X syndrome and autism spectrum disorder have a sim-
ilar profile of scores on the Autism Diagnostic Observation
Schedule79 as children with autism spectrum disorder; how-
ever, the individuals with fragile-X syndrome and autism spec-
trum disorder also perform significantly lower on performance
and verbal IQ.13 These studies and a longitudinal study of boys
with fragile-X syndrome find that autism spectrum disorder can
be reliably diagnosed in fragile-X syndrome during the pre-
school years.80
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Down Syndrome
Prevalence of autism spectrum disorder in Down syndrome was
reported as 18% (24% of males and 9% of females), based on clin-
ical diagnosis of autism spectrum disorder in a cohort of 123 indi-
viduals with Down syndrome,81 also coinciding with the review
by Moss and Howlin,14 reporting 5-39% of individuals with
Down syndrome had co-occurring autism spectrum disorder.
Interestingly, it appears as though autism spectrum disorder is
most frequently found in children with Down syndrome who also
have intellectual disability. Indeed, the Moss and Howlin14
review found that individuals with Down syndrome who met cri-
teria for autism spectrum disorder also fell within the ‘‘moderate
to severe’’ degree of intellectual disability. Molloy et al82 found
that the deficits in social communication and restricted and repe-
titive behaviors are not entirely explained by the intellectual dis-
ability, suggesting that the autism spectrum disorder in Down
syndrome is not directly caused by cognitive impairment. Rather,
children with Down syndrome and autism spectrum disorder
begin to display atypical behaviors during infancy or toddlerhood,
including social disinterest, lack of sustained joint attention, few
gestures, repetitive motor behavior, self-injurious behaviors, sen-
sory seeking, and unusual play with objects.83 As with fragile-X
syndrome, diagnosis of autism spectrum disorder in Down syn-
drome can also reliably be performed in the preschool years.81
Prader-Willi Syndrome
The prevalence of autism spectrum disorder in Prader-Willi syn-
drome was reported as 25% in a recent systematic review,84 con-
firming previous findings.85 One interesting recurring finding is a
higher prevalence of autism spectrum disorder symptoms in the
uniparental disomy genetic subtype of Prader-Willi syndrome
when compared to the deletion subtype,86,87 presumably due to
the correlation between chromosome 15q11-13 and autism spec-
trum disorder.88,89 Specifically, adolescents and adults with the
uniparental disomy subtype have scored similar in autism spec-
trum disorder symptomatology to comparison groups with autism
spectrum disorder, and higher than those with the deletion sub-
type.86 Of note, individuals with Prader-Willi syndrome and aut-
ism spectrum disorder display repetitive behaviors, a need for
sameness, verbal perseverations, poor peer relations, and anxiety,
symptoms also present in autism spectrum disorder.90 However,
there is paucity in the literature concerning autism spectrum dis-
order in younger children with Prader-Willi syndrome. To date,
no study investigating autism spectrum disorder in Prader-Willi
syndrome has had a mean age below 8 years. Recent research has
suggested that autism spectrum disorder symptoms might not
emerge in Prader-Willi syndrome until children are older,91,92 but
further research is required to confirm these findings.
Summary
Prospective studies of autism spectrum disorder with high-risk
infants have been informative for identifying early behaviors
that are predictive of autism spectrum disorder. Interestingly,
Sacrey et al
such studies have proposed that the diagnostic characteristics
of the disorder, social-communication and restricted interests
and repetitive behaviors, may be preceded by prodromal symp-
toms, specifically, sensory and motor impairments. Indeed,
early differences have been identified in the brains of children
who will later be diagnosed with autism spectrum disorder as
early as 6 to 9 months of age, appearing prior to or concurrently
with symptom onset. There has been progress in establishing
developmentally appropriate and evidence-based interventions,
yet scholars still have a long way to go toward the goal of ear-
lier diagnosis and intervention for all children with autism
spectrum disorder. As such, research findings need to be trans-
lated into clinical practice must address health systems issues,
including access to specialized care.
Author Contributions
LRS and LZ developed the objectives for this review article. LRS,
JAB and LZ drafted initial sections of the manuscript and LRS inte-
grated the sections into an overall first draft. LRS, JAB and LZ criti-
cally revised the manuscript and approved of its final version.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship,
and/or publication of this article.
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