Autism and Other Neurodevelopmental Disabilities

Autism Spectrum Disorders

Diagnostic Criteria

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in two areas: (1) deficits in social communication and social interactions; and (2) restricted and repetitive patterns of behavior, interests, and activities ( ). With the revised Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), ASD now subsumes what were previously separate diagnostic categories of autistic disorder (also referred to as classic autism or early infantile autism), pervasive developmental disorder–not otherwise specified (PDD-NOS), and Asperger syndrome. The changes are based on research results which, thus far, have failed to document either PDD-NOS or Asperger syndrome as separate biological entities. The prior diagnostic manual also included deficits in language expression as a criterion, but this is no longer the case as not all children with ASD have language disorders. However, pragmatic language skills are incorporated into the social domain as all individuals with ASD have deficits in this domain of language. Under the DSM-5, diagnosis of ASD requires an individual to exhibit three deficits in social communication and at least two symptoms in the category of restricted range of activities/repetitive behaviors. Within the second category, a new symptom is included: hyper- or hyporeactivity to sensory input or unusual interests in sensory aspects of the environment. Deficits in social communication and interactions include those in social reciprocity, nonverbal communication, and skills in developing, maintaining, and understanding social relationships. Symptoms must be present in early development but need not be shown until social demands exceed the individual’s capacity. Furthermore, DSM-5 specifies three levels of severity (mild, moderate, severe) rated separately for social communication and restricted, repetitive behaviors, based on what level of support the individual requires. In addition to the diagnosis, individuals are also described in terms of any known genetic cause (e.g., fragile X syndrome [FXS], Rett syndrome), level of language and intellectual disability (ID), and presence of medical conditions such as seizures, psychiatric disorders (e.g., anxiety, depression), and/or gastrointestinal disorders. (See Box 90.1 and Table 90.1 for DSM-5 criteria for ASD.) The range of disabilities seen among children on the spectrum cannot be overemphasized.

BOX 90.1

DSM-5 Criteria for an Autistic Spectrum Disorder

A.
Persistent deficits in social communication and social interaction across multiple contexts, as manifested by the following, currently or by history (examples are illustrative, not exhaustive, see text):
- 1.
  Deficits in social-emotional reciprocity, ranging, for example, from abnormal social approach and failure of normal back-and-forth conversation; to reduced sharing of interests, emotions, or affect; to failure to initiate or respond to social interactions.
- 2.
  Deficits in nonverbal communicative behaviors used for social interaction, ranging, for example, from poorly integrated verbal and nonverbal communication; to abnormalities in eye contact and body language or deficits in understanding and use of gestures; to a total lack of facial expressions and nonverbal communication.
- 3.
  Deficits in developing, maintaining, and understanding relationships, ranging, for example, from difficulties adjusting behavior to suit various social contexts; to difficulties in sharing imaginative play or in making friends; to absence of interest in peers.
- Specify current severity:
- Severity is based on social communication impairments and restricted repetitive patterns of behavior (see Table 90.8 ).
B.
Restricted, repetitive patterns of behavior, interests, or activities, as manifested by at least two of the following, currently or by history (examples are illustrative, not exhaustive; see text):
- 1.
  Stereotyped or repetitive motor movements, use of objects, or speech (e.g., simple motor stereotypies, lining up toys or flipping objects, echolalia, idiosyncratic phrases).
- 2.
  Insistence on sameness, inflexible adherence to routines, or ritualized patterns or verbal nonverbal behavior (e.g., extreme distress at small changes, difficulties with transitions, rigid thinking patterns, greeting rituals, need to take same route or eat food every day).
- 3.
  Highly restricted, fixated interests that are abnormal in intensity or focus (e.g., strong attachment to or preoccupation with unusual objects, excessively circumscribed or perseverative interest).
- 4.
  Hyper- or hyporeactivity to sensory input or unusual interests in sensory aspects of the environment (e.g., apparent indifference to pain/temperature, adverse response to specific sounds or textures, excessive smelling or touching of objects, visual fascination with lights or movement).
- Specify current severity:Severity is based on social communication impairments and restricted, repetitive patterns of behavior (see Table 90.8 ).
C.
Symptoms must be present in the early developmental period (but may not become fully manifest until social demands exceed limited capacities, or may be masked by learned strategies in later life).
D.
Symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning.
E.
These disturbances are not better explained by intellectual disability (intellectual developmental disorder) or global developmental delay. Intellectual disability and autism spectrum disorder frequently co-occur; to make comorbid diagnoses of autism spectrum disorder and intellectual disability, social communication should be below that expected for general developmental level.

Note: Individuals with a well-established DSM-5 diagnosis of autistic disorder, Asperger disorder, or pervasive developmental disorder not otherwise specified should be given the diagnosis of autism spectrum disorder. Individuals who have marked deficits in social communication, but whose symptoms do not otherwise meet criteria for autism spectrum disorder, should be evaluated for social (pragmatic) communication disorder.

Specify if:

With or without accompanying intellectual impairment
With or without accompanying language impairment
Associated with a known medical or genetic condition or environmental factor
Associated with another neurodevelopmental, mental, or behavioral disorder
With catatonia

TABLE 90.1

Severity Levels for Autism Spectrum Disorder

Severity Level	Social Communication	Restricted, Repetitive Behaviors
Level 3 “Requiring very substantial support”	Severe deficits in verbal and nonverbal social communication skills cause severe impairments in functioning, very limited initiation of social interactions, and minimal response to social overtures from others. For example, a person with few words of intelligible speech who rarely initiates interaction and, when he or she does, makes unusual approaches to meet needs only and responds to only very direct social approaches	Inflexibility of behavior, extreme difficulty coping with change, or other restricted/repetitive behaviors markedly interfere with functioning in all spheres. Great distress/difficulty changing focus or action
Level 2 “Requiring substantial support”	Marked deficits in verbal and nonverbal social communication skills; social impairments apparent even with supports in place; limited initiation of social interactions; and reduced or abnormal responses to social overtures from others. For example, a person who speaks simple sentences, whose interaction is limited to narrow special interests, and who has markedly odd nonverbal communication	Inflexibility of behavior, difficulty coping with change, or other restricted/repetitive behaviors appear frequently enough to be obvious to the casual observer and interfere with functioning in a variety of contexts. Distress and/or difficulty changing focus or action
Level 1 “Requiring support”	Without supports in place, deficits in social communication cause noticeable impairments. Difficulty initiating social interactions, and clear examples of atypical or unsuccessful response to social overtures of others. May appear to have decreased interest in social interactions. For example, a person who is able to speak in full sentences and engages in communication but whose to-and-fro conversation with others fails, and whose attempts to make friends are odd and typically unsuccessful	Inflexibility of behavior causes significant interference with functioning in one or more contexts. Difficulty switching between activities. Problems of organization and planning hamper independence

Epidemiology

There has been a significant increase in the prevalence of ASD in the United States, particularly since the late 1990s. In the 1990s, the estimated frequency was about 1 per 1000 for autism and 2 per 1000 for ASD ( ), while, more recently, the estimated prevalence is much higher. The Autism and Developmental Disabilities Monitoring Network (2018), which identifies ASD through screening and review of health and education records that document behaviors associated with ASD in 11 sites in the United States, most recently reported a prevalence rate of 16.8 per 1000 (1 in 59) among 8 year olds, with prevalence estimates varying from 5.7 to 21.9 per 1000 in the different sites. Non-Hispanic White children were approximately 7% more likely to be identified with ASD than non-Hispanic Black children and 22% more than Hispanic children. ASDs are four times more likely in males than in females.

Whether there has been an actual increase in ASD prevalence or if the apparent increase is due to other factors is still under investigation. Factors such as increased awareness among parents and professionals ( ), broadening of the diagnosis with emphasis on the spectrum aspect of the disorder, including mildly affected individuals ( ), change in referral patterns, and using the diagnosis as a basis for intervention services ( ) may account for an apparent increase in prevalence rates. Both advanced maternal and paternal age may play a role in increasing the frequency of autism ( ). The theory that the measles, mumps, rubella (MMR) vaccine plays any role in the increase has been completely discredited ( ).

The prevalence of ASD in siblings of children with ASD ranges from 2% to 18% ( ). The high concordance in monozygotic twins ( ), the increased risk for recurrence in siblings (≈5%–10%), a broader autistic phenotype in families with an autistic proband, which includes anxiety and mood as well as social style and obsessive characteristics ( ), and the association with a number of genetic disorders support a hereditary basis in many cases ( ).

Developmental regression or loss of previously established skills during the first 1–3 years of life has been estimated as occurring in approximately one-third of children with ASD at an average age of 1.78 years ( ). A meta-analysis of studies on the prevalence of developmental regression in children with ASD found that rates differed based on type of regression measured. Studies focusing on language regression (e.g., loss of words) were estimated as occurring in 25%; those on both language and social regression (e.g., play skills, joint attention, response to name) in 38%; mixed regression (including cognitive and/or motor skills) in 33%; and unspecified regression in 39%. Similarly, regression prevalence differed based on sampling methods, with population-based studies showing a prevalence rate of 22%; clinic-based prevalence at 34%; and parent survey-based prevalence as 41% ( ). While most studies on regression in autism have relied on retrospective parent reports, recently there has been a shift towards prospective studies that focus on infants who are at genetically high risk for autism. These studies have tracked early-appearing social behaviors such as shared affect, social interest, gaze to face and eyes, and response to name. In a review of these prospective studies, found evidence that most children with autism had a period of relatively typical development followed by decline in social behaviors starting at about 9 months. In some studies, as many as 80% of infants with ASD demonstrated this early regression in social behaviors (Jones et al., 2014; Ozonoff et al., 2018b; Pearson et al., 2018).

While ASD cannot be reliably diagnosed until 18 months of age, there is evidence that ASD can be detected as early as 12 months old based on early social behaviors, including looking at people, use of gestures, response to name, and repetitive motor actions ( ). An eye-tracking study found that typical eye gaze is present but declines in 2- to 6-month-old children who are later diagnosed with ASD ( ).

Clinical Features

The intelligence quotient (IQ) is not one of the defining criteria for an ASD diagnosis ( ). The Autism and Developmental Disabilities Monitoring Network (2018) found that 31% of children with ASD have an ID (IQ < 70), 25% are in the borderline range (IQ 71–85), and 44% have IQ scores in the average to above average range (i.e., IQ > 85). Normal range IQ is a positive prognostic sign. Having a higher verbal IQ at 2–3 years of age appears to predict better outcome, particularly if intervention is delivered early ( ) Long-term prognosis also correlates with acquisition of language skills. An estimated one-third of people with autism are nonverbal, and those with verbal language often demonstrate significant difficulties with prosody and pragmatic language ( ). Individuals with conversational language by age 5–6 do significantly better than children with little or no language. Early joint attention (the ability to draw another person’s attention to an object of interest through the use of eye gaze and gestures, such as pointing), as well as vocal and motor imitation skills, was more impaired in children who did not develop language by age 5 (but had relatively strong nonverbal cognitive skills) than in children who did develop language by 5 years ( ).

The dominant feature of ASD is a difference in a child’s social communication and interaction. Typically developing children show a natural proclivity to learn from the social world, and they seek out social input spontaneously and frequently starting in the first weeks of life. By contrast, children with ASD tend to be more drawn to interaction with the physical world (Klin et al., 2002) and are less likely to show interest in interacting with others. They tend to have difficulty attending to others, interpreting the social intent of others, and sharing enjoyment. In toddlers and preschoolers, social deficits include reduced eye contact, reduced enjoyment in social games, lack of joint attention, and lack of interest in other children. Because of these social vulnerabilities, they struggle to learn appropriate social communication strategies including verbal speech as well as nonverbal communication strategies such as gestures and body language. They also tend to struggle to engage in age-appropriate functional and pretend play with others. As children with ASD progress through school, they can struggle with forming friendships, engaging appropriately in back-and-forth conversation, appropriate body language, and knowing how to initiate and respond to interactions with their peers appropriately.

A restricted range of behaviors, interests, and activities is another hallmark feature of autism. Many children with ASD demonstrate stereotypic motor behaviors such as hand flapping, tensing and shaking, toe walking, or spinning. In addition, they may use language in repetitive or idiosyncratic ways such as echoing statements made by others or heard on television, or repeating certain sounds/words/phrases over and over again. They may also like spinning, dropping, or lining up objects, or opening and closing doors. Second, children with ASD often are highly dependent on routines or rituals and have significant difficulty with change or transitions. Third, children with autism may be overly focused on a particular topic, object, or area of interest. For example, a child may be fixated on trains, super heroes, bunnies, the constitutional convention, or air conditioning units. Finally, children with ASD often demonstrate differences in how they respond to sensory input. They may seek out sensory input in unusual ways such as smelling or licking objects, or rubbing items on their face. In other instances, they may be highly sensitive to sensory input such as loud noises, textures, or crowded environments.

Evaluation

The clinical history and observations of the child are the basis for the diagnosis of an ASD. Research indicates that ASDs may be identified as young as 18 months of age or younger. By age 2 years, it is expected that a qualified professional can reliably make the diagnosis. The American Academy of Pediatrics recommends screening all children at well-child visits at 18 months and at 24 months of age ( ). A number of questionnaires and observation measures are available to screen for ASDs. Probably the most commonly used is the Modified Checklist for Autism in Toddlers–Revised (M-CHAT-R), which is a parent-completed questionnaire designed to identify children at risk for autism in the general population.

There are a number of tools used to assess ASDs, but experts believe that no single tool should be used to make a diagnosis. The Autism Diagnostic Observation Schedule-2 (ADOS-2) is considered the “gold standard” in diagnosing ASD. It consists of a semi-structured, standardized assessment of social interaction, play, and imaginative use of material for individuals suspected of having ASDs from 12 months old to adults. The ADOS often is used in conjunction with the Autism Diagnostic Interview–Revised (ADI-R), a clinical diagnostic interview for diagnosing autism in children and adults with mental ages of 18 months and above that focuses on assessing reciprocal social interactions, communication, and language; and restricted and repetitive, stereotyped interests and behaviors. Both the ADOS and ADI-R are time consuming and the ADOS requires special training to administer and score. Other well-known assessments include the Childhood Autism Rating Scale–Second Edition (CARS-2) that is appropriate for children over age 2 and draws from observations on different areas of behavior associated with ASDs. Several rating scales, such as the Social Responsiveness Scale (SRS-2) and the Social Communication Questionnaire (ScQ) can be helpful for eliciting information from parents and teachers.

The standard neurological examination is generally normal, although children with ASDs are often clumsy and have mild hypotonia. Macrocephaly occurs in about one-third of children with autism and generally becomes apparent around the age of 1–3 years. The fact that macrocephaly is not present at birth suggests there is an increased rate of brain growth in the first years of life that diminishes and may become subnormal in later childhood; macrocephaly in adults with autism is less common than in children with ASD ( ). Skin examination requires careful attention, given high co-occurrence with tuberous sclerosis ( ). Dysmorphology examination should be performed to facilitate the diagnosis of genetic syndromes (e.g., FXS, velocardiofacial syndrome, and Smith-Magenis syndrome). Hearing impairment should be excluded by a formal audiology assessment. Electroencephalogram (EEG), including a sleep record or overnight video-EEG monitoring, is appropriate when seizures occur or if developmental regression has occurred (see the Epilepsy section).

There are multiple neurometabolic causes of ASD, many of which are not usually associated with any dysmorphology. Primary inborn errors of metabolism in simple (e.g., nonsyndromic) autism are a rare occurrence. Treatable conditions include PKU (phenylketonuria), hyperammonemia/urea cycle defects, and creatine synthesis/creatine transporter defects. Other conditions include purine and pyrimidine abnormalities, Smith-Lemli-Opitz syndrome, and lysosomal storage disorders. Primary mitochondrial disease and ASD is a subject of much debate. Some investigators report a significant incidence of mitochondrial DNA changes or functional disturbances in children with ASD but whether these are the primary cause of ASD remains to be defined. The extent of the evaluation for an underlying metabolic disorder depends on clinical suspicion and the relevance to family counseling. Box 90.2 lists some disorders that can be associated with an ASD phenotype.

BOX 90.2

Double Syndromes: Medical Disorders Associated With Autistic Spectrum Disorder Phenotypes

Modified from Gillberg, C., 2010. Double syndromes: autism associated with genetic, medical and metabolic disorders. In: Nass, R.D., Frank, Y. (Eds.), Cognitive and Behavioral Manifestations of Pediatric Diseases. Oxford University Press, New York, pp. 100–110.

Genetic and Metabolic Disorders

Angelman
CHARGE association
Cohen
de Lange
DiGeorge (22q11 deletions)
Fragile X
Hypomelanosis of Ito
Joubert
Lujan-Fryns
Moebius sequence
Neurofibromatosis
Noonan
Oculoauriculovertebral spectrum (including Goldenhar)
Partial monosomy 1p36
Partial tetrasomy 15
Prader-Willi
PTEN
Rett complex
Sex chromosome aneuploidies
Sotos
Smith-Magenis
Timothy
Tuberous sclerosis
Williams

Metabolic Disorders

Adenylosuccinate lyase deficiency
Cerebral folate deficiency
Cystathionine β-synthase deficiency
Dihydropyrimidinase deficiency
Disorders of creatine transport or metabolism
Ehlers-Danlos syndrome
Homocysteine
Marfan syndrome
Mitochondrial disorders
Mucopolysaccharidosis, including Sanfilippo
Smith-Lemli-Opitz syndrome
Succinic semialdehyde dehydrogenase deficiency
Urea cycle disorders

Medical Comorbidities

Medical comorbidities frequently occur in ASD, including epilepsy, gastrointestinal dysfunction, sleep disorders, and psychiatric conditions (e.g., anxiety, depression, obsessive-compulsive disorder [OCD]). It is important to consider medical causes for any change in behavior, especially in those individuals who are nonverbal or with limited language capability. Examples of such medical conditions include, but are not limited to, the following: pain (due to migraine headaches, ear infection, fractures, etc.), gastrointestinal disorders (e.g., gastroesophageal reflux disorder [GERD], constipation), gastrourinary conditions (e.g., urinary tract infection [UTI]), hormonal imbalance/endocrine dysfunction (e.g., menstruation), and sleep disturbance (e.g., sleep apnea).

Epilepsy

The association of epilepsy with autism provided one of the first clues to suggest that autism was a neurodevelopmental disorder of brain function. It is now well established that individuals with ASD have a higher risk of epilepsy than the general population. Epilepsy is commonly reported to occur in approximately one-third of individuals with ASD but the exact prevalence is unknown, with reports in the literature ranging from 5% to 46% ( ). Variation in estimates is likely related to multiple factors such as sample ascertainment, degree of ID, age, gender, and type of ASD (simple/nonsyndromic vs. complex/syndromic). ID and motor impairments (e.g., cerebral palsy) have been identified most commonly as significant risk factors for epilepsy in ASD, with higher rates in those with more severe cognitive impairments ( , Viscidi et al., 2013). Age of onset of epilepsy in ASD has generally been thought to occur in two peaks, one in early childhood (<5 years) and the other in adolescence (10–15 years) ( ). However, the peak, before age 5 years, includes those children with ASD secondary to infantile spasms (frequently as part of tuberous sclerosis) and other epileptic encephalopathies. A community-based study of ASD in children with epilepsy has found that only 5%–15% of children with epilepsy have autism ( ).

Given the prevalence of epilepsy in autism, it is important to consider the possibility of seizures when evaluating an individual with autism, but currently there is inadequate evidence to recommend EEG in all individuals with autism ( ). Although all seizure types are present in ASD, the most commonly observed are complex partial seizures (85%) and generalized tonic-clonic seizures (7%). Absence and myoclonic seizures occur less commonly (1%–4%) ( ).

ASD can occur in the context of other comorbid medical conditions. Some of the most widely recognized syndromes associated with ASD and epilepsy include tuberous sclerosis, FXS, MECP2-related disorders (Rett syndrome), Angelman syndrome, and 15q duplication syndrome. A targeted physical examination should consider other risk factors for epilepsy including head circumference (microcephaly), dysmorphisms, skin lesions (tuberous sclerosis, neurofibromatosis type 1 [NF-1]), and focal neurological findings. It is crucial to assess for medical comorbidities which may mimic seizures, including sleep disorders, GERD, and other gastrointestinal disorders, and psychiatric disorders including attention-deficit/hyperactivity disorder (ADHD).

Epileptiform EEG abnormalities are frequently seen in children with ASD, with or without epilepsy. Interictal epileptiform discharges (IEDs) are detected in approximately 20% of ASD children without epilepsy and 80% of ASD children with epilepsy on routine EEG ( ). Since these background or epileptiform EEG abnormalities can occur in ASD individuals without a clinical history of seizures, they are not to be considered evidence for epilepsy. The significance of these abnormalities, especially in the absence of clinical seizures, is quite unclear. At the present time, there are no data to support the use of antiepileptic drugs or epilepsy surgery in the treatment of these abnormalities in the absence of clinical seizures ( ). The relationship of autistic regression to epilepsy and epileptiform EEG abnormalities is unclear. Findings in the literature are inconsistent with some studies reporting higher rates of epilepsy in children with ASD and regression, and others showing no relationship ( ). However, language regression is a hallmark of Landau-Kleffner syndrome (LKS), a rare childhood-onset epileptic encephalopathy in which loss of previously acquired language skills occurs in the context of an epileptiform EEG activated in sleep. Electrical status epilepticus (ESES) during slow-wave sleep is the electroencephalographic pattern seen in LKS. The degree of overlap between LKS, ESES, and autistic regression with epileptiform EEG is currently poorly understood, although it is known that this ESES is rarely seen in children with a more global autistic regression ( ). At the current time, there are no data to support the use of LKS- or ESES-specific treatment regimens in those with more classic autistic regression and epileptiform EEG without clinical seizures.

Etiology

Genetics

ASDs are clinically and etiologically heterogeneous. Twin and family studies provide evidence for ASD as a highly genetic disorder with heritability estimates of 85%–92%. A recent large multinational population-based cohort study, which included more than 2 million individuals from five countries, estimated the heritability of ASD to be approximately 80% ( ). With routine use of chromosomal microarray (CMA) and more recently whole-exome and genome sequencing, a genetic correlate can be identified in 30%–40% of children with ASD ( ). Having an etiological diagnosis offers clinicians the opportunity to provide better guidance regarding recurrence risks, as well as prognostic information, and obviates the need for additional medical or neurodiagnostic testing. Furthermore, a specific diagnosis can alert clinicians to be aware of other comorbidities associated with certain genetic syndromes to provide more personalized care.

Known genetic causes of ASD include cytogenetically visible chromosomal abnormalities (5%), copy number variants (CNVs) (e.g., submicroscopic deletions and duplications) (10%–20%), and single-gene disorders in which neurological findings are associated with ASD (5%–10%). CMA has replaced high-resolution chromosomes as the initial test of choice to evaluate children with ASD. CMA has identified clinically relevant de novo genetic imbalances in 7%–20% of individuals with autism of unknown cause. As CMA will not detect balanced translocations or low-level mosaicism, a karyotype should be done when there is a family history of multiple miscarriages or there is high suspicion of mosaic aneuploidy.

The most frequent chromosome abnormality found in 1%–3% of individuals with ASD is maternally derived 15q11q13 duplication ( ). Aneuploidies are also found in ASD: 21 (Down syndrome), X (Turner syndrome, Klinefelter syndrome, XXX syndrome), and Y (XYY syndrome) ( ).

Monogenic syndromes are found in 5%–10% of individuals with ASD. The most common is FXS, which is found in 1.5%–3%, and is caused by mutations in the FMR1 gene. Tuberous sclerosis ( TSC1 and TSC2 genes) occurs in about 1% of patients diagnosed with ASD. Mutations in the MECP2 protein (methyl CpG-binding protein 2) are known to cause Rett syndrome and are found in 1% of females with ASD. Mutations in the PTEN gene are found in ASD with macrocephaly (occipital frontal head circumference [OFD] > 3 standard deviations [3 SD] above the mean). Other single gene disorders associated with ASD include neurofibromatosis, type 1 ( NF1 gene), Duchene muscular dystrophy ( DMD gene), and Timothy syndrome ( CACNA1C gene) ( ).

The most common autism-related CNVs are 16p11.2 microdeletions and microduplications that are identified in about 1% of individuals with ASD. Individuals with deletions have commonly been found to have macrocephaly versus those with duplications often have microcephaly. Other recurrent CNVs found in ASD include 1q21.1, 15q13.3, 17p11.2, 22q11.2, 16p13.1, and microduplication of 7q11.23 ( ).

Mutations in genes encoding synaptic adhesion molecules like neuroligin, neurexin, contactin-associated protein (CNTNAP), and cell-adhesion molecule 1 (CADM1) suggest that impaired synaptic function underlies ASDs ( ). However, knockout mouse models of these mutations do not show the full range of autistic symptoms. This could mean that gain of function as well as loss of function arising from these mutations is required for the full ASD picture. Endoplasmic reticulum stress due to these mutations may cause a trafficking disorder of synaptic receptors like gamma-aminobutyric acid B (GABA _b ) receptors, resulting in impaired synaptic function and signal transduction. This theory provides for epigenetic factors playing a role as well ( ). Genes encoding postsynaptic scaffold proteins (SHANK2 and SHAN3) and ion channel proteins (CACNA1A, CACNA1H, SCN1A, SCN2A) also have been implicated in ASD ( ).

Neuropathology

Based on the core symptoms of autism, neuropathological abnormalities would be anticipated and are found in regions important to social function (frontal lobe, superior temporal cortex, parietal cortex, and amygdala), language function (language cortex), and repetitive behaviors and stereotypies (orbital frontal cortex and caudate) ( ). Functional imaging studies demonstrate that neural systems related to social functioning, such as emotional face recognition, are abnormal ( ). Abnormalities of mirror neurons are also seen when subjects imitate and observe emotions ( ).

ASDs are now considered disorders of the development of the connectivity of the neurons of the cerebral cortex, which results in disturbances in the highly specialized connections that provide for uniquely human abilities. The occurrence of mutations in genes that act on molecular signaling pathways involved in the development and maintenance of neuronal and synaptic connections has reinforced the centrality of disruption of cortical connectivity in ASD ( ).

Studies of brain structure have implicated multiple events in the prenatal and postnatal brain development, particularly neuronal organizational events. A recent study supports a prenatal onset of ASD, occurring during the second and third trimester of pregnancy. Courchesne and colleagues found focal patches of abnormal laminar cytoarchitecture and cortical disorganization of neurons, but not glia, in the prefrontal and temporal cortical tissue from 10 of 11 children with autism and from 1 of 11 unaffected children, supporting a probable dysregulation of layer formation and layer-specific neuronal differentiation prenatally ( ).

Increased total brain volume, primarily due to increased white matter, is the most frequently replicated imaging finding ( ). Very young children with autism (18 months to 4 years) have a 5%–10% increase in brain volume, especially in the frontal lobe compared to controls, which parallels the increasing head circumference during this period. A recent study suggests that changes in brain growth rate between the ages of 6 and 12 months may predict changes in the brain that occur between the ages of 12 and 24 months and correspond with the development of ASD symptoms (Hazlett, 2017).

In contrast to other white-matter structures, both volume and density of the corpus callosum are reduced ( ), perhaps resulting in decreased interhemispheric communication ( ). Imaging studies also highlight the dissociation between white-matter tract overgrowth and gray-matter dendritic and synaptic underdevelopment. Spectroscopy studies suggest that the gray matter is abnormal and dendritic arborization and synaptosome density reduced. Some investigators speculate that gray-matter abnormalities trigger the white-matter overgrowth ( ).

The white-matter abnormalities result in abnormality of connectivity. At the cytoarchitectonic level, minicolumns that determine connectivity are abnormal, especially in the dorsolateral prefrontal cortex ( ). As a result, and well delineated on diffusion tensor (DT) imaging ( ), short-range connectivity is increased, and long-range connectivity is decreased ( ). The hyperconnected local networks may become partially isolated and acquire novel functional properties. By contrast, the decrease in long-range connections could explain the problems with top-down control and integration ( ). A recent study of toddlers, ages 1–4 years, with ASD found axonal overconnectivity in frontal lobes with growth pathology thought to be due to neuron excess. This is thought to lead to underfunctional connectivity and resultant impairments in social communication ( ).

Given that the brain mechanisms causing ASD are largely at the level of connections among neurons and are not detectable on gross structural neuroimaging, imaging is not considered a routine part of the evaluation of individuals with ASD.

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