Autistic Spectrum Disorders
The autistic spectrum disorders are a neurobiologically diverse group of conditions whose precise relationship to each other is unclear, yet they present with a consistent, diffuse pattern of abnormality across several areas of behavior. Individuals with these disorders do not present merely with slow or limited development, but rather with development that is atypical in the pervasive but diffuse areas of functions affected.
Three main clusters of behaviors define autism, as follows: (1) social abnormalities, especially a lack of social reciprocity; (2) language abnormalities, with deviant communication features and limited development of language; and (3) rigid, stereotyped, repetitive patterns of unusual behavior.
Case reports consistent with autism exist from the 1890s, but Kanner first defined the syndrome in 1943, as did Asperger a year later.
The Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III), published in 1980, offered the first official definition and description of autism in the United States.
The prevailing public face of autism comes from the movie Rain Man in which actor Dustin Hoffman played an adult with autism with not only the behavioral rigidity, peculiar language, and social abnormality characteristic of the syndrome but also the savant abilities present in a quarter of individuals with autism who also have an intelligence quotient (IQ) of at least 35. Autistic spectrum disorders include autistic disorder, Asperger disorder, PDD not otherwise specified (PDD-NOS), Rett disorder, and childhood disintegrative disorder.
For more information, see Medscape’s Autism Resource Center.
Despite extensive investigation, no consistent pattern of the cause of autism has emerged. In fact, more than 60 different disease entities have been shown to be likely causes of autism, including genetic, infectious, endocrine, toxic, and space-occupying etiologies. This suggests that autism is a final common clinical presentation of a variety of underlying neurobiological and genetic processes.
The rest of this section presents some of the many proposed mechanisms behind the development of autism.
Although abnormalities have been reported on every chromosome as associated with autism, some of the more common genes of interest are on the X chromosome. This makes intuitive sense, as the incidence of the disorder is much higher in males, and they have only one X chromosome. Genes of interest on the X chromosome include FMR1 (fragile X) and FMR2 (FRAXE syndrome), MECP2 (Rett syndrome), ARX, NGLN3, and NGLN4. The 22nd chromosome is also of particular interest, with sites at band 22q11 and 22q13 responsible for velocardiofacial syndrome, DiGeorge syndrome, and adenylosuccinate lyase deficiency. Interest in mitochondrial DNA is growing, as a recent unreplicated Portuguese study had estimated that more than 7% of children with autism have mitochondrial disease.
The first biochemical abnormality discovered in autism was found in 1961 in a group of 23 patients, one third of whom were reported to have high levels of whole blood serotonin. Subsequent studies have confirmed this observation, as well as noting that about 5% of autistic children instead have low levels of serotonin. The significance of this is still unclear, but one explanation is that these abnormalities may be secondary to still another etiology. When certain disorders associated with autism are treated, the associated serotonin abnormality disappears; this happens when treating hypothyroidism with thyroid hormone and when treating phenylketonuria (PKU) with a low phenylalanine diet.
Endogenous brain opioids are suggested to be increased in autism, but studies have shown both increased and decreased levels of opioids in different case series. Some open clinical trials suggest that naltrexone, an opioid antagonist, can affect the core symptoms, but these findings have not been replicated. A subsequent controlled trial of naltrexone showed no impact on core symptoms.
Vasopressin and oxytocin have been shown to play a role in social attachment, but no evidence exists as yet of such problems in autism. Studies of the dopaminergic, noradrenergic, and neuropeptide systems do not reveal evidence of consistent abnormalities.
Searches for structural abnormalities produce similar inconsistent results. Abnormalities of the ventricular system are reported, but these abnormalities are neither consistent nor specific. The frontal lobes, the insula, the limbic system, the corpus callosum, the thalamus, the brainstem, and the cerebellum have all had reported structural and/or functional abnormalities noted in autism, but again, no location has a consistent pattern of dysfunction. A current belief is that autism may more likely reflect abnormalities within a particular neural system or multiple neural systems, which are the connected networks of a variety brain regions.
Several immune dysfunctions were detected, including anomalies in cell-mediated immunity, with some measures inversely correlated with severity of autistic symptoms. Abnormally elevated interferon-alpha levels, antibodies against myelin basic protein, and antibodies in both subjects and first-degree relatives to neuron-axon filament proteins also have been found. Allergic reactions may play a role, as autistic children have increased eosinophil and basophil response to immunoglobulin E (IgE)–mediated reactions. Finally, enhanced immune response to viral infections, with autoimmune activation, is postulated. All together, these and other findings suggest depressed immune function, autoimmune mechanisms, or faulty immune regulation may be associated with the etiology of autism, but the causal connection between immune changes and autistic symptoms has yet to be made.
Abnormal electroencephalogram (EEG) results can be found in as many as 43% of individuals with autism, particularly in those with lower IQs. Seizures are estimated to occur in as many as 30% of children with autistic disorder. A few epileptic syndromes are clearly linked to the diagnosis of autism, including tuberous sclerosis, Lennox-Gastaut, West syndrome, Landau-Kleffner syndrome, and pyridoxine-dependent seizures. However, the authors’ experience with seizures in autism has not generally led to better understanding of the origin of autistic symptoms.
The pathophysiology of childhood disintegrative disorder and Asperger disorder is unknown, although Asperger disorder appears to follow a familial transmission pattern. Associated disorders like seizures are less common in Asperger disorder than in autism.
Rett disorder is transmitted as a dominant X-linked illness with full or nearly full penetrance, with early death of most male fetuses through spontaneous abortion. Diffuse generalized atrophy of the cerebrum and cerebellum is present, with nonspecific, generalized EEG abnormalities present by age 2 years. Mutations in MECP2 gene (methyl-CPG-binding protein 2) are present in 80% of classic Rett disorder patients, with recent reports of CDKL5 gene mutations present in some of the MECP2 negative cases. Phenotypic variability in Rett syndrome is now thought to be related to X chromosome inactivation patterns and variations in the location of the mutation. Autism cases without Rett features have been shown to not have mutations in MECP2, further confirmation that Rett syndrome and autism are separate entities.
Current estimates are that slightly more than 0.1% of the general population has classic autism by DSM-IV criteria. When the full autism spectrum is viewed, the prevalence is higher, with 0.3-0.7% having the disorder: Asperger disorder is estimated to occur in 0.2-0.5% of school-aged children, Rett disorder occurs in 5-15 girls per 100,000, and childhood disintegrative disorder occurs with a frequency of 1-4 cases in 100,000. Prevalence rates of autistic disorder in more recent studies have been noted to be as much as 40 times higher than past studies, but this does not necessarily mean that the true prevalence of the disorder is increasing. This is because more recent studies are performed in an environment of higher awareness of the disorder and use more inclusive diagnostic criteria. Remember that as recent as the 1970s, autistic children were more commonly labeled as “psychotic,” thus making comparisons with this era of data highly suspect.
Depending upon diagnostic criteria used, rates are similar to those in the United States.
Increased mortality is seen in autism, with a risk that increases with age, and it is observed to be an even greater problem with females with the disorder. The increased mortality may be due to associations with severe mental retardation and other medical conditions, such as epilepsy. Mental retardation is present in 75% of affected individuals. Depending on the population studied, epilepsy develops in 4-42% of affected individuals, with some of the increased rates due to associated mental retardation. The course of illness is often unpredictable. A gradual clearing of some of the symptoms can occur in adulthood but with the persistence of residual deficits. An intellectual decline can occur during adolescence. Depending on severity, 2-17% of patients may achieve a nonretarded level of cognitive and adaptive functioning. Marriage is rare, but as they mature, adult patients may have greater success in achieving employment and developing the capacity for independent residence.
Studies have shown 3 consistent factors that relate to improved outcome: (1) higher IQ, (2) presence of speech, and (3) overall severity of disorder. Mentally retarded autistic individuals who have not gained useful verbal communication by age 5 years are unlikely to live independently as adults. Intensive early preschool intervention of 25 or more hours per week with either applied behavior analysis (ABA) or other therapies focused on improving functioning (language and social interactions) have been shown by a few well controlled and many more retrospective studies to improve outcomes.
Male-to-female ratio for autism is 3:4. Female prevalence increases as disease severity increases.
Asperger disorder and childhood disintegrative disorder show a similar male-to-female ratio of about 4:1.
Rett disorder was previously believed to never occur in males, but case reports and improved genetic studies have now shown this is possible.
In most cases, these disorders can be detected and distinguished from other forms of developmental delay before age 3 years. Parent interviews and videotapes have demonstrated manifestations as early as age 12 months. Parental concern develops at the mean child age of 19 months, and they first seek professional advice at a mean child age of 24 months.
Childhood disintegrative disorder typically develops in children aged 3-4 years, while Rett disorder becomes apparent in children aged 18 months to 4 years. Individuals with Asperger disorder may have delayed detection because of the greater subtlety of presentation.
According to some parents and investigators, a subset of children have social and verbal regression between age 2 and 5 years that heralds the onset of more typical autistic symptoms. These children, due to their atypical presentation, are among those labeled as PDD-NOS.
Diagnosis of autism
The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), from which the symptom list below is taken directly, requires the presence of at least 6 of the below symptoms and at least 1 item from each of the 3 symptom groupings. In addition, at least 2 symptoms must come from the social impairment group of symptoms. Delays or abnormal functioning as depicted in any one of the symptom groups must be present by age 3 years. This means that patients with autism have impairments in social interactions, in communication, and in patterns of behavior.
(Group 1) Qualitative impairment in social interaction, as manifested by at least 2 of the following:
Marked impairment in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures to regulate social interaction
Failure to develop peer relationships appropriate to developmental level
A lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (eg, by a lack of showing, bringing, or pointing out objects of interests)
Lack of social or emotional reciprocity
(Group 2) Qualitative impairments in communication as manifested by at least 1 of the following:
Delay in, or total lack of, development of spoken language (not accompanied by an attempt to compensate through alternative modes of communication such as gestures or mime)
In individuals with adequate speech, marked impairment in the ability to initiate or sustain conversation with others
Stereotyped and repetitive use of language or idiosyncratic language
Lack of varied, spontaneous make-believe play or social imitative play appropriate to developmental level
(Group 3) Restricted repetitive and stereotyped patterns of behavior, interests, and activities, as manifested by at least 1 of the following:
Encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or in focus
Apparently inflexible adherence to specific, nonfunctional routines or rituals
Stereotyped and repetitive motor mannerisms (eg, hand or finger flapping or twisting, or complex whole body movements)
Persistent preoccupation with parts of objects
Characteristic deviant communication features in autism include a lack of social chat, pragmatic deficits, pronoun reversal, delayed echolalia, neologisms, lack of emotion in speech, phrase repetitions, and idiosyncratic use of language. Behavioral manifestations frequently involve repetitive, self-stimulatory behavior, especially in more severely affected individuals. This behavior can be self-injurious in some, as with arm biting, head slapping, and skin picking.
Childhood disintegrative disorder is characterized, in contrast, by normal development for at least 2 years, followed by loss of previously acquired skills in language, social skills, bowel or bladder control, play, and motor skills, while presenting with the autistic triad of abnormal communication and social interaction and repetitive, stereotyped behavior.
Rett disorder is characterized by normal development for 7-18 months, followed by rapid deterioration of behavior and mental status, deceleration of previously normal head growth, loss of hand skills and social engagement (both of which were developing normally), the appearance of poorly coordinated gait or trunk movements, and the development of severe impairment of language and psychomotor retardation. Abnormal sleep patterns have been noted to develop as early as age 4 months, heralding the change in developmental trajectory.
Individuals with Asperger disorder are often seen as having a milder version of autism. Similar to autism, patients with Asperger disorder have restricted and stereotyped behavior patterns and interests, plus significant social impairments. However, unlike autism, patients with Asperger disorder have much less impairment in cognitive development and have no significant general delay in language development.
PDD-NOS is diagnosed when no other specific autistic spectrum disorder can be diagnosed, but a severe and pervasive impairment in relating to others still is present. In addition, to receive a PDD-NOS diagnosis, either (1) verbal or nonverbal communication difficulties or (2) stereotyped behaviors or interests should be present.
Some controversy exists of the difference between PDD-NOS and Asperger disorder. DSM-IV-TR actually gives both diagnoses the same diagnostic code (299.80), though it states that the PDD-NOS label cannot be used if any of the more specific autistic disorders can be diagnosed. PDD-NOS has the broadest definition in the category: impairment in 2 of 3 autistic symptom clusters (difficulty relating to others, communication problems, and repetitive behaviors) makes the diagnosis.
In addition to the specific disorders included in DSM-IV-TR, evidence from genetic studies (see Causes) suggests that many family members of autistic persons have a broader autistic phenotype with milder features and characterized by (1) less severe stereotyped repetitive behaviors, (2) more subtle social deficits, (3) normal intelligence, (4) the lack of abnormal language features (including pronoun reversal and echolalia), and (5) lack of association with epilepsy.
Reading the DSM-IV-TR criteria carefully is advisable when making an autistic spectrum diagnosis.
See Medscape’s CME Activity, Diagnosis of Autism Spectrum Disorders in the First 3 Years of Life.
Overall, relatively little is found on physical examination other than the characteristics of comorbid conditions, where present, such as fragile X syndrome or tuberous sclerosis.
A neurological examination can screen for possible inborn metabolic and degenerative diseases.
Head circumference is greater than the 97th percentile in 25% of individuals with autistic disorder; arrest of head circumference growth in Rett disorder can occur in children older than 5 months.
Motor clumsiness may occur, especially with Asperger disorder.
A slight increased risk of nonspecific minor congenital abnormalities exists.
Mental status examination findings include poor eye-to-eye gaze, lack of social interaction, stereotypic and repetitive use of language, inability to carry a conversation, preoccupation with a few stereotyped patterns of interest, and stereotyped and repetitive motor mannerisms.
Genetics: An estimated 3-9% of those with autistic traits have chromosome aberrations, and the location of these abnormalities have been reported on every chromosome. The most frequently observed associated chromosomal anomaly is fragile X, which is reported to be present in 2-4% of individuals with autism. Tuberous sclerosis seems to be the next most common chromosomal anomaly in autism, with estimates from 1-4% of cases.
The rate of autism in siblings of autistic individuals is 2-6%. This means that the risk or occurrence among siblings is 6 times the risk in the general population, which, though suggesting a genetic cause, is a rate much lower than that found in single gene diseases. The concordance rate for monozygotic twins is 60-90%; for dizygotic twins, it is less than 5%. The rate for dizygotic twins rises to 10% when broad-spectrum diagnostic criteria are used. Possible increased risk for anxiety and depressive disorders is seen in family members, which may present even before the patient with autism shows signs of illness. Six to twenty-four percent of siblings have some form of cognitive disorder, including learning disabilities.
Most studies indicate that relatives of individuals who are autistic have an increased rate of social deficits that are qualitatively similar to those found in autism. Two studies show that the pattern and the severity of autism in one family member or between monozygotic twins is of little or no predictive value in determining the severity or pattern of illness in the other affected family member. This indicates that even when the genetic liability is identical, the variations in clinical manifestation are wide.
Autoimmune mechanisms have been postulated, but thus far, little consistent evidence exists beyond that outlined in Pathophysiology to support these hypotheses. Major epidemiologic studies have failed to find evidence that measles, mumps, and rubella (MMR) vaccine use or thimerosal (mercury vaccine preservative) exposure is associated with autism. Birth season of March or August was once proposed to be a risk for autism, with the implication that seasonal viral exposures trigger autoimmune responses, but this has not been a consistent finding.
No specific cause has been detected for childhood disintegrative disorder.
Genetic abnormalities are the likely cause of Rett disorder, as a small group of monozygotic twins showed 100% concordance, while dizygotic twins showed no concordance. A dominant X-linked inheritance with full or nearly full penetrance and with early death of affected males through spontaneous abortion is probable. Genetics have determined that 80% of classic Rett syndrome cases have mutations in one gene, methyl-CPG-binding protein 2 (MECP2). Two studies looking for this mutation in autism cases without Rett features were negative, further arguing that autism and Rett syndrome are distinct entities.
Early data in Asperger disorder are strongly suggestive of a genetic component. Although specific genetic mutations have been found in a few patients (Xp22.13, Xp22.3, Xq13, Xp22.1), the vast majority of Asperger disorder cases have no specific explanation yet.
Research had suggested that environment and season of birth predicted the development of an autistic disorder, but subsequent investigators have not confirmed these associations. In particular, the observation of an increased incidence of autistic disorder among children of immigrant parents now appears to point to genetics rather than environment as the culprit.