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Chapter 31: Child Psychiatry
in autism spectrum disorder. These will be discussed further in
the next section.
A number of known genetically caused syndromes include
autism spectrum disorder as part of a broader phenotype. The
most common of these inherited disorders is fragile X syn-
drome, an X-linked recessive disorder that is present in 2 to
3 percent of individuals with autism spectrum disorder. Fragile
X syndrome exhibits a nucleotide repeat in the 5’ untranslated
region of the
FMNR1
gene, resulting in symptoms of autism
spectrum disorder. Children with fragile X syndrome charac-
teristically exhibit intellectual disability, gross and fine motor
impairments, an unusual facies, macroorchidism, and signifi-
cantly diminished expressive language ability. Tuberous sclero-
sis, another genetic disorder characterized by multiple benign
tumors, inherited by autosomal dominant transmission, is found
with greater frequency among children with autism spectrum
disorder. Up to 2 percent of children with autism spectrum dis-
order also have tuberous sclerosis.
Researchers who screened the DNA of more than 150 pairs
of siblings with autism spectrum disorder found evidence of
two regions on chromosomes 2 and 7 containing genes that
may contribute to autism spectrum disorder. Additional genes
hypothesized to be involved in autism spectrum disorder were
found on chromosomes 16 and 17.
Biomarkers in Autism Spectrum Disorder
Autism spectrum disorder is associated with several biomark-
ers, potentially resulting from interactions of genes and envi-
ronmental factors, which then influence neuronal function,
dendrite development, and contribute to altered neuronal infor-
mation processing. Several biomarkers of abnormal signaling in
the 5-HT system, the mTOR-linked synaptic plasticity mecha-
nisms, and alterations of the
γ
-aminobutyric acid (GABA)
inhibitory system.
The first biomarker identified in autism spectrum disorder
was elevated serotonin in whole blood, almost exclusively in the
platelets. Platelets acquire 5-HT through the process of SERT
(serotonin transporter), known to be hereditary, as they pass
through the intestinal circulation. The genes that mediate SERT
(
SLC64A
), and the 5-HT receptor 5-HT 2A gene (
HTR2A
) are
known to be more heritable than autism spectrum disorder,
and encode the same protein in the platelets and in the brain.
Because 5-HT is known to be involved in brain development,
it is possible that the changes in 5-HT regulation may lead to
alterations in neuronal migration and growth in the brain.
Both structural and functional neuroimaging studies have
suggested specific biomarkers associated with autism spectrum
disorder. Several studies found increased total brain volume in
children younger than 4 years of age with autism spectrum dis-
order, whose neonatal head circumferences were within normal
limits or slightly below. By about age 5 years, however, 15 to
20 percent of children with autism spectrum disorder devel-
oped macrocephaly. Additional studies found confirmatory data
in samples of infants who were later diagnosed with autism
spectrum disorder, who exhibited normal head circumferences
at birth; by 4 years, 90 percent had larger brain volumes than
controls, with 37 percent of the autism spectrum disorder group
meeting criteria for macrocephaly. In contrast, structural mag-
netic resonance imaging (sMRI) studies of children with autism
spectrum disorder ranging from 5 to 16 years did not find mean
values of total brain volume increased. One study followed the
size of the amygdala in youth with autism spectrum disorder
in the first few years of life, and similarly, found an increased
size in the first few years of life, followed by a decrease in
size over time. The size of the striatum has also been found
in several studies to be enlarged in young children with autism
spectrum disorder, with a positive correlation of striatal size
with frequency of repetitive behaviors. The dynamic process
of the atypical and changing total brain volume observed in
children with autism spectrum disorder lends support for the
overarching hypothesis that there are sensitive periods or “criti-
cal periods” within the brain’s plasticity that may be disrupted
in ways that may contribute to the emergence of autism spec-
trum disorder.
Functional MRI (fMRI) studies have focused on identify-
ing biomarkers, that is, the functional brain correlates of vari-
ous observed core symptoms in autism spectrum disorder.
fMRI studies of children, adolescents, and adults with autism
spectrum disorder have employed tasks including face percep-
tion, neutral face tasks, “theory of mind” deficits, language and
communication impairments, working memory and repetitive
behaviors. fMRI studies have provided evidence that individu-
als with autism spectrum disorder have a tendency to scan faces
differently than controls, in that they focus more on the mouth
region of the face rather than on the eye region and rather than
scan the entire face multiple times, individuals with autism
spectrum disorder focus more on individual features of the face.
In response to socially relevant stimuli, researchers have come
to the conclusion that individuals with autism spectrum disor-
der have greater amygdala hyperarousal. In terms of “theory of
mind,” that is, the ability to attribute emotional states to oth-
ers, and to oneself, fMRI studies find differences in activation
in brain regions such as the right temporal lobe and other areas
of the brain known to become activated in controls during tasks
involving theory of mind. This difference has been hypothesized
by some researchers to represent dysfunction of the mirror neu-
ron system (MNS). Atypical patterns of frontal lobe activation
have been found in multiple studies of autism spectrum disorder
during face processing tasks, suggesting that this area of the
brain may be critical in social perception and emotional reason-
ing. Decreased activation in individuals with autism spectrum
disorder in the left frontal regions of the brain during memory
and language-based tasks led researchers to hypothesize that
individuals with autism spectrum disorder utilized more visual
strategies during language processing than controls did.
Both sMRI and fMRI research has contributed to demon-
strating brain correlates of core impairments observed in indi-
viduals with autism spectrum disorder.
Immunological Factors
Several reports have suggested that immunological incom-
patibility (i.e., maternal antibodies directed at the fetus) may
contribute to autistic disorder. The lymphocytes of some
autistic children react with maternal antibodies, which raises
the possibility that embryonic neural tissues may be damaged
during gestation. These reports usually reflect single cases
rather than controlled studies, and this hypothesis is still
under investigation.
