Virtual Mentor. November 2010, Volume 12, Number 11: 867-872.
The Spectrum of Autism—From Neuronal Connections to Behavioral Expression
Etiology, pathophysiology, and diagnosis of autism spectrum disorder.
Carla A. Mazefsky, PhD, and Nancy J. Minshew, MD
Autism spectrum disorders are defined behaviorally by the Diagnostic and Statistical Manual (DSM) IV-TR based on abnormal development in social interaction and communication and restricted, repetitive, and stereotyped patterns of behaviors and interests that are evident before the age of 3. After decades of debate, research has demonstrated that the distinctions among autism, Asperger disorder, and pervasive developmental disorder not otherwise specified are neither clinically reliable nor based on valid neurobiological or genetic differences. The fifth edition of the DSM therefore proposes to collapse all of the clinical syndromes under the single diagnosis of autism spectrum disorder (ASD).
There will continue to be no separate category of ASD diagnoses for cases with a known etiology in DSM-5. These etiologies are typically discovered after the diagnosis is made, though autism spectrum disorder sometimes manifests after an early diagnosis of a primary disorder such as Down syndrome, neurofibromatosis, or inborn errors of metabolism. Currently, the most common identifiable causes of ASD are tuberous sclerosis and fragile X syndrome. Many other disorders are infrequently associated with ASD. ASD cases co-occurring with recognizable genetic syndromes are classified as syndromic autism spectrum disorder, and those without a recognizable syndrome are termed nonsyndromic or idiopathic .
The list of identifiable causes is growing as a result of the rapid pace of genetic discoveries about autism spectrum disorder . At present, about 15 or 20 genes or chromosomal syndromes have been identified that each account for a small percentage of cases. The distribution of these genes over the genome explains why ASD has been “nonspecifically” associated with chromosomal abnormalities. The study of families with these rare genes has shown that they are associated with autism, ASD, and intellectual disability without ASD, all of which can occur within the same family. Genes code for protein formations, which, in this context, affect brain development; disorders with similar manifestations likely have overlapping brain differences. Likewise, a number of the genes associated with autism spectrum disorder have also been associated with attention deficit disorder/hyperactivity (ADHD), depressive disorders, schizophrenia, and obsessive compulsive disorder (OCD).
Major strides have also been made in understanding the pathophysiology of ASD. Alterations in cortical connectivity are now widely accepted as a central pathophysiologic mechanism [2, 3]. The alteration is typically characterized as (functional) underconnectivity of cortical systems (cortico-cortical intra-hemispheric connectivity) and (functional) overconnectivity of local cortical connections . In many respects, ASD could be conceptualized as a failure or underdevelopment of the specialization of cortical systems and organization responsible for both voluntary and automatic functions .
The idea that ASD stems from genes that guide neuronal development is supported by “neuropathologic studies indicating malformations in the minicolumnar structure of the cortex, volumetric studies indicating early brain overgrowth and a subsequent abnormal trajectory of brain growth, and the functional imaging studies that indicate abnormalities in the functional connections between brain regions during cognitive processing” . The importance of this pathophysiologic characterization is that it provides a framework for interpreting all of the clinical manifestations of ASD: selective underdevelopment of higher-order abilities with or without enhanced basic abilities in the same domain of function. This perspective makes it possible to understand why ASD not only affects the social, communication, and reasoning domains (those with the highest information processing demands) but also higher cortical sensory and motor abilities, balance, and memory. Altered connectivity also appears to explain the co-occurrence of anxiety disorder, affective disorder, and OCD with ASD.
Despite autism spectrum disorder’s neurobiological and genetic basis, diagnosis remains focused on behavior. The behavioral manifestations are variable in nature and degree, as would be expected from the underlying pathophysiology and genetics described above. Even among individuals of the same age and similar IQ with rigorously diagnosed autistic disorder, there are variations in everything from motor apraxia to developmental trajectory of head and brain growth. The most noticeable phenotypic heterogeneity is in IQs, which can range from severely impaired to superior, and in language, which can vary from nonverbal to overly verbose. Many comorbid medical conditions or associated psychiatric disorders and symptoms also contribute to ASD’s heterogeneity .
Further, even the most common symptoms of ASD are not definitive in isolation or universal (e.g., while poor eye contact is frequently considered indicative of ASD, it is present in other disorders such as ADHD, and some individuals with ASD do make natural eye contact or learn to do so through intervention). Therefore, evaluation by a specialist in autism spectrum disorder (usually a psychologist, psychiatrist, neurologist, or related team) is typically needed to make a formal diagnosis. Nonetheless, all physicians should be aware of the common presentations and refer individuals for further assessment when ASD is suspected.
Lower-Functioning and Younger Children
A recent summary of research on the infant siblings of children with autism has provided new insights into the early development of ASD, with some surprising findings . Few differences are apparent at 6 months in children who eventually receive ASD diagnoses despite the social nature of infants of this age. In fact, at 9 months old, most infants who go on to receive ASD diagnoses demonstrate some social engagement and many normal social behaviors, such as anticipation during peekaboo and orienting to their name and others’ voices. Onset patterns are variable, but the infant research suggests that the earliest signs for many children with ASD are differences in motor development and unusual visual interest in objects.
Most differences in development become more apparent between 12 and 24 months, including general developmental delays (including dramatic decreases in IQ for some children), more prominent repetitive behaviors, atypical sensory responsivity (e.g. being either hyper- or hyposensitive to touch, sounds, and so on), and increasingly difficult temperaments. Social and communicative impairments certainly still play a major role, but they are only two of many domains impacted in ASD and tend to appear later. This is consistent with principles governing the presentation of neurologic disorders of brain development in childhood. Specifically, signs and symptoms manifest when development reaches the point at which the defective mechanism is called into operation to support brain development and function.
While symptoms in the three diagnostic domains (social, communication, and repetitive behaviors) are not necessarily the first signs, they do remain the principal considerations for the differential diagnosis of autism spectrum disorder. The best predictors of later ASD diagnosis are lack of response to one’s name at 14 months and lack of self-initiated and spontaneous use of eye contact to direct someone’s attention to an object or activity of interest (“joint attention”) . Several practice parameters have been developed to aid in the early diagnosis of ASD [9, 10] due to research supporting the benefit of early, intensive intervention [11, 12]. Both routine developmental surveillance and ASD-specific screening (particularly at 18 months or when risk factors are present) are supported by both the Child Neurology Society  and the American Academy of Pediatrics . Each has a detailed algorithm for when and how to make referrals, as well as key warning signs that warrant an immediate referral for further assessment. For example, the Child Neurology Society notes that the following developmental patterns should be considered abnormal :
Higher-Functioning and Older Children, Adolescents, and Adults
ASD diagnoses for children in the average or greater range of intellectual ability and with on-time language development often go undetected or misdiagnosed until later childhood, or even adulthood, in some cases. Many of these individuals are thought of as “weird” or eccentric and go without a diagnosis. Alternatively, emotional or behavioral concerns may be what draws clinical attention to higher-functioning individuals with ASD . A red flag for a missed ASD diagnosis in older children, adolescents, or adults is a history of other psychiatric diagnoses. Common previous diagnoses include combinations of ADHD, oppositional defiant disorder, bipolar disorder, OCD, and schizophrenia-spectrum disorders. Often individuals have received treatment for these other concerns without much success or are on a medley of medications and still have poor functioning.
The presentation of individuals with high-functioning ASDs changes over the course of their development . In 3- to 6-year-olds, poor peer relationships may emerge, though attention problems and difficulty regulating emotions and arousal may be the prominent features. They may have a limited range of play skills and exhibit unusual sensory sensitivity.
Over the next few years, peers further notice and highlight their differences. Some higher-functioning children with ASD may self-isolate, whereas others have great interest in making friends, but are awkward or pushy in their attempts. As high-functioning children with autism spectrum disorder go through elementary school, a perseverative interest, disruptive behaviors, and problems with social speech may emerge or worsen. Even among children with ASD who are thought to have normal language development, many higher-order language concerns become evident as they get older, including problems with conversational speech (especially a tendency to be “one-sided”), atypical prosody, overly literal comprehension, and formal or stilted speech .
Learning difficulties also often emerge, particularly as academic demands become more integrative. Individuals with ASD have a characteristic pattern of cognitive development that includes intact or enhanced skills in some areas (attention, sensory perception, elementary motor movement, simple memory, formal language, rule-learning, and visuospatial processing), and deficits in higher-order skills involved in complex information processing (e.g., concept formation, aspects of abstract reasoning, face recognition, skilled motor movements, higher cortical sensory perception, and complex memory) .
Increased social isolation is also likely to occur throughout adolescence and adulthood and may be accompanied by depression and disorganized thinking. Particularly as their peers mature, the level of social and emotional immaturity in the adolescent or adult with high-functioning autism spectrum disorder becomes more noticeable. This, combined with poor problem solving, lack of flexibility, and difficulty with perspective taking, often leads to many functional challenges in achieving independence.
Carla A. Mazefsky, PhD, is a licensed psychologist and research assistant professor of psychiatry at the University of Pittsburgh. Dr. Mazefsky’s work focuses on clarifying potential contributors to the complexity of emotional functioning in older children and adolescents with high-functioning autism, including individual behavioral and cognitive characteristics, co-occurring psychiatric disorders, family history factors, and underlying brain differences.
Nancy J. Minshew, MD, is the director of the NIH Autism Center of Excellence at the University of Pittsburgh, director of Pitt’s Autism Speaks autism treatment network site, and a professor of psychiatry and neurology at the University of Pittsburgh School of Medicine. Dr. Minshew’s research on the cognitive, neurological, and genetic bases of autism has led to the conceptualization of autism as a disorder of information processing and brain connectivity. Dr. Minshew received her medical degree from the Washington University School of Medicine and was trained as a behavioral child neurologist at the University of Texas Southwestern Medical School.
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This work was supported by award numbers HD060601 (PI Mazefsky) and HD055748 (PI Minshew) from the Eunice Kennedy Shriver National Institute of Child Health & Human Development, and SAT 4100047816 from the Pennsylvania Department of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or Pennsylvania Department of Health.
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