Autism Spectrum Disorder

Updated: Mar 18, 2020
  • Author: James Robert Brasic, MD, MPH; Chief Editor: Caroly Pataki, MD  more...
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Overview

Practice Essentials

Autism spectrum disorder (ASD) manifests in early childhood and is characterized by qualitative abnormalities in social interactions, markedly aberrant communication skills, and restricted repetitive behaviors, interests, and activities (RRBs). [1] ASD is the broad current designation for a group of conditions with deficits in social interaction and communication and RRBs. ASD includes a variety of disorders that fit two broad classes: (1) genetic disorders with features of ASD including fragile X syndrome, Rett syndrome, and tuberous sclerosis, and (2) idiopathic with unknown causes. Idiopathic forms of ASD have been called a variety of terms over the years, including autistic disorder, pervasive developmental disorder, and Asperger syndrome. Further information about the subtypes can be located in the articles for each condition. Readers can benefit from recognizing that the terms "autism" and "autistic disorder" have been used to describe ASD. "Pervasive developmental disorder" had been used to describe disorders including ASD and conditions with some traits characteristic of autism. Asperger syndrome refers to high-functioning individuals with ASD; these are people who have normal or superior intellectual abilities. People with Asperger syndrome may lack the communication abnormalities characteristic of ASD. Indviduals with the genetic disorders associated with ASD may or may not manifest the symptoms and signs of ASD. The development of techniques to help people with ASD attain favorable educational and occupational outcomes in community settings provide opportunities for the successful lives of people with ASD and their families. [2]

Signs and symptoms

Behavioral and developmental features that suggest autism include the following:

  • Developmental regression

  • Absence of protodeclarative pointing, i.e., failure to look where the examiner is looking and pointing

  • Abnormal reactions to environmental stimuli

  • Abnormal social interactions

  • Absence of smiling when greeted by parents and other familiar people

  • Absence of typical responses to pain and physical injury

  • Language delays and deviations

  • Absence of symbolic play
  • Repetitive and stereotyped behavior

Regular screening of infants and toddlers for symptoms and signs of ASD is crucial because it allows for early referral of patients for further evaluation and treatment. [1] Siblings of children with ASD are at risk for developing traits of ASD and even a full-blown diagnosis of ASD. Therefore, siblings should also undergo screening not only for autism-related symptoms but also for language delays, learning difficulties, social problems, and anxiety or depressive symptoms. [3]

Having parents fill out the Autism Screening Checklist can identify children who merit further assessment for possible ASD. See the image below for a printable version of the checklist.

The significance of answers to individual Autism S The significance of answers to individual Autism Screening Checklist items is as follows: Item 1- A "yes" occurs in healthy children and children with some pervasive developmental disorders; a "no" occurs in children with autism, Rett syndrome, and other developmental disorders. Item 2 - A "yes" occurs in healthy children, not children with autism. Item 3 - A "yes" occurs in healthy children and children with Asperger syndrome (ie, high-functioning autism); a "no" occurs in children with Rett syndrome; children with autism may elicit a "yes" or a "no"; some children with autism never speak; some children with autism may develop speech normally and then experience a regression with the loss of speech. Item 4 - A "yes" occurs in healthy children and children with Asperger syndrome and some other pervasive developmental disorders; a "no" occurs in children with developmental disorders; children with autism may elicit a "yes" or a "no." Items 5-10 - Scores of "yes" occur in some children with autism and in children with other disorders. Item 11 – A "yes" occurs in healthy children; a "no" occurs in some children with autism and in children with other disorders. Items 12, 13 - Scores of "yes" occur in some children with autism and in children with other disorders. Items 14-19 - Scores of "yes" occur in children with schizophrenia and other disorders, not in children with autism, Asperger syndrome, or other autism spectrum disorders. The higher the total score for items 5-10, 12, and 13 on the Autism Screening Checklist, the more likely the presence of an autism spectrum disorder.

See Clinical Presentation for more detail.

Diagnosis

Examination for patients with suspected ASD may include the following findings:

  • Abnormal motor movements (eg, clumsiness, awkward walk, hand flapping, tics)

  • Dermatologic anomalies (eg, aberrant palmar creases)

  • Abnormal head circumference (eg, small at birth, increased from age 6 months to 2 years, [4] normal in adolescence [5] )

  • Orofacial, extremity, and head/trunk stereotypies (eg, purposeless, repetitive, patterned motions, postures, and sounds)

  • Self-injurious behaviors (eg, picking at the skin, self-biting, head punching/slapping)

  • Physical abuse inflicted by others (eg, parents, teachers)

  • Sexual abuse: External examination of genitalia is appropriate; if bruises and other evidence of trauma are present, pelvic and rectal examinations may be indicated

Diagnostic criteria

The definition of ASD in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) encompasses the previous manual's autistic disorder (autism), Asperger's disorder, childhood disintegrative disorder (Heller's syndrome), and pervasive developmental disorder not otherwise specified. ASD is characterized by the following: [6]

  • Deficits in social communication and social interaction

  • Restricted repetitive behaviors, interests, and activities (RRBs)

These symptoms are present from early childhood and limit or impair everyday functioning. Both components are required for diagnosis of ASD.

Testing

There are no blood studies recommended for the routine assessment of ASD. Although several metabolic abnormalities have been identified in investigations of people with ASD (eg, elevated serotonin, reduced serum biotinidase, abnormal neurotransmitter functions, impaired phenolic amines metabolism), a metabolic workup should be considered on an individual basis. No biologic markers for autism currently exist.

Studies that may be helpful in the evaluation of ASD include the following:

  • EEG, sleep-deprived: [7] To exclude seizure disorder, acquired aphasia with convulsive disorder (Landau-Kleffner syndrome), biotin-responsive infantile encephalopathy, related conditions

  • Psychophysiologic assessment: To show lack of response habituation to repeatedly presented stimuli (in respiratory period, electrodermal activity, vasoconstrictive peripheral pulse amplitude response); auditory overselectivity may be seen

  • Polysomnography: To identify sleep disorders and to demonstrate seizure discharges

Neuroimaging studies

There is currently no clinical evidence to support the role of routine clinical neuroimaging in the diagnostic evaluation of ASD, even in the presence of megalencephaly. [3] Although characteristic abnormalities have been identified, no single finding is diagnostic.

The following imaging techniques have yielded inconsistent results in evaluating ASD:

  • MRI with or without diffusion tensor imaging

  • CT scanning

  • PET scanning

  • SPECT scanning

See Workup for more detail.

Management

The established therapies for ASD are nonpharmacologic and may include individual intensive interventions. Individuals with ASD  typically benefit from behaviorally oriented therapeutic programs developed specifically for this population. Children with ASD should be placed in these specialized programs as soon as the diagnosis is suspected.

Nonpharmacologic therapy

  • Intensive individual special education

  • Speech, behavioral, occupational, and physical therapies (eg, assisted communication, auditory integration training, sensory integration therapy, exercise/physical therapy)

  • Social skills training is helpful for children with ASD, including those with comorbid anxiety disorders; [8] . While social skills interventions appear modestly effective for young people with ASD, the effects may not readily generalize to educational settings [9]

  • Cognitive behavioral therapy [9]

Pharmacotherapy

No pharmacologic agent is effective in the treatment of the core behavioral manifestations of ASD, but drugs may be effective in treating associated behavioral problems and comorbid disorders (eg, self-injurious behaviors, movement disorders). The possible benefits from pharmacotherapy must be balanced against the likely adverse effects on a case-by-case basis (eg, venlafaxine may increase high-intensity aggression in some adolescents with ASD [10] )

Medications used in managing related behavioral problems and comorbid conditions in children with ASD include the following:

  • Second-generation antipsychotics (eg, risperidone, aripiprazole, ziprasidone)

  • SSRI antidepressants (eg, fluoxetine, citalopram, escitalopram)

  • Stimulants (eg, methylphenidate)

  • Alpha-2 adrenergic receptor agonists (e.g., clonidine, guanfacine) [11]

See Treatment and Medication for more detail.

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Background

ASD is a condition that manifests in early childhood and is characterized by qualitative abnormalities in social interactions, markedly aberrant communication skills, and restricted repetitive and stereotyped behaviors. A heterogeneous group of disorders includes the trait of ASD.

Motion anomalies

Motion anomalies are a prominent feature in a subset of individuals and have been reported at birth in some persons with ASD. Motion analysis may provide evidence of ASD in early infancy, before other manifestations occur. [12]

The motion anomalies demonstrated by children with ASD are often highly characteristic and noticeable. An example of a motion typical in ASD occurs when the child places a hand with fingers separately outstretched before the eyes and rapidly moves the hand back and forth. A similar experience results from moving up and down while gazing through the slats of Venetian blinds. This action is described as self-stimulation because it produces a visual sensation of movement. (See Presentation.)

Many of the motions of children with ASD appear to be attempts to provide themselves with sensory input in a barren environment. Through special education, children may learn to suppress the movements, although these may subsequently be exhibited at times of particular stress or excitement.

Causes

Although the etiology of ASD is unknown, hypotheses include genetic abnormalities, obstetric complications, exposure to toxic agents, and prenatal, perinatal, and postnatal infections. [13, 14, 15, 16]

Genetic studies have contributed to our understanding of the inheritance of ASD. A susceptibility to ASD is likely associated with 400 to 1000 genes. [17] A heritability plays a role in 74% to 93% of the risk for ASD. [18] Increasing risk for ASD is independently associated with maternal age of 40 years and older, paternal age of 50 years and older, and interpregnancy intervals less than 24 months. [19, 20]

Maternal rubella is associated with significantly higher rates of ASD and other conditions in children. Additionally, tuberous sclerosis is associated with ASD as a comorbid disorder. [21]

On the other hand, anecdotal reports that ASD may be linked with vaccinations (eg, for measles, mumps, and rubella) have not been supported by broader research. [22] Research from the CDC indicates that the number of childhood vaccines administered, either in a single day or during a child's first 2 years, has no effect on the risk of developing ASD. According to results of a case-control study of more than 1000 children born between January 1994 and December 1999, exposure to antibody-stimulating proteins or polysaccharides from vaccines between the ages of 3 months and 2 years was not associated with an increased risk of developing an ASD. The study included 256 children with an ASD and 752 healthy controls. [23, 24] Parents should be encouraged to fully immunize their children. [25] (See Etiology.)

Effective treatment of associated behavioral problems includes intensive behavioral, educational, and psychological components. Interventions initiated at the time of diagnosis increase the likelihood of a favorable outcome. [26] Regular screening of infants and toddlers for symptoms and signs of autistic disorder is crucial because it allows for early referral of patients for further evaluation and treatment. (See Treatment.)

The initial clinical descriptions of ASD suggested that cold, rejecting parents ("refrigerator mothers") caused autism in offspring; however, careful study of children with ASD and their parents has disproved this hypothesis. Autism is not caused by a lack of warmth and affection in parents, nor by any other emotional or psychological parental deficits. Blaming parents for the development of ASD in their children is inappropriate.

Diagnosis

The Autism Screening Checklist is provided as a preliminary tool for use by parents, teachers, and other members of the general community to identify children with some symptoms and signs suggestive of ASD.(See the screening checklist below.)

The significance of answers to individual Autism S The significance of answers to individual Autism Screening Checklist items is as follows: Item 1- A "yes" occurs in healthy children and children with some pervasive developmental disorders; a "no" occurs in children with autism, Rett syndrome, and other developmental disorders. Item 2 - A "yes" occurs in healthy children, not children with autism. Item 3 - A "yes" occurs in healthy children and children with Asperger syndrome (ie, high-functioning autism); a "no" occurs in children with Rett syndrome; children with autism may elicit a "yes" or a "no"; some children with autism never speak; some children with autism may develop speech normally and then experience a regression with the loss of speech. Item 4 - A "yes" occurs in healthy children and children with Asperger syndrome and some other pervasive developmental disorders; a "no" occurs in children with developmental disorders; children with autism may elicit a "yes" or a "no." Items 5-10 - Scores of "yes" occur in some children with autism and in children with other disorders. Item 11 – A "yes" occurs in healthy children; a "no" occurs in some children with autism and in children with other disorders. Items 12, 13 - Scores of "yes" occur in some children with autism and in children with other disorders. Items 14-19 - Scores of "yes" occur in children with schizophrenia and other disorders, not in children with autism, Asperger syndrome, or other autism spectrum disorders. The higher the total score for items 5-10, 12, and 13 on the Autism Screening Checklist, the more likely the presence of an autism spectrum disorder.

One goal of this article is to convey fundamental concepts related to ASD and related conditions.

Several instruments have been developed to diagnose ASD. Administering these tools in a reliable and valid manner requires extensive training and experience. Therefore, unless they have wide experience with children with ASD and understand the concepts implicit in the diagnostic criteria and rating scales, pediatricians and other clinicians are advised to refer patients with possible ASD to experienced clinicians for definitive diagnostic evaluations. Readers of this article must obtain considerable additional training before they can reliably and validly apply diagnostic criteria and rating tools.

Treatment

Individualized, intensive behavioral and psychological interventions must be instituted immediately after the diagnosis of ASD in order for the patient to achieve an optimal outcome. Although controversy surrounds the appropriate form of special education, some evidence suggests that an individual educational program must be developed by a special educator familiar with ASD and related conditions.

Because deficits in language and communication are often major impediments to progress in educational, work, and personal settings, patients often benefit from specialized communication devices and training. Persons experienced in the needs and treatment of individuals with serious communication handicaps (ie, speech and language specialists) may help the patient to maximize communication skills.

Although psychoanalytic approaches to treatment of children with ASD were common in the mid-20th century, these approaches were not found to be effective and are no longer used. Pharmacotherapy is ineffective in treating the core deficits of ASD but may be effective in treating associated behavioral problems and comorbid disorders. The possible benefits from pharmacotherapy must be balanced against the likely adverse effects on a case-by-case basis. (See Treatment.)

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Pathophysiology

Neural anomalies

In patients with autism, neuroanatomic and neuroimaging studies reveal abnormalities of cellular configurations in several regions of the brain, including the frontal and temporal lobes and the cerebellum. Enlargements of the amygdala and the hippocampus are common in childhood. Markedly more neurons are present in select divisions of the prefrontal cortex of autopsy specimens of some children with ASD, compared with those without ASD. [27]

Magnetic resonance imaging (MRI) studies have suggested evidence for differences in neuroanatomy and connectivity in people with ASD compared with normal controls. Specifically, these studies have found reduced or atypical connectivity in frontal brain regions, as well as thinning of the corpus callosum in children and adults with ASD and related conditions.

In a study that included 17 adults with high-functioning ASD and 17 age- and IQ-matched control subjects, functional magnetic resonance imaging (fMRI) of the brain that showed neural representations of social interactions was able to accurately identify individuals with ASD. Scans were performed as study subjects thought about a set of social interaction verbs from both an action and a recipient perspective. [28, 29]

Importantly, some of the regional differences in neuroanatomy correlate significantly with the severity of specific autistic symptoms. [30, 31] For example, social and language deficits of people with ASD likely are related to dysfunction of the frontal and temporal lobes. [32]

In a study of postmortem brain tissue from 11 children with ASD and 11 unaffected controls, researchers found focal disruption of cortical laminar architecture in the cortexes of 10 of the children with ASD and 1 of the controls, suggesting that brain irregularities in ASD may have prenatal origins. The patches of abnormal neurons were found in the frontal and temporal lobes, regions involved in social, emotional, communication, and language functions. Since the changes were in the form of patches, the researchers believe that early treatment could rewire the brain and improve ASD symptoms. [33, 34]

On MRI scans, the brains of children with ASD demonstrate greater myelination in bilateral medial frontal cortices and less myelination in the left temporoparietal junction. [35] Similarly, region-specific differences in the concentrations of gray matter, made up of neuronal cell bodies, dendrites, unmyelinated axons and glial cells, are also found in the brains of people with autism. [36]

Gamma-amino butyric acid (GABA)

Increased risk of developmental delay and ASD is associated with prematurity. Reductions in cerebral GABA likely contribute to the sensorimotor and behavioral anomalies of individuals with ASD. [37, 38, 39] Reductions in sensorimotor GABA were observed by magnetic resonance spectroscopy (MRS) in participants with ASD in contrast to matched controls without ASD. [37, 38] Behavioral measures of inhibition correlated with the reductions in sensorimotor GABA concentrations. [37, 38] By contrast, GABA concentrations were similar in a different cohort of boys with ASD and typical boys. [37, 40] In the boys with ASD the ratio of GABA/creatine on MRS was associated with symptoms of ASD. [37, 41]

Postmortem specimens of the brains of people with ASD demonstrated reductions for gamma-aminobutyric acid–B (GABAB) receptors in the cingulate cortex, a key region for the evaluation of social relationships, emotions, and cognition, and in the fusiform gyrus, a crucial region to evaluate faces and facial expressions. [42] These findings provide the basis for further investigation of autism and other pervasive developmental disorders.

Glutathione (GSH)

As the main brain antioxidant glutathione (GSH) may play a role in the development of ASD. ASD is hypothesized to be caused by oxidative stress. MRS demonatrated reduced GSH, Cr, and myoinositol (MI) in the doral anterior cingulate cortex (dACC) of participants with ASD in contrast to healhty participants without dACC. [37, 43]

N-acetylaspartate (NAA)

Diminished neuronal activity indicated by reductions of NAA in frontal, parietal, and temporal lobes, amygdala, hippocampus, and thalamus of children with ASD was observed on MRS. [37, 44] MRS also showed diminished concentrations of creatine (Cr) and phosphocreatine (PCr) in the cortex and the white matter of people with ASD, suggesting reduced cellular oxidative metabolism. [45, 37] Diminished neuronal metabolsm in the anterior white matter of boys with ASD in contrast to age-matched controls was indicated by the reduced NAA/Cr ratios on MRS. [46, 37]

Metabolic anomalies

In animal studies, dysfunction of serotonin and the neuropeptides oxytocin and vasopressin has been associated with abnormalities in affiliative behaviors. Neurophysiologic dysfunction involving one or more of these substances may also be present in humans with ASD.

Elevations of blood serotonin levels occur in approximately one third of individuals with ASD and are also reported in the parents and siblings of patients. Functional anomalies in other neurotransmitters (eg, acetylcholine, glutamate) have also been identified in some people with ASD. [32, 47]

Serum biotinidase is reduced in some people with ASD. This enzyme is required for the use and recycling of the B vitamin biotin. Deficiency of biotin has been linked with behavioral disorders.

Immunologic studies have identified abnormalities such as decreased plasma concentrations of the C4B complement protein. Such abnormalities may be the source of the increased susceptibility to infection seen in some people with ASD.

Diet is a controversial aspect of ASD. The greatest attention has been given to gluten- and casein-free diets; anecdotal information suggests that these diets help some children with ASD. [48] Test findings suggest that low-functioning children with ASD may have impairment in the metabolism of phenolic amines. [49] Therefore, symptoms of ASD are possibly aggravated by the consumption of dairy products, chocolates, corn, sugar, apples, and bananas; however, no large population studies have confirmed this.

Oxidative stress may play a role in the pathogenesis and the pathophysiology of ASD. [50] Compared with normal children, children with ASD have decrements in the following: [50]

  • Plasma levels of cysteine, glutathione, and methionine

  • The ratio of S -adenosyl-L-methionine (SAM) to S -adenosyl-L-homocysteine (SAH)

  • The ratio of reduced to oxidized glutathione

Some children with ASD display hyperlacticacidemia [51] as well as evidence of mitochondrial disorders [51] including carnitine deficiency. [52] These abnormalities may reflect disturbed neuronal energy metabolism.

Mitochondrial dysfunction

Since mitochondrial function may be impaired in some individuals with ASD, [51, 53]  a lack of dietary components containing key cofactors [54] may play a role in the pathogenesis.

Neural inflammation

A low concentration of anti-inflammatory cytokines may produce an imbalance between anti-inflammatory and pro-inflammatory cytokines to trigger inflammation in ASD. [55]  Infection in pregnancy may release inflammatory cytokines crossing the placenta to result in neuronal inflammation in the fetus. [56]

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Etiology

In the 1940s, in his seminal papers that first identified ASD, the child psychiatrist Leo Kanner conjectured that ASD resulted from rejection of the infant by emotionally cold parents ("refrigerator mothers"). In the 1950s and 1960s, Bruno Bettelheim popularized this idea. Since then, careful family studies have disproved the hypothesis that the development of ASD in children is caused by faulty parenting. Sensitive clinicians communicate to parents that their parenting skills did not cause their child's ASD. Repeated communication of this fact will help to minimize the guilt often experienced by parents of children with ASD.

The causes of ASD are unknown. Hypotheses include obstetric complications, infection, genetics, and toxic exposures. [57, 58, 59] None of these, however, has been established as a definite etiology.

Many factors have been associated with the risk for ASD, including maternal and paternal ages of 35 years or older, Caucasian or Asian race of mother or father, and college graduation of mother or father. [60]  

Obstetric complications

Many individuals with ASD and related conditions experienced untoward events in their prenatal and neonatal periods and during delivery. [13, 14, 15, 61] It is unclear whether the obstetric complications caused ASD or whether ASD and obstetric complications resulted from environmental or other problems.

During the perinatal period, the factors associated with ASD risk were hypertension or diabetes in mother, threatened abortion, antepartum hemorrhage, caesarian delivery, gestational age ≤ 36 weeks, parity ≥ 4, spontaneous labor, induced labor, no labor, breech presentation, preeclampsia, and fetal distress. During the postnatal period, the factors associated with ASD risk were low birth weight, postpartum hemorrhage, male gender, and brain anomaly. [60]

In a large Danish study published in JAMA, maternal use of valproate during pregnancy was associated with a significantly increased risk for ASD in offspring. The drug is already not recommended for use in pregnant women due to the risk of congenital malformations and its possible association with low intelligence in children exposed during pregnancy.

Researchers used data on all children born in Denmark between 1996 and 2006. Of the 655,615 children born in the study period, 5437 had ASD. There were 2644 children exposed to antiepileptic drugs during pregnancy, 508 of whom were exposed to valproate. Analysis showed that the children exposed to valproate had a 3-fold increased risk for ASD compared with unexposed children, even after adjustment for parental psychiatric disease and epilepsy. [62, 63]

The management of women with epilepsy who desire to bear children can be challenging. A woman with an ongoing seizure disorder requires treatment because maternal seizures can result in serious morbidity and mortality for the mother and the fetus. To stop anticonvulsant therapy when a woman with a seizure disorder becomes pregnant to avoid teratologic effects may precipitate uncontrolled seizures that may be fatal to the mother and the fetus. Therefore physicians treating women with child-bearing potential can appropriately initiate frank conversations about future pregnancies. Juvenile myoclonic epilepsy and other seizure disorders typically cause seizures throughout adulthood so pharmacotherapy throughout adulthood is a reasonable treatment plan. While valproate is an excellent agent to control a vast spectrum of seizure disorders, its use in women of child-bearing potential is fraught with danger due to the great risk of producing ASD, spina bifida, and other birth defects. A frank conversation between the physician and the woman of child-bearing potential about the risks and benefits of specific antiepileptic drugs for the mother and the fetus is indicated. Documentation of these conversations is the medical record is needed. This record may be useful in court if legal action is initiated if a child has birth defects.

Exposure of the mother to selective serotonin reuptake inhibitors, particularly during the first trimester, may increase the risk that her offspring will develop ASD. [64, 65]

Severe, early-gestation maternal hypothyroxinemia is associated with an increased risk of having a child with ASD, according to a study that involved 5100 women and 4039 of their children. Severe maternal hypothyroxinemia early in gestation increased the likelihood of having a child with ASD by almost 4-fold. By age 6, children of mothers with severe hypothyroxinemia had higher autistic symptom scores on the Pervasive Developmental Problems subscale of the Child Behavior Checklist and the Social Responsiveness Scale. [66, 67]

Infection

An infectious basis for some cases of ASD is suggested by the large number of children with ASD born to women who contracted rubella during pregnancy. This finding supports the hypothesis that this infection triggers a vulnerability to the development of ASD in the fetus.

Familial and genetic factors

Familial factors influence the risk for ASD. The rate of ASD in children born into families that already have a child with an autism spectrum disorder is as high as 18.7%, and the risk is twice as high in children born to families with 2 or more children with an ASD. [68] Girls born to a family that has a child with an ASD have 2.8 times the risk of having such a disorder. [68]

Twin studies have demonstrated a moderate degree of genetic heritability for ASD, [69, 70, 71] with environment making a substantial contribution to the development of these conditions in the study subjects. [71]

Multiple family studies have suggested genetic components in many cases of ASD. [72, 61, 73] For example, some asymptomatic first-degree relatives of some probands with ASD have abnormalities in serotonin and other chemicals similar to the probands.

Finding genetic bases for ASD is a promising research goal. Factor analysis of datasets from the Autism Genome Project has suggested linkage of a joint attention factor with 11q23 and of a repetitive sensory-motor behavior factor with 19q13. [74]

While a third of monozygotic twins are concordant for ASD, dizygotic twins are concordant for autism at rates of 4-8%, [75] which is comparable to siblings. A focused neurogenetic evaluation of children with ASD yields a genetic disorder in two fifths of the children. [76] For example, mutations in the gene SHANK3 are associated with ASD. [77, 78]

Fragile X syndrome, a subtype of ASD, can be identified through genetic testing. [79] Antagonists to metabotropic glutamate receptors can reverse the symptoms in mouse models of fragile X syndrome. [80] Another subtype of ASD is tuberous sclerosis, a disorder with specific genetic mutations. [81, 82]

Toxic exposure

Exposures to toxins, chemicals, poisons, and other substances have been hypothesized to cause ASD.

Roberts et al [83] and Samson [84] have reported an association between exposure to the organochlorine pesticides dicofol and endosulfan during the first trimester of pregnancy and the subsequent development of ASD in children. Potential mothers can wisely be advised to avoid exposure to organochlorine pesticides.

In parts of the world, exposure to specific toxins may influence local ASD rates. For example, the high incidence of ASD in areas of Japan has been hypothesized to be due to a toxic effect of certain fish. Although toxins may play a role in the development of isolated cases of ASD in Japan, they have not been proved to be generally causative of ASD there. Another possible explanation for the high ASD rates in Japan is the excellent training of Japanese clinicians; low rates elsewhere may reflect the limited abilities of clinicians to diagnose ASD.

Some studies have documented associations between ASD and air pollution. One, from North Carolina found a link between exposure to traffic-related air pollution, particularly during the third trimester, to the development of ASD in offspring. These results add to the evidence already provided by previous studies conducted in California. [85]

Another study of children living in counties in Pennsylvania found that children with ASD were 1.4 to two times more likely to have been exposed to higher levels of air pollution, especially the toxins styrene and chromium, during pregnancy and the first 2 years of life than children without the disorder. [86] Cyanide, methylene chloride, methanol, and arsenic were also linked to increased risk of ASD. [87]  

Parental age

Meta-analyses of epidemiologic studies have shown that ASD risk in offspring increases when the age of either parent is 35 years or higher. [60] Sandin et al reported that, after controlling for paternal age, the adjusted relative risk for ASD was 1.52 in the offspring of mothers aged 35 years or older compared with mothers aged 25–29 years. [88] Hultman et al found that, after controlling for maternal age, offspring of men aged 50 years or older were 2.2 times more likely to have ASD than offspring of men aged 29 years or younger. [89]

Vaccination

Some children have developed ASD after immunizations, including inoculations for measles, mumps, and rubella. However, several population studies have demonstrated no association between childhood immunization and the development of ASD and related conditions. [90, 91, 92, 93, 94, 95]

Thompson and colleagues detected no causal association between exposure to vaccines that contain thimerosal and neuropsychological deficits at age 7–10 years. [93] In fact, in early 2010, the Lancet retracted the 1998 article by Wakefield et al that originally linked ASD with measles-mumps-rubella (MMR) vaccination, citing flaws in the study and 2 claims in it that were "proven to be false." [94]

Parents can permit the recommended childhood immunizations without fear of causing ASD and related conditions. Adherence to recommended immunization schedules, including immunization for measles, mumps, and rubella, is highly recommended. [95]

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Epidemiology

Reported rates of ASD have been rising in many countries over the past 2 decades. [96, 97]

Epidemiological studies of relatively uncommon conditions such as ASD are expensive. A suitable research strategy is the administration of multiple screenings in a population, each time identifying more likely subjects for detailed investigation.

For example, a reporting tool, such as the Autism Screening Checklist, can be distributed to all parents and guardians in a target population. See the image below.

The significance of answers to individual Autism S The significance of answers to individual Autism Screening Checklist items is as follows: Item 1- A "yes" occurs in healthy children and children with some pervasive developmental disorders; a "no" occurs in children with autism, Rett syndrome, and other developmental disorders. Item 2 - A "yes" occurs in healthy children, not children with autism. Item 3 - A "yes" occurs in healthy children and children with Asperger syndrome (ie, high-functioning autism); a "no" occurs in children with Rett syndrome; children with autism may elicit a "yes" or a "no"; some children with autism never speak; some children with autism may develop speech normally and then experience a regression with the loss of speech. Item 4 - A "yes" occurs in healthy children and children with Asperger syndrome and some other pervasive developmental disorders; a "no" occurs in children with developmental disorders; children with autism may elicit a "yes" or a "no." Items 5-10 - Scores of "yes" occur in some children with autism and in children with other disorders. Item 11 – A "yes" occurs in healthy children; a "no" occurs in some children with autism and in children with other disorders. Items 12, 13 - Scores of "yes" occur in some children with autism and in children with other disorders. Items 14-19 - Scores of "yes" occur in children with schizophrenia and other disorders, not in children with autism, Asperger syndrome, or other autism spectrum disorders. The higher the total score for items 5-10, 12, and 13 on the Autism Screening Checklist, the more likely the presence of an autism spectrum disorder.

The checklist identifies those children with characteristics of an ASD and differentiates them from children with child-onset schizophrenia. (See History).

Occurrence in the United States

Estimates of the prevalence of ASD suggest that as many as 400,000 individuals in the United States have ASD or a related condition.

The Autism and Developmental Disabilities Monitoring (ADDM) Network surveillance system provides estimates of the prevalence of ASD among children aged 8 years whose parents or guardians reside within 11 ADDM sites in the United States (Arizona, Arkansas, Colorado, Georgia, Maryland, Minnesota, Missouri, New Jersey, North Carolina, Tennessee, and Wisconsin). The Network's 2018 report, based on 2014 data, shows the overall prevalence of ASD among the 11 ADDM sites was 16.8 per 1,000 (one in 59) children aged 8 years. [98]

According to survey results from parents across the United States, 1 in 40 children (2.5%) has ASD, representing an estimated 1.5 million children ages 3 to 17 years [99]  an increase from 11 in 1000 in 2007. [100]

International occurrence

A global prevalence of 7.6 cases of ASD per 100 (1 in 132) was estimated on review of epidemiological studies. [101] ASD and related conditions are estimated to affect up to 10-15 people per 10,000 population worldwide. In a population-based study of all 7- to 12-year-old children (N = 55,266) in a South Korean community, Kim et al estimated that the prevalence of ASD was 2.64% [102]

Studies in Japan report much higher rates than are found in other countries. [103] Japanese investigators suggest that these findings reflect the careful evaluations performed by Japanese clinicians, which may identify cases that would be overlooked in other countries. Alternatively, ASD may be more common in Japan because of gastrointestinal and other infections transmitted through the ingestion of seafood and other aquatically derived foods that are characteristic of the Japanese diet.

Sex-related demographics

Estimates of the prevalence of ASD vary widely by sex. Combining data from all 11 Autism and Developmental Disabilities Monitoring (ADDM) Network communities, ASD prevalence was 26.6 per 1,000 boys and 6.6 per 1,000 girls (prevalence ratio: 4.0). ASD prevalence was significantly (p< 0.01) higher among boys than among girls in all 11 ADDM sites, with male-to-female prevalence ratios ranging from 3.2 (Arizona) to 4.9 (Georgia). [98]

ASD is most common in boys who have the 46,XY karyotype (ie, the normal male karyotype). In some studies, fragile X is reported in approximately 10% males with autistic disorder. [104, 105, 106, 107, 108, 109]

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Prognosis

The prognosis in patients with ASD is highly correlated with their IQ. Low-functioning patients may never live independently; they typically need home or residential care for the rest of their lives. High-functioning patients may live independently, hold jobs successfully, and even marry and have children. Remission of ASD has been described in anecdotal case reports.

High-functioning individuals with ASD are similar to people with Asperger syndrome. Please refer to the Medscape Reference article Asperger Syndrome for further information and to learn more about high-functioning autism. Under the current nomenclature Asperger syndrome is a subtype of ASD.

Comorbid disorders

Gastrointestinal disorders, particularly constipation and chronic diarrhea, are more common in children with ASD. The risk of gastrointestinal disorders increases with the severity of autism symptoms. [110]  Additionally, cancer, [111]  cerebral palsy, [112]  attention-deficit/hyperactivity disorder, [112]  insomnia and other sleep disorders, [113]  and epilepsy [114] are conditions more common in ASD. Psychiatric conditions common in ASD include psychosis, [115]  depression, [116]  and anxiety disorders including specific phobias and obsessive-compulsive disorder (OCD). [117, 118, 119]

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Patient Education

Because local boards of education may be ignorant about the needs of children with ASD and related conditions, pediatricians and parents should seek advice from knowledgeable sources such as the Autism Society, which maintains a Web site and offers a toll-free hotline at 1-800-3-AUTISM (1-800-238 8476), providing information and referral services to the public. Legal assistance may be necessary to influence a board of education to fund appropriate education for a child with ASD and related conditions.

People with developmental disabilities, including ASD, are vulnerable to sexual abuse, with the most severely disabled being at highest risk. Parents and caregivers need to be aware of this increased risk. Additionally, children with ASD must be trained to recognize impending sexual abuse and to develop plans of action to abort it. [120]

Almost half of a sample of more than 1000 children with ASD exhibited elopement, wandering away from home, school, and other safe environments. [121] Parents of children with ASD need to be warned that there is a fair chance that their child, without warning, may walk away from home or school to go to an environment where there is a risk for potential danger. Additionally, parents need to be advised to request that teachers and other caregivers vigilantly watch the child to prevent elopement.

For patient education information, see the Brain and Nervous System Center, as well as Asperger Syndrome.

Obtaining informed consent

People with ASD are identified as a highly vulnerable population because of the presence of cognitive, social, and mental impairments. Regulatory agencies have expressed particular concern that the rights of children with ASD and related conditions be carefully protected.

Some have suggested that parents may not be impartial guardians and that third parties be used instead of parents to provide informed consent for clinical and research purposes. However, parents are generally excellent advocates seeking the best for their children. Nevertheless, clinicians must take particular care to ensure that informed consent is obtained in order to prevent misinterpretations and eventual medicolegal problems.

Except in emergencies, patients, parents, guardians, and surrogates must be aware of the diagnostic and treatment possibilities and must provide permission for possible interventions. By making a video recording of the process of explaining to the parent the recommended procedures, in addition to the signing of written release forms, the clinician establishes evidence that he/she imparted appropriate information to the correct party.

Published resources for parents

Recommended readings for parents include the following:

  • Attwood T. The Complete Guide to Asperger's Syndrome. London, UK: SK Kingsley Publishers; 2006

  • Cohen S. Targeting Autism. Berkeley, CA: University of California Press; 1998

  • Gaus VL. Cognitive/Behavioural Therapy for Adult Asperger's Syndrome. New York, NY: The Guilford Press; 2007

  • Hollander E. Autism Spectrum Disorders. Volume 24 of the Medical Psychiatry Series. New York, NY: Marcel Dekker; 2003
  • Lovaas I. The Autistic Child: Language Development through Behavior Modification. New York, NY: Irvington Press; 1977

  • Wing L. The Autistic Spectrum: A Parent's Guide to Understanding and Helping Your Child. London, England: Ulysses Press; 2001

Additional resources

Individuals with autism and related conditions, as well as their advocates, can benefit from the experiences of other individuals and advocates who are dealing with autism. (See the organizations and resources listed below.)

Autism Society

4340 East-West Highway, Suite 350

Bethesda, MD 20814

Phone: 1-800-328-8476

URL http://www.autism-society.org/

 

Autism Canada

140 Yonge Street, Suite 200

Toronto, Ontario

MSC 1X6

Canada

URL https://autismcanada.org/about-us/one-strong-voice/autism-society-canada/

 

The National Autistic Society

393 City Road

London EC1V 1NG

United Kingdom

Phone: +44 (0)20 7833 2299

FAX: +44 (0)20 7833 9666

Email: nas@nas.org.uk

URL: https://www.autism.org.uk

 

The National Institute of Mental Health Information Resource Center

Office of Science Policy, Planning, and Communications

6001 Executive Boulevard, Room 6200, MSC 9663

Bethesda, Maryland 20892-9663

Phone: 1 866 615 6464

Fax:     1 301 443 4279

Email: nimhinfo@nih.gov

URL: http://www.nimh.nih.gov/health/topics/autism-spectrum-disorders-pervasive-developmental-disorders/index.shtml

 

Asperger Syndrome Coalition of the United States

URL: http://www.ldonline.org/resources_new/8241

 

Autism Research Institute

Phone: 833 281 7165

email info@autism.org

URL: https://www.autism.com/

 

Autism Speaks

1 East 33rd Street, 4th Floor

New York, NY 10016

USA

Phone (646) 385-8500

Fax (212) 252 8676

URL: https://www.autismspeaks.org/

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