Autism Spectrum Disorders

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Autism Spectrum Disorders

Basic Characteristics

• Description

Autism Spectrum Disorders is a clinical description of the developmental disorders which are characterized by impaired language development, social development, and learning. According to NIMH estimates, 3.4 out of every 1000 children between 3-10 years of age have a one of the disorders in the spectru.

They include:

1. Autism
2. PDD-NOS
3. Asperger's Syndrome
4. Rett Syndrome
5. Childhood Disintegrative Disorder

Children with ASD have extremely delayed development. Symptoms of this disorder usually start to appear between 12 to 36 months and consist of not reaching normal development benchmarks such as babbling by 12 months, speaking by 16 months, or a gradual loss of language or social skills. All children with ASD show deficits in social interactions, verbal and nonverbal communication. They may also show repetitive behaviors and interests, or aggressive behavior.

Although all children with ASD show similar deficits, the depth of these deficits can range drastically. Some have very mild deficits like in Asperger's Syndrome, where children have high levels of vocabulary and language skills. Others may have little to no spoken language functionality.

• Causes

Scientists have not found the exact cause of ASD, although all would agree that there is a genetic basis. Strong genetic factors have been found for some of these disorders such as in Rett Syndrome, and there are simple tests for diagnostic purposes for these disorders.

The difficulty in finding the cause of ASD partially lies in its definition, and partially on the complex interplay between genes that happens during development. ASD, like most other behavioral disorders, is diagnosed based off of observable characteristics of the child. However, these diagnosis offer no direction as to which specific genes are defective. Furthermore, two patients with ASD can present very similar symptoms and yet have different defective genes or causes. For example, Rett Syndrome is caused by mutations in the gene MeCP2 while Tuberous Sclerosis is caused by mutations in TSC1 and TSC2. It should be noted that both Rett Syndrome and Tuberous Sclerosis are very rare. It may be that there are certain genes which are more susceptible to environmental influences. If these environmental triggers are there, then the child will develop specific ASD phenotypes, such as a poor language development.⁹

There are many theories for the cause of ASD. Some include the Theory of Mind explanation, the Simulation of Systems explanation, and the Weak Coherence account. In the Weak Coherence account, those with ASD are thought to have a preference for local processing (detail oriented) over global processing, which explains their better performance on certain tasks over typically developing groups. ASD groups are still able to do global processing, but preferentially employ local processing tactics when given a choice. There are two main neural models for the mechanisms of Weak Coherence. One explanation is that weak coherence is a result of reduced connectivity throughout the brain caused by a lack of synchronization of activities in the brain, lack of connecting fibers, and faulty top down regulation. A second explanation is that there are specific pathways that are abnormal in people with ASD, specifically the right hemisphere., because individuals with right hemisphere damage show deficits in integrating information for global meaning. ¹⁰

• History

Prior to the 1970's, many people thought Autism Spectrum Disorders were a result of psychological causes, such as having an aloof mothering style. However, during the 1980's people began to note that chromosomal disorders and rare syndromes often co-occurred with ASD. As a result, people began to suspect that ASD could have genetic underpinnings. These suspicions were confirmed when, after the development of the ADI-R and ADOS as diagnostic tools and other technical advances, the first candidate gene association and resequencing studies, followed by whole-genome linking studies were done in the late 1990's. These studies were used to identify loci of potential interest.

Core Deficits

Those who have ASD have identifiable core deficits recognized by scientists and clinicians.

1. Core Deficit of Joint Attention
2. Core Deficit of Social Communication
3. Repetitive behaviors or interests

Treatments

There are no drugs that can “cure” ASD. There are a variety of treatments available which aim to improve social and communication skills. Because of the complexity of ASD, there is no one treatment that works equally well for all people with ASD. Some common treatments are:

• Applied Behavior Analysis interventions
• Joint Attention interventions

Some clinicians may prescribe medications to target certain symptoms.

Neuroimaging

There are have been many differences observed between typically developing children and those with ASD in neuroimaging studies using fMRI, EEG, transcranial magnetic stimulation, EMG, and structural MRI. It has been hypothesized in the Mirror Neuron System Theory of Autism that the social/communication deficits in ASD arise because of differences in activation of the Mirror Neuron System (MNS), since the mirror neuron system plays an integral role in mediating understanding of emotional states of others. However, many different areas of the brain can participate in complex social/communicative tasks, making it difficult to single out just one neural area responsible for the widespread abnormalities in socialization and communication experienced by patients with ASD. Much of current neuroimaging research in ASD operates under one of two different camps that attribute autism to different areas of less activation in the brain.

1. Theory of Mind-Patients with ASD show lower or no activation in midline structures as compared to a control groups in many tasks, lending credence to the 'Theory Of Mind' explanation for social/communication deficits in patients with ASD. In this theory, patients with ASD have lower activation of mirror neurons in the midline structures which are responsible for "reflecting" about others' emotions or wants^1,. Thus, patients have social/communication deficits because they have are unable to process the meaning of other peoples' emotions, which suggests a problem in executive processing.
2. Embodied Simulation Theory- Scientists who want to test this theory focus their research on shared circuits that are involved in both one's own emotions and other's emotions. Numerous studies have shown that when subjects witness a goal oriented task many different types of neurons are activated in addition to those in the midline structures. For example, when a person watches another person drink a glass of milk with an expression of disgust on his face, the premotor and parietal areas are activated for the action itself, the insula areas are activated in response to the emotion of disgust, and the secondary somatosensory area is activated for the sensations involved in the task. These are the same areas that would have been activated if we drank the milk and were ourselves disgusted. Thus, we are able to understand others' emotional states and intentions because contextual cues activate the same neural circuits that are activated when we perform the same task. However, patients with ASD show diminished activation of these areas as compared to control groups. So, in this theory, the social and communication difficulties arise in patients with ASD because these areas are less activated. Consequently, they have difficulty "understanding" another's actions.¹

These two theories are not entirely incompatible and there have been some hypothesis on how the two theories could be integrated to provide a better explanation for the differences seen.

Facial Processing Patients with ASD show less interest in human faces. Normal people perform much better at tasks where they have to identify or match faces that are upright versus inverted. ASD children on the other hand, show a noticeably less pronounced 'inversion effect' as compared to the normal population. Some scientists speculate that this may be because children with ASD process faces similarly to regular objects rather than assigning particular significance to faces, thereby reducing the inversion effect. Another hypothesis is that ASD children may engage more in component processing rather than configural processing, thereby making the activation difference between processing upright faces versus inverted faces smaller. Differences in activation areas are in the frontal cortex and the amygdala, perhaps reflecting a difference in processing the meaning and significance of faces. ² Typically developing children also seem to activate the right prefrontal areas of the brain when doing self and other face processing while ASD children only activate this area when processing their own face.³

Multi-Voxel Pattern Analysis suggests that although ASD patients can often perform similarly on tasks as control groups, they usually do this through different neurological mechanisms. In one study the prefrontal cortex was imaged and analyzed using MVPA while subjects performed verbal and spacial tasks that may, or may not require the subject to think about another player's state of mind. The group found that there were differences in activation between those with ASD and controls when using MVPA to analyze the fMRI data, but no significant differences in activation if we used convential analysis techniques.⁷

Analytical Techniques

• Multi-Voxel Pattern Analysis

Genetics

A host of genes of interest have been identified through gene association studies, resequencing and, recently, the assessment of copy number variation (CNV).In particular, given the pathology of ASD, genes dealing with electrical conductance and neural transmission have been popular sites of study since synaptic dysfunction has been suggested as a unifying theme behind the various disorders in ASD. It has been difficult to find a specific gene mutation that is present in all cases of ASD, probably because of the heterogeneity of the ASD population. However, one group found that when they stratified an ASD group into subgroups based off of severity of symptoms and applied cluster analysis and various genetic profiling techniques, there were 20 novel genes that were shared by all three ASD subgroups. Additionally, most of the highly significantly differentially expressed genes in the ASD group that was found in the study are differentially regulated within the context of androgen insensitivity. This supports one hypothesis that higher levels of fetal testosterone are a risk factor for ASD.¹¹

The high occurrence of differential expression profiles for 15 clock genes only for those in the severely affected ASD subgroup suggest that the severity of symptoms may be a connected with the dysregulation of the circadian rhythm. Scientists have demonstrated a genetic association of PER1 and NPAS2 with autistic disorder, and other theories have been proposed interplays between Fragile-X related proteins and synaptic genes with circadian rhythm genes.¹¹

Most approaches to finding loci of interest are under one of two assumptions:

1. ASD is a result of interplay between many genes
2. There is one principle gene which contributes to many aspects of the disease.

The idea that the symptoms of ASD is a result of the interaction of many different genes has been supported by linkage studies, and the fact that although many genes have been identified with causing ASD symptoms, each of these individual genes do not cause more than 1-2% of all ASD cases. However, data mining techniques such as hierarchical clustering and principle components analysis find that it is highly likely that there is 1 continuously distributed factor contributing to many aspects of ASD, thereby validating the existence of the second hypothesis. Additionally, statistical analysis of ASD family data suggest a large portion of ASDs may be the result of dominant de novo mutations that have reduced penetrance in families.

Methylation-One other hypothesis that may account for the widespread genetic defects found in ASD patients is that there may be abnormal methylation of brain-expressed genes on the X chromosome which in turn causes abnormal expression levels of genes important during development. These alternations cause one or more genes on the single X chromosome in males to be either partially silenced or over-expressed. This similarly happens in females, but the random X-chromosome inactivation might lesson autism predisposition and prevalence in females. This proposal is consistent with the findings that males make up a significantly larger amounts of ASD cases than females.⁴

Linkage and Association Studies

Successful linkage studies in the past have been mostly based on affected sibling-pair designs in multiplex families. However, there were no genome wide significant results probably because of small effect sizes that were a result of any single gene. Even large scale studies showed only minor overlap, likely because of variety of phenotypes in ASD. Recently though, use of endophenotypes and QTL mapping have increased the power of linkage and association studies.

Endophenotypes can help genetic studies by defining more etiologically homogenous subgroups. Furthermore, endophenotypes are measurable in both affected and control groups, thus allowing for larger sample sizes. Language phenotypes such as the age at which the child speaks their first word, are very promising endophenotypes because they show significant linkage in many samples and the support has been lent at implicating the 7q region to this language development, thereby raising hypothesis that the 7q region is home to other loci that are associated with the autism language phenotype⁵.

Copy-Number Variation

CNVs in certain dosage sensitive genes have been suggested as the root cause of ASD. This theory is particularly appealing because CNVs have a high locus-specific rate of new nucleotide mutations, 3-4 times the rate for single nucleotide polymorphisms. Additionally, CNVs can account for the phenotypic variation seen in ASD. The type of copy number rearrangement and whether it was inherited maternally or paternally can further affect the phenotype. For example, duplications of chromosome 15q11-q13 that are derived maternally confers a high risk of ASD (>85%) while those inherited paternally have anywhere from no phenotypic affects to mild developmental and cognitive impairment. There is relative enrichment within CNVs for neuronal synaptic complex genes, particularly SHANK3, NLGN4, and NRXN1. However, it is difficult to know right now how harmful a particular inherited CNV will be because the extent of the CNV and what genes are included, as well as which geens are nearby can influence the phenotypes. Specifically, other genes can modulate the risk of genes that normally confer genes, and other genes can even act protectively to decrease the risk of developing a particular genetic disease⁷.

Some likely candidate genes that have been explored include

Gene	Function	Location	source
UBE3A	transcribed protein is an enzyme that works in protein degradation	15q11-q13	PMID 18414403
GABRB3	encodes a member of of a ligand gated ionic channels responsible for inhibition in nervous system	15q11-q12	PMID 18414403
MET	encodes receptor tyrosine kinase involved in neuroal growth and organization, immunological and gastrointestinal functioning	7q31	PMID 18716561
SLC6A4	serotonin transporter	17q11	PMID 18716561
RELN	encodes protein that controls intercellular interactions involved in neuronal migration and positioning in brain development	7q22	PMID 18716561
CNTNAP2	part of neurexin superfamily, encodes CASPR2, a transmembrane scaffolding protein	7q35-q36	PMID 18179894

Related Information

• Task or test associated with this construct (vote for your favorite, or nominate a new one by editing this page):
  • ADOS
  • ADI-R

• Indicators (dependent variables, conditions, or contrasts; measurement variables used for analysis) associated with this construct (vote or nominate by editing this page):

• Closely related pages (vote or nominate related pages by editing this page):

• CNP Level
  • Syndrome

External Resources

• Links out:
  • Google: Autism Spectrum Disorder
  • Wikipedia: Autism Spectrum
  • PubMed: Autism Spectrum Disorders
  • -ucla cognitive atlas- (coming soon!)

• Database links

Citations

1. Keysers, Christian and Valeria Gazzola. Integrating simulation and theory of mind: from self to social cognition. Trends in Cognitive Sciences. Vol 11:5 pg. 194-6; 2007 PMID 17344090

2. Bookheimer, S.Y. et. al. Frontal contributions to face processing differences in autism: Eviedence from fMRI of inverted face processing. "Journal of the International Neuropsychological Society". Cambridge University Press:14:922-32;2008 PMID 18954473

3. Uddin et. al. Neural Basis of Self and Other Representation in Autism: An fMRI Study of Self-Face Recognition. PLoS ONE. 2008;3(10):e3526. Epub 2008 Oct 29 PMID 18958161

4. Jones, J.R. et. al. Hypothesis: Dysregulation of Methylation of Brain-Expressed Genes on the X Chromosome and Autism Spectrum Disorders. American Journal of Medical Genetics Part A 146A:2213-2220 (2008). PMID 18698615

5. Lush, Molly et. al. Current Developments in the Genetics of Autism: From Phenome to Genome. J Neuropathol Exp Neurol. 2008 September; 67(9):829-837. PMID 18716561

6. Arking DE et. al. A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am J Hum Genet 2008;82:160-64. PMID 18179894

7. Cook, E.H. and S. W. Scherer. Copy-number variations associated wtih neuropsychiatric conditions. Nature.2008 October;455(16) 919-23. PMID 18923514

8. Gilbert, S.J. et. al. Abnormal functional specialization within medial prefrontal cortex in high-functioning autism: a multi-voxel similarity analysis. Brain: 2009(1). PMID 19174370

9. Grandgeorge, Marine et. al. Environmental Factors Influence Language Development in Children with Autism Spectrum Disorders. PLoS ONE. 2009;4(4):e4683. Epub 2009 Apr 9 PMID 19357766

10. Happe, F. and Uta Frith. The Weak coherence Account: Detail-focused Cognitive Style in Autism Spectrum Disorders. J Autism Dev Disord. 2006 Jan;36(1):5-25. PMID 16450045