Autism

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

The first reported case of autism dates back to 1798, discovered by a medical student, Jean Itard, who treated the patient using a behavioral program. In 1943, Leo Kanner first described 11 cases of autism in his paper called autistic disturbances of affective contact. In 1910, Eugen Bleuler, a Swiss psychiatrist coined the term autism form latin word autismus. In 1981, Asperger was the first to separate Asperger syndrome, from autism.

• The first reported case of autism dates back to 1798, discovered by a medical student, Jean Itard, who treated the patient using a behavioral program.^[1]
• In 1910, Eugen Bleuler, a Swiss psychiatrist coined the term autism form latin word autismus.^[2][3]
• In 1938, Hans Asperger of the Vienna University Hospital adopted Bleuler’s terminology “autistic psychopaths” in a lecture in German about child psychology.^[4]

• In 1981, Asperger was the first to separate Asperger syndrome, from autism.^[1]
• In 1943, Leo Kanner first described 11 cases of autism in his paper called autistic disturbances of affective contact.^[5][6]

• In 1960, autism was established as a separate syndrome for the first time in medical history differentiating it from mental retardation and schizophrenia and from other developmental disorders.^[7]
• As late as the mid-1970s there was little evidence of a genetic role in autism; now it is thought to be one of the most heritable of all psychiatric conditions.^[8][1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

DSM 5 categorized autism under autistic spectrum disorders/pervasive developmental disorders (PDD). Autistic spectrum of disorders are characterized by widespread abnormalities of social interactions, communication associated with severely restricted interests and repetitive behavior and can be classified into 5 types.

DSM 5 categorized autism under autistic spectrum disorders/pervasive developmental disorders (PDD). Autistic spectrum of disorders are characterized by widespread abnormalities of social interactions, communication associated with severely restricted interests and repetitive behavior.^[1][2][3]

Autistic spectrum disorder

Autistic disorder

Retts disorder

Childhood disintegrative disorder

Pervasive developmental disorder

Asperger’s disorder

Based on the degree of severity and level of support ASD are classified into 3 types^[2][4][5]

Severity level		Social communication	Restricted, repetitive behaviors
Level 3	Requiring very substantial support	Severe deficits in verbal and non-verbal communication skills Severe impairment in functioning Very limited initiation of social interactions Minimal response to social overtures from others	Inflexibility of behavior Extreme difficulty in coping with change Repeated behavior markedly interferes with functioning in all spheres Great distress/difficulty changing focus or action
Level 2	Requiring substantial support	Marked deficits in verbal and non-verbal communication skills Marked impairment in functioning Limited initiation of social interactions	Difficulty in coping with change Distress/difficulty changing focus or action Repetitive behaviors occur frequently
Level 1	Requiring support	Without support, deficits in verbal and non-verbal communication skills Atypical and unusual social responses	Interference with functioning in one or more context Problems of organization and planning hamper independence

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Autism and autism spectrum disorders are complex neurodevelopmental disorders. Many causes of autism have been proposed, but its theory of causation is still incomplete. Heritability contributes about 90% of the risk of a child developing autism, but the genetics of autism are complex and typically it is unclear which genes are responsible. In rare cases, autism is strongly associated with agents that cause birth defects. Many other causes have been proposed, such as exposure of children to vaccines; these proposals are controversial and the vaccine hypotheses have no convincing scientific evidence.

The most important causative factor for autism is genetic abnormality. Other causes include prenatal and post natal infections.

• Genetic factors are the most significant cause for autism spectrum disorders.
• Early studies of twins estimated heritability to be over 90% to develop autism.^[1][2]
• For adult siblings the risk for having one or more features of the broader autism phenotype might be as high as 30%.^{[3][4][1][5][6]}

• The genetics of autism is complex.^[1]
• Typically, autism cannot be traced to a Mendelian (single-gene) mutation or to single chromosome abnormalities such as Angelman syndrome or fragile X syndrome, and none of the genetic syndromes associated with ASDs has been shown to selectively cause ASD.
• There may be significant interactions among mutations in several genes, or between the environment and mutated genes.
• Numerous candidate genes have been located, with only small effects attributable to any particular gene.
• The large number of autistic individuals with unaffected family members may result from copy number variations (CNVs)—spontaneous deletions or duplications in genetic material during meiosis.^[8]
• Hence, a substantial fraction of autism may be highly heritable but not inherited: that is, the mutation that causes the autism is not present in the parental genome.^[7]
• Linkage analysis has been inconclusive; many association analyses have had inadequate power.^[2]
• More than one gene may be implicated, different genes may be involved in different individuals, and the genes may interact with each other or with environmental factors.^[9]
• Several candidate genes have been located, but the mutations that increase autism risk have not been identified for most candidate genes.^[10][4]

The deletion of the tip of the chromosome 22 is related to autism, moderate to severe developmental delay, and mental retardation. It is known as 22q13 deletion syndrome or Phelan-McDermid syndrome.

The deletion affects the terminal region of the long arm of chromosome 22 (the paternal chromosome in 75% of cases), from 22q13.3 to 22qter. Although the deletion is most typically a result of a de novo mutation, there is an inherited form resulting from familial chromosomal translocations involving the 22 chromosome. In the de novo form, the size of the deletion is variable and can go from 130kbp (130,000 base pairs) to 9Mbp (9,000,000 base pairs). While some clinical signs correlate with the size of the deletion, the main traits of the syndrome appear to be independent of the deletion size, and only related to the presence of the SHANK3 gene ^[11]. The haploinsufficiency of SHANK3 is thought to be the responsible for the neurological deficits of the syndrome (Wilson et al., 2003).

The proteins encoded by the SHANK genes assemble glutamate receptors with their intracellular signaling apparatus and cytoskeleton at the postsynaptic density. They are important for the formation and stabilisation of synapses:

• Experimentally induced expression of SHANK3 has been shown to be sufficient to induce functional dendritic spines in aspiny cerebellar neurons (Roussignol et al., 2005).
• Neural network activity up- or down regulates large groups of postsynaptic proteins through ubiquitin-mediated protein degradation. SHANK proteins were identified as one of the few postsynaptic density proteins that can be degraded by ubiquitination (Waites et al., 2005)

In 2006, a group lead by Thomas Bourgeron from the Pasteur Institute in France, found anomalies of the 22q13 locus in five children with diagnosis of autism and Asperger syndrome. While the absence of the SHANK3 gene was found in children with the typical characteristics of the Phelan-McDermid syndrome, its duplication was found in one child diagnosed with Asperger syndrome,^[12][13] a type of high-functioning autism.

Van Bokhoven et al. (1997) have also assigned the WNT7B gene to 22q13 ^[14]. Wnt7b acts through Dvl1 to the regulation of dendritic development. Rosso et al. (2005) found that its overexpression resulted in increased dendritic branching in cultured mouse hippocampal neurons. Knockout mice for Dvl1 are viable, fertile and structurally normal, but show reduced social interaction and abnormal sleeping patterns (Lijam et al, 1997)

The incidence of the 22q13 deletion syndrome is uncertain. The advanced genetic technique essential for diagnosis, fluorescent in situ hybridization (FISH), has only been available since 1998, and currently requires specialized laboratory facilities. Current thinking is that 22q13 deletion syndrome remains largely under-diagnosed, and may be one of the principal causes of idiopathic mental retardation (Manning and al. 2004).

The heritability of autism is a source of controversy about the causes of autism. Though it is agreed that there is a genetic susceptibility to autism, disagreements arise over the whether the condition is genetically determined and therefore inevitable, or is triggered by factors in the environment. The controversy is made more difficult by the broad spectrum of phenotypes labeled “autism”, ranging from near total disability to mild social difficulties.

Identical twin studies put autism’s heritability in a range between 0.36 and 0.957, with concordance for a broader phenotype usually found at the higher end of the range.^[15] Autism concordance in siblings and fraternal twins is anywhere between 0 and 23.5%. This is more likely 2–4% for classic autism and 10–20% for a broader spectrum. Assuming a general-population prevalence of 0.1%, the risk of classic autism in siblings is 20- to 40-fold that of the general population.

Researchers usually note that autism is among the most heritable of all neurological conditions, even among the more than 90% of cases not associated with known genetic diseases such as fragile X syndrome or muscular dystrophy.^[16][17]

Twin studies are a helpful tool in determining the heritability of disorders and low-prevalence human traits in general. They involve determining concordance of characteristics between identical (monozygotic or MZ) twins and between fraternal (dizygotic or DZ) twins. Possible problems of twin studies are: (1) errors in diagnosis of monozygocity, and (2) the assumption that social environment sharing by DZ twins is equivalent to that of MZ twins.

A condition that is environmentally caused without genetic involvement would yield a concordance for MZ twins equal to the concordance found for DZ twins. In contrast, a condition that is completely genetic in origin would theoretically yield a concordance of 100% for MZ pairs and usually much less for DZ pairs depending on factors such as the number of genes involved and assortative mating. An example of a condition that appears to have very little if any genetic influence is irritable bowel syndrome (IBS), with a concordance of 28% vs. 27% for MZ and DZ pairs respectively.^[18] An example of a human characteristics that is extremely heritable is eye color, with a concordance of 98% for MZ pairs and 7–49% for DZ pairs depending on age.^[19] Notable twin studies have attempted to shed light on the heritability of autism.

A small scale study in 1977 was the first of its kind to look into the heritability of autism. It involved 10 DZ and 11 MZ pairs in which at least one twin in each pair showed infantile autism. It found a concordance of 36% in MZ twins compared to 0% for DZ twins. Concordance of “cognitive abnormalities” was 82% in MZ pairs and 10% for DZ pairs. In 12 of the 17 pairs discordant for autism, a biological hazard was believed to be associated with the condition.^[20]

A 1979 case report discussed a pair of identical twins concordant for autism. The twins developed similarly until the age of 4, when one of them spontaneously improved. The other twin, who had suffered infrequent seizures, remained autistic. The report noted that genetic factors were not “all important” in the development of the twins.^[21]

In 1985, a study of twins enrolled with the UCLA Registry for Genetic Studies found a concordance of 95.7% for autism in 23 pairs of MZ twins, and 23.5% for 17 DZ twins.^[22]

In a 1989 study, Nordic countries were screened for cases of autism. Eleven pairs of MZ twins and 10 of DZ twins were examined. Concordance of autism was found to be 91% in MZ and 0% in DZ pairs. The concordances for “cognitive disorder” were 91% and 30% respectively. In most of the pairs discordant for autism, the autistic twin had more perinatal stress.^[23]

A British twin sample was reexamined in 1995 and a 60% concordance was found for autism in MZ twins vs. 0% concordance for DZ. It also found 92% concordance for a broader spectrum in MZ vs. 10% for DZ. The study concluded that “obstetric hazards usually appear to be consequences of genetically influenced abnormal development, rather than independent aetiological factors.”^[24]

A 1999 study looked at social cognitive skills in general-population children and adolescents. It found “poorer social cognition in males”, and a heritability of 0.68 with higher genetic influence in younger twins.^[25]

In 2000, a study looked at reciprocal social behavior in general-population identical twins. It found a concordance of 73% for MZ, i.e. “highly heritable”, and 37% for DZ pairs.^[26]

A 2004 study looked at 16 MZ twins and found a concordance of 43.75% for “strictly defined autism”. Neuroanatomical differences (discordant cerebellar white and grey matter volumes) between discordant twins were found. The abstract notes that in previous studies 75% of the non-autistic twins displayed the broader phenotype.^[27]

Another 2004 study examined whether the characteristic symptoms of autism (impaired social interaction, communication deficits, and repetitive behaviors) show decreased variance of symptoms among monozygotic twins compared to siblings in a sample of 16 families. The study demonstrated significant aggregation of symptoms in twins. It also concluded that “the levels of clinical features seen in autism may be a result of mainly independent genetic traits.”^[28]

An English twin study in 2006 found high heritability for autistic traits in a large group of 3,400 pairs of twins.^[29]

One critic of the pre-2006 twin studies said that they were too small and their results can be plausibly explained on non-genetic grounds.^[30]

The importance of sibling studies lies in contrasting their results to those of fraternal (DZ) twin studies, plus their sample sizes can be much larger. Environment sharing by siblings is presumably different enough to that of DZ twins to shed some light on the magnitude of environmental influence. This should even be true to some extent regarding the prenatal environment. Unfortunately DZ twin study findings have yielded a very large range of variance and are error prone because of the apparent low concordance and the fact that they typically look at a small number of DZ pairs. For example, in studies involving 10 DZ pairs, a concordance below 10% would be impossible to determine precisely.

A study of 99 autistic probands which found a 2.9% concordance for autism in siblings, and between 12.4% and 20.4% concordance for a “lesser variant” of autism.^[31]

A study of 31 siblings of autistic children, 32 siblings of children with developmental delay, and 32 controls. It found that the siblings of autistic children, as a group, “showed superior spatial and verbal span, but a greater than expected number performed poorly on the set-shifting, planning, and verbal fluency tasks.”^[32]

A 2005 Danish study looked at “data from the Danish Psychiatric Central Register and the Danish Civil Registration System to study some risk factors of autism, including place of birth, parental place of birth, parental age, family history of psychiatric disorders, and paternal identity.” It found an overall prevalence rate of roughly 0.08%. Prevalence of autism in siblings of autistic children was found to be 1.76%. Prevalence of autism among siblings of children with Asperger’s syndrome or PDD was found to be 1.04%. The risk was twice as high if the mother had been diagnosed with a psychiatric disorder. The study also found that “the risk of autism was associated with increasing degree of urbanisation of the child’s place of birth and with increasing paternal, but not maternal, age.”^[33]

A study in 2007 looked at a database containing pedigrees of 86 families with two or more autistic children and found that 42 of the third-born male children showed autistic symptoms, suggesting that parents had a 50% chance of passing on a mutation to their offspring. The mathematical models suggest that about 50% of autistic cases are caused by spontaneous mutations. The simplest model was to divide parents into two risk classes depending on whether the parent carries a pre-existing mutation that causes autism; it suggested that about a quarter of autistic children have inherited a copy number variation from their parents.^[34]

A 1994 looked at the personalities of parents of autistic children, using parents of children with Down’s syndrome as controls. Using standardized tests it was found that parents of autistic children were “more aloof, untactful and unresponsive.”^[35]

A 1997 study found higher rates of social and communication deficits and stereotyped behaviors in families with multiple-incidence autism.^[36]

Autism was found to occur more often in families of physicists, engineers and scientists. Other studies have yielded similar results.^[37][38] Findings of this nature have led to the coinage of the term “geek syndrome”.^[39]

A 2001 study of brothers and parents of autistic boys looked into the phenotype in terms of one current cognitive theory of autism. The study raised the possibility that the broader autism phenotype may include a “cognitive style” (weak central coherence) that can confer information-processing advantages.^[40]

A study in 2005 showed a positive correlation between repetitive behaviors in autistic individuals and obsessive-compulsive behaviors in parents.^[41] Another 2005 study focused on sub-threashold autistic traits in the general population. It found that correlation for social impairment or competence between parents and their children and between spouses is about 0.4.^[42]

A 2005 report examined the family psychiatric history of 58 subjects with Asperger’s syndrome (AS) diagnosed according to DSM-IV criteria. Three (5%) had first-degree relatives with AS. Nine (19%) had a family history of schizophrenia. Thirty five (60%) had a family history of depression. Out of 64 siblings, 4 (6.25%) were diagnosed with AS.^[43]

It has been suggested that the twinning process itself is a risk factor in the development of autism, presumably due to perinatal factors.^[44] However, three large-scale epidemiological studies have refuted this idea.^[45][46]

Evidence has mounted indicating that clinical pictures that look like autism (phenocopies) may not be due to the same genetic liability. Examples are congenital blindness,^[47] profound institutional privation,^[48][49] and a number of conditions related to mental retardation.^[50] Fragile-X syndrome, Rett syndrome and tuberous sclerosis are well-known causes of autism-like symptoms.

The original Mendelian model tried to explain observations using distinct genes existing in clearly dominant or recessive alleles. That would imply a recessive “autism gene” inherited from each of the parents. This kind of model is clearly too simple:

• It indicates that a sibling of an autistic individual should have 25% risk of having the autistic genotype, which is inconsistent with fraternal twin and sibling study results.
• It would require several characteristic features of autism to be caused by a single allele at a single locus.

Further considerations for the ‘autism gene model’ of also show contradictory implications:

• (a) only a small number of cases can be clearly linked to a possible genetic cause and these are often allele deletions;
• (b) the majority of patients with autism do not marry and do not have offspring which should result in a decreased incidence of the presumed gene in the general population.
• (c) the incidence of autism in the population has been increasing instead, making the likelihood of a single genetic cause extremely remote.

Mendel’s later work and work based on it introduced polygenic inheritance, but taking into account linkage of genes required understanding where they were located – elucidating the role of the chromosomes

Reduced risk to relatives of probands and identical/fraternal twin ratios indicate that a multigene model is more likely to account for the autistic genotype. That is, at least two alleles would be involved, and most likely three to five. Researchers have suggested models of 15 and even up to 100 genes.

The fraternal twin results found by Ritvo et al (1985)^[22] and the broader phenotype results of Bolton et al (1994)^[31] suggest that a 2-gene model is plausible. Kolevzon et al (2004) proposed that the 3 characteristic symptoms of autism may be the result of 3 different alleles. Data supports the multiple-locus hypothesis and also that a 3-loci model is the best fit.^[51] Risch et al (1999) found results most compatible with a large number of loci (>= 15).^[52]

Given the significant prevalence of autism, perhaps 0.1% for classic autism and at least 0.6% for a broader spectrum, a multigene model has important implications. Since intelligence appears to be independent of the recognized characteristic symptoms of autism (and the diagnostic criteria) it is likely that many individuals are very autistic yet highly functional, allowing them to escape a diagnosis altogether. So the prevalence of the autistic genotype may be considerably higher than thought. And if multiple alleles are part of the genotype, then each allele must have relatively high prevalence in the general population.

In this model most families fall into two types: in the majority, sons have a low risk of autism, but in a small minority their risk is near 50%. In the low-risk families, sporadic autism is mainly caused by spontaneous mutation with poor penetrance in daughters and high penetrance in sons. The high-risk families come from (mostly female) children who carry a new causative mutation but are unaffected and transmit the dominant mutation to grandchildren.^[34]

A number of epigenetic models of autism have been proposed as have several genetic imprinting models.^[53][54] These are suggested by the occurrence of autism in individuals with fragile X syndrome, which arises from epigenetic mutations, and with Rett syndrome, which involves epigenetic regulatory factors. An epigenetic model would help explain why standard genetic screening strategies have so much difficulty with autism.^[55]

A number of alleles have been shown to have strong linkage to the autism phenotype. In many cases the findings are inconclusive, with some studies showing no linkage. Alleles linked so far strongly support the assertion that there is a large number of genotypes that are manifested as the autism phenotype. At least some of the alleles associated with autism are fairly prevalent in the general population, which indicates they are not rare pathogenic mutations. This also presents some challenges in identifying all the rare allele combinations involved in the etiology of autism.

17q11.2 region, SERT (SLC6A4) locus – This gene locus has been associated with rigid-compulsive behaviors. Notably, it has also been associated with depression but only as a result of social adversity, although other studies have found no link.^[56] Significant linkage in families with only affected males has been shown.^[57][58] Researchers have also suggested that the gene contributes to hyperserotonemia.^[59]

GABA receptor subunit genes – GABA is the primary inhibitory neurotransmitter of the human brain. Ma et al (2005) concluded that GABRA4 is involved in the etiology of autism, and that it potentially increases autism risk through interaction with GABRB1.^[60] The GABRB3 gene has been associated with savant skills.^[61] The GABRB3 gene deficient mouse has been proposed as a model of ASD.^[62]

Engrailed 2 (EN2) – Engrailed 2 is believed to be associated with cerebellar development. Benayed et al (2005) estimate that this gene contributes to as many as 40% of ASD cases, about twice the prevalence of the general population.^[63] But at least one study has found no association.^[64]

3q25-27 region – A number of studies have shown a significant linkage of autism and Asperger’s syndrome with this locus.^[65][66] The most prominent markers are in the vicinity of D3S3715 and D3S3037.^[67]

7q21-q36 region, REELIN (RELN) – In adults, Reelin glycoprotein is believed to be involved in memory formation, neurotransmission, and synaptic plasticity. A number of studies have shown an association between the REELIN gene and autism,^[68][69] but a couple of studies were unable to duplicate linkage findings.^[70]

SLC25A12 – This gene, located in chromosome 2q31, encodes the mitochondrial aspartate/glutamate carrier (AGC1). It has been found to have a significant linkage to autism in some studies,^[71][72] but linkage was not replicated in others,^[73] and a 2007 study found no compelling evidence of an association of any mitochondrial haplogroup in autism.^[74]

HOXA1 and HOXB1 – A link has been found between HOX genes and the development of the embryonic brain stem. In particular, two genes, HOXA1 and HOXB1, in transgenic ‘knockout’ mice, engineered so that these genes were absent from the genomes of the mice in question, exhibited very specific brain stem developmental differences from the norm, which were directly comparable to the brain stem differences discovered in a human brain stem originating from a diagnosed autistic patient.^[75]

Conciatori et al (2004) found an association of HOXA1 with increased head circumference.^[76] A number of studies have found no association with autism.^[77][78][79] The possibility remains that single allelic variants of the HOXA1 gene are insufficient alone to trigger the developmental events in the embryo now associated with autistic spectrum conditions. Tischfield et al published a paper which suggests that because HOXA1 is implicated in a wide range of developmental mechanisms, a model involving multiple allelic variants of HOXA1 in particular may provide useful insights into the heritability mechanisms involved.^[80] Additionally, Ingram et al alighted upon additional possibilities in this arena.^[81] Transgenic mouse studies indicate that there is redundancy spread across HOX genes that complicate the issue, and that complex interactions between these genes could play a role in determining whether or not a person inheriting the requisite combinations manifests an autistic spectum condition^[82]—transgenic mice with mutations in both HOXA1 and HOXB1 exhibit far more profound developmental anomalies than those in which only one of the genes differs from the conserved ‘norm’.

In Rodier’s original work, teratogens are considered to play a part in addition, and that the possibility remains open for a range of teratogens to interact with the mechanisms controlled by these genes unfavourably (this has already been demonstrated using valproic acid, a known teratogen, in the mouse model).

PRKCB1 – Philippi et al (2005) found a strong association between this gene and autism. This is a recent finding that needs to be replicated.^[83]

FOXP2 – The FOXP2 gene is of interest because it is known to be associated with developmental language and speech deficits. An association to autism appears to be elusive, nonetheless.^[84][85]

UBE3A – The UBE3A gene has been associated with Angelman syndrome. Samaco et al (2005) suggest reduced expression of UBE3A in autism, as is the case in Rett syndrome.^[86] In any case, it appears that the role of UBE3A is limited.

Shank3/ProSAP2, 22q13 and Neuroligins – The gene called SHANK3 (also designated ProSAP2) regulates the structural organization of neurotransmitter receptors in post-synaptic dendritic spines making it a key element in chemical binding crucial to nerve cell communication.^[87] SHANK3 is also a binding partner of chromosome 22q13 (i.e. a specific section of Chromosome 22) and neuroligin proteins; deletions and mutations of SHANK3, 22q13 (i.e. a specific section of Chromosome 22) and genes encoding neuroligins have been found in some people with autism spectrum disorders.^[88]

Mutations in the SHANK3 gene have been strongly associated with the autism spectrum disorders. If the SHANK3 gene is not adequately passed to a child from the parent (haploinsufficiency) there will possibly be significant neurological changes that are associated with yet another gene, 22q13, which interacts with SHANK3. Alteration or deletion of either will effect changes in the other.^[88]

A deletion of a single copy of a gene on chromosome 22q13 has been correlated with global developmental delay, severely delayed speech or social communication disorders and moderate to profound delay of cognitive abilities. Behavior is described as “autistic-like” and includes high tolerance to pain and habitual chewing or mouthing^[88] (see also 22q13 deletion syndrome). This appears to be connected to the fact that signal transmission between nerve cells is altered with the absence of 22q13.

SHANK3 proteins also interact with neuroligins at the synapses of the brain further complicating the widespread effects of changes at the genetic level and beyond.^[89]

Neuroligin is a cell surface protein (homologous to acetylcholinesterase and other esterases) that binds to synaptic membranes.^[90] Neuroligins organize postsynaptic membranes that function to transmit nerve cell messages (excitatory) and stop those transmissions (inhibitory);^[91] In this way, neuroligins help to ensure signal transitions between nerve cells. Neuroligins are also regulate the maturation of synapses and ensure there are sufficient receptor proteins on the synaptic membrane.

Mice with a neuroligin-3 mutation exhibit poor social skills but increased intelligence.^[92] Though not present in all individuals with autism, these mutations hold potential to illustrate some of the genetic components of spectrum disorders.^[89]

MET – The MET gene (MET receptor tyrosine kinase gene) linked to brain development, regulation of the immune system, and repair of the gastrointestinal system, has been linked to autism. This MET gene codes for a protein that relays signals that turn on a cell’s internal machinery. Impairing the receptor’s signaling interferes with neuron migration and disrupts neuronal growth in the cerebral cortex and similarly shrinks the cerebellum—abnormalities also seen in autism.^[93]

It is also known to play a key role in both normal and abnormal development, such as cancer metastases (hence the name MET). A mutation of the gene, rendering it less active, has been found to be common amongst children with autism.^[93] Mutation in the MET gene demonstrably raises risk of autism by 2.27 times.^[94]

neurexin 1 – In February 2007, researchers in the Autism Genome Project (an international research team composed of 137 scientists in 50 institutions) reported possible implications in aberrations of a brain-development gene called neurexin 1 as a cause of some cases of autism.^[95] Linkage analysis was performed on DNA from 1,181 families in what was the largest-scale genome scan conducted in autism research at the time.

The objective of the study was to locate specific brain cells involved in autism to find regions in the genome linked to autism susceptibility genes. The focus of the research was copy number variations (CNVs), extra or missing parts of genes. Each person does not actually have just an exact copy of genes from each parent. Each person also has occasional multiple copies of one or more genes or some genes are missing altogether. The research team attempted to locate CNVs when they scanned the DNA.

Neurexin 1 is one of the genes that may be involved in communication between nerve cells (neurons). Neurexin 1 and other genes like it are very important in determining how the brain is connected from cell to cell, and in the chemical transmission of information between nerve cells. These genes are particularly active very early in brain development, either in utero or in the first months or couple of years of life. In some families their autistic child had only one copy of the neurexin 1 gene.

Besides actually locating yet another possible genetic influence (the findings were statistically insignificant), the research also reinforced the theory that autism involves many forms of genetic variations.

GSTP1 – A 2007 study suggested that the GSTP1*A haplotype of the glutathione S-transferase P1 gene (GSTP1) acts in the mother during pregnancy and increases the likelihood of autism in the child.^[96]

Others – There is a large number of other candidate loci which either should be looked at or have been shown to be promising. Several genome-wide scans have been performed identifying markers across many chromosomes.^[97][98][99]

A few examples of loci that have been studied are the 17q21 region, the 3p24-26 locus,^[97] PTEN,^[100] and 15q11-q13.^[61]

Other possible candidates include:

• SLC6A2 (Social phobia)
• FMR1 (Fragile-X)
• 5-HT-1Dbeta (OCD)
• 7q11.23 (William’s syndrome, language impairment)
• 4q34-35, 5q35.2-35.3, 17q25 (Tourette syndrome)
• 2q24.1-31.1 (Intelligence)
• 6p25.3-22.3 (Verbal IQ)
• 22q11.2 (Visio-Spatial IQ)

The risk of autism is associated with several prenatal risk factors. Autism has been linked to birth defect agents acting during the first eight weeks from conception, though these cases are rare. Other potential prenatal environmental factors do not have convincing scientific evidence.

Teratogens are environmental agents that cause birth defects. Some agents that are known to cause other birth defects have also been found to be related to autism risk. These include exposure of the embryo to thalidomide, valproic acid, or misoprostol, or to rubella infection in the mother. These cases are rare.^[101] Questions have also been raised whether ethanol (grain alcohol) increases autism risk, as part of fetal alcohol syndrome or alcohol-related birth defects, but current evidence is insufficient to determine whether autism risk is actually elevated with ethanol.^[102] All known teratogens appear to act during the first eight weeks from conception, and though this does not exclude the possibility that autism can be initiated or affected later, it is strong evidence that autism arises very early in development.^[6] Infection-associated immunological events in early pregnancy may affect neural development more than infections in late pregnancy, not only for autism, but also for other psychiatric disorders of presumed neurodevelopmental origin, notably schizophrenia.^[103]

A 2007 study by the California Department of Public Health found that women in the first eight weeks of pregnancy who live near farm fields sprayed with the organochlorine pesticides dicofol and endosulfan are several times more likely to give birth to children with autism. The association appeared to increase with dose and decrease with distance from field site to residence. The study’s findings suggest that on the order of 7% of autism cases in the California Central Valley might have been connected to exposure to the insecticides drifting off fields into residential areas. These results are highly preliminary due to the small number of women and children involved and lack of evidence from other studies.^[104] It is not known whether these pesticides are human teratogens, though endosulfan has significant teratogenic effects in laboratory rats.^[105]

A 2005 study showed indirect evidence that prenatal exposure to organophosphate pesticides such as diazinon and chlorpyrifos may contribute to autism in genetically vulnerable children.^[106] Several other studies demonstrate the neurodevelopmental toxicity of these agents at relatively low exposure levels.^[107]

Folic acid taken during pregnancy might play an important role in causing autism by modulating gene expression through epigenetic mechanism. This hypothesis is untested.^[108]

The fetal testosterone theory hypothesizes that higher levels of testosterone in the amniotic fluid of mothers pushes brain development towards improved ability to see patterns and analyze complex systems while diminishing communication and empathy, emphasizing “male” traits over “female”, or in EQ SQ Theory terminology, emphasizing “systemizing” over “empathizing”.^[109] One project has published several reports suggesting that high levels of fetal testosterone could produce behaviors relevant to those seen in autism.^[110] The theory and findings are controversial and many studies contradict the idea that baby boys and girls respond differently to people and objects.^[111]

A 2006 study found that sustained exposure of mouse embryos to ultrasound waves caused a small but statistically significant number of neurons to fail to acquire their proper position during neuronal migration.^[112] It is highly unlikely that this result speaks directly to risks of fetal ultrasound as practiced in competent and responsible medical centers.^[113] There is no scientific evidence of an association between prenatal ultrasound exposure and autism, but there are very little data on human fetal exposure during diagnostic ultrasound, and the lack of recent epidemiological research and human data in the field has been called “appalling”.^[114]

Autism is associated with some perinatal and obstetric conditions. A 2007 review of risk factors found associated obstetric conditions that included low birth weight and gestation duration, and hypoxia during childbirth. This association does not demonstrate a causal relationship; an underlying cause could explain both autism and these associated conditions.^[9] A 2007 study of premature infants found that those who survived cerebellar hemorrhagic injury (bleeding in the brain that injures the cerebellum) were significantly more likely to show symptoms of autism than controls without the injury.^[115]

A wide variety of postnatal contributors to autism have been proposed, including gastrointestinal or immune system abnormalities, allergies, and exposure of children to drugs, vaccines, infection, certain foods, or heavy metals. The evidence for these risk factors is anecdotal and has not been confirmed by reliable studies.^[5] The subject remains controversial and extensive further searches for environmental factors are underway.^[101]

Parents have reported gastrointestinal (GI) disturbances in autistic children, and several studies have investigated possible associations between autism and the gut.^[116] The controversial Wakefield et al. vaccine paper discussed in “MMR vaccine” below also suggested that some bowel disorders may allow antigens to pass from food into the bloodstream and then to contribute to brain dysfunction.^[117] This produced several lines of investigation.

For example, employing secretin‘s effects on digestion, a 1998 study of three children with ASD treated with secretin infusion reported improved GI function and dramatic improvement in behavior, which suggested an association between GI and brain function in autistic children.^[118] After this study, many parents sought secretin treatment and a black market for the hormone developed quickly.^[116] However, later studies found secretin ineffective in treating autism.^[119]

Leaky gut syndrome theories also inspired several dietary treatments, including gluten-free diets, casein-free diets, antifungal diets, low-sugar diets, as well as supplements that include nystatin, [[B12|BTemplate:Ssub]], and probiotics. Parents are more likely to get advice about these diets from other parents, the media, and the Internet than from medical experts. There is no solid research evidence that autistic children are more likely to have GI symptoms than typical children.^[116] In particular, design flaws in studies of elimination diets mean that the currently available data are inadequate to guide treatment recommendations.^[120]

Many studies have presented evidence for and against association of autism with viral infection after birth. Laboratory rats infected with Borna disease virus show some symptoms similar to those of autism but blood studies of autistic children show no evidence of infection by this virus. Members of the herpes virus family may have a role in autism, but the evidence so far is anecdotal. Viruses have long been suspected as triggers for immune-mediated diseases such as multiple sclerosis but showing a direct role for viral causation is difficult in those diseases, and mechanisms whereby viral infections could lead to autism are speculative.^[121]

This theory hypothesizes that toxicity and oxidative stress may cause autism in some cases by damaging Purkinje cells in the cerebellum after birth. One possibility is that glutathione is involved.^[122]

This theory hypothesizes that an early developmental failure involving the amygdala cascades on the development of cortical areas that mediate social perception in the visual domain. The fusiform face area of the ventral stream is implicated. The idea is that it is involved in social knowledge and social cognition, and that the deficits in this network are instrumental in causing autism.^[123]

This theory hypothesizes that autism is caused by vitamin D deficiency, and that recent increases in diagnosed cases of autism are due to medical advice to avoid the sun. The theory has not been studied scientifically.^[124]

Lead poisoning has been suggested as a possible risk factor for autism, as the lead blood levels of autistic children has been reported to be significantly higher than typical. The atypical eating behaviors of autistic children, along with habitual mouthing and pica, make it hard to determine whether increased lead levels are a cause or a consequence of autism.^[125]

This theory hypothesizes that autism is associated with mercury poisoning, based on perceived similarity of symptoms.^[126] The principal source of human exposure to organic mercury is via fish consumption and for inorganic mercury is dental amalgams. Other forms of exposure, such as in cosmetics and vaccines, also occur. The evidence so far is indirect for the association between autism and mercury exposure after birth, as no direct test has been reported, and there is no evidence of an association between autism and postnatal exposure to any neurotoxicant.^[127]

A 2003 study reported that mercury measurements of hair samples from autistic children’s first haircuts were significantly lower than a matched group of normal children, declining as measures of severity increased,^[128] but a later meta-analysis based on two studies found that there was not enough evidence to conclude that hair mercury level is lower in autistic children.^[129] A 2006 study found an association between autism and environmental releases of mercury, primarily from coal power plants; this study used Texas county-wide data and did not distinguish between prenatal and postnatal exposure.^[130]

Although parents may first become aware of autistic symptoms in their child around the time of a routine vaccination, and parental concern about vaccines has led to a decreasing uptake of childhood immunizations and an increasing likelihood of measles outbreaks, there is overwhelming scientific evidence showing no causal association between the measles-mumps-rubella vaccine and autism, and there is no scientific evidence that the vaccine preservative thiomersal helps cause autism.^[131]

Three economists hypothesized that early childhood television viewing acts as an environmental trigger for an underlying genetic predisposition. They found that precipitation was associated with autism by examining county-level autism data for California, Oregon, and Washington. Precipitation is also associated with television watching, and their analysis concluded that just under 40% of autism diagnoses in the three states result from television watching due to precipitation.^[132] This study has not been published in a refereed journal and its results have not been confirmed by others.

Bruno Bettelheim believed that autism was linked to early childhood trauma, and his work was highly influential for decades both in the medical and popular spheres. Parents, especially mothers, of individuals with autism were blamed for having caused their child’s condition through the withholding of affection.^[133] Leo Kanner, who first described autism,^[134] suggested that parental coldness might contribute to autism.^[135] Although Kanner eventually renounced the theory, Bettelheim put an almost exclusive emphasis on it in both his medical and his popular books. Treatments based on these theories failed to help children with autism, and after Bettelheim’s death it came out that his reported rates of cure (around 85%) were found to be fraudulent.^[136]

Psychogenic theories in general have become increasingly unpopular, particularly since twin studies have shown that autism is highly heritable. Nevertheless, some case reports have found that deep institutional privation can result in “quasi-autistic” features without the neuroanatomical differences.^[137][138] Other case reports have suggested that children predisposed genetically to autism can develop “autistic devices” in response to traumatic events such as the birth of a sibling.^[139]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Diagnosis of autism is based on behavior, but not cause or mechanism. Autism must be differentiated from other group of diseases with similar neurological presentations such as lack of social or emotional reciprocity, stereotyped and repetitive use of language or idiosyncratic language, and persistent preoccupation with parts of objects. Most common differential include Reitts disorders, other differentials include Leigh syndrome, Niemann-Pick disease type C, infantile muscle spasms.

Diagnosis of autism is based on behavior, not cause or mechanism. Autism must be differentiated from other group of diseases with similar neurological presentations such as lack of social or emotional reciprocity, stereotyped and repetitive use of language or idiosyncratic language, and persistent preoccupation with parts of objects. ^[1][2]

The following table summaries the common diseases that need to be considered during differentials of autism include .^{[3][4][5][6][7][8][9][7][10]}

Diseases	Type of motor abnormality				Clinical findings	Laboratory findings and diagnostic tests	Radiographic findings
	Spasticity	Hypotonia	Ataxia	Dystonia
Leigh syndrome	–	–	+	+	Progressive psychomotor regression Seizures External ophthalmoplegia Lactic acidosis Vomiting	Increased lactate levels in blood and CSF Genetic testing	MRI: abnormal white matter signal in the putamen, basal ganglia, and brainstem on T2 images
Niemann-Pick disease type C	–	–	+	+	Progressive neurodegeneration Hepatosplenomegaly Systemic involvement of liver, spleen, or lung preceedes neurologic symptoms	Abnormal liver function tests Fibroblast cell culture with filipin staining	MRI: Cerebral and cerebellar atrophy Thinning of the corpus callosum
Infantile Refsum disease	–	+	+	–	Abnormalities of the optic nerve and disc Retinitis pigmentosa Sensorineural hearing loss Hepatomegaly and cirrhosis Neurologic deterioration is slower than in Zellweger syndrome or ALD	Elevated plasma VLCFA levels	—
Adrenoleukodystrophy	+	–	–	–	Cognitive and behavioral abnormalities Adrenal insufficiency Hyperpigmented skin Gonadal dysfunction Neurologic deterioration progresses at a variable rate	Elevated plasma VLCFA levels Molecular genetic testing for mutations in the ABCD1 gene	—
Zellweger syndrome	–	+	–	–	Craniofacial dysmorphism Hepatomegaly Neonatal seizures Profound developmental delay MRI findings include cortical and white matter abnormalities Neurologic deterioration is rapid and infants rarely survive beyond six months of age	Elevated plasma VLCFA levels Elevated levels of phytanic acid, pristanic acid, and pipecolic acid in plasma and fibroblasts Reduced plasmalogen in erythrocytes Molecular genetic testing for mutations in the PEX1 or PEX6 genes	—
Pyruvate dehydrogenase deficiency	+	+	+	–	Lactic acidosis Seizures Intellectual disability	Elevated lactate and pyruvate levels in blood and CSF Abnormal PDH enzymatic activity in cultured fibroblasts	—
Arginase deficiency	+	–	–	–	Hyperammonemia Encephalopathy Respiratory alkalosis	Elevated ammonia level Elevated arginine level	—
Holocarboxylase synthetase deficiency	–	+	–	–	Ketoacidosis Dermatitis Alopecia Seizures Developmental delay	Elevated levels of: Beta-hydroxyisovalerate Beta-methylcrotonylglycine Beta-hydroxypropionate Methylcitrate Tiglylglycine	—
Glutaric aciduria type 1	–	–	–	+	Episodes of metabolic decompensation and encephalopathy often precipitated by infection and fever Rarely presents in the newborn period Microencephalic macrocephaly Seizures (approximately 20 percent) Cognitive function is preserved	Elevated levels of: glutaric acid 3-hydroxyglutaric acid	MRI: Frontal and temporal atrophy
Ataxia telangiectasia	–	–	+	–	Progressive cerebellar ataxia Abnormal eye movements Oculocutaneous telangiectasias Immune deficiency Increased risk of malignancy	Elevated serum alpha-fetoprotein level Low IgA and IgG levels Lymphopenia Genetic testing for mutation in the ATM gene	—
Pontocerebellar hypoplasias	–	+	–	–	Progressive muscle atrophy Microcephaly Developmental delay	Genetic testing for PCH gene mutations	MRI : Small cerebellum and brainstem including the pons
Metachromatic leukodystrophy	–	+	+	–	Regression of motor skills Seizures Optic atrophy Reduced or absent deep tendon reflexes Intellectual disability	Deficient arylsulfatase A enzyme activity in leukocytes or cultured skin fibroblasts	—
Pelizaeus-Merzbacher	+	–	+	–	Nystagmus Cognitive impairment Onset in infancy Slowly progressive Language development may be normal	Genetic testing for mutations in PLP1 gene	MRI: White matter abnormalities
Angelman syndrome	–	–	+	–	Profound intellectual disability Postnatal microcephaly Typical abnormal behaviors (paroxysmal laughter, easily excitable)	Methylation studies and chromosome microarray to detect chromosome 15 anomalies and UBE3A mutations	—
Rett syndrome	+	–	–	+	Occurs almost exclusively in females Normal development during first six months followed by regression and loss of milestones Loss of speech capability Stereotypic hand movements Seizures Autistic features	Clinical diagnosis Genetic testing for MECP2 mutations	—
Lesch-Nyhan syndrome	+	–	–	+	Self-mutilating behavior Urinary stones due to hyperuricemia	Elevated uric acid level Abnormal enzymatic activity of HPRT in cultured fibroblasts Genetic testing for HPRT gene mutations	—
Miller-Dieker lissencephaly	+	+	–	–	Lissencephaly Microcephaly Dysmorphic features Seizures Failure to thrive	Cytogenetic testing for 17p13.3 microdeletion	—
Dopa-responsive dystonia	+	–	–	+	Onset in early childhood Symptoms worsen with fatigue and exercise	Positive response to a trial of levodopa	—

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Most recent reviews estimate a prevalence of 100- 200 cases per 100,000 people for autism, and about 600 per 100,000 for ASD, with ASD averaging a 4.3:1 male-to-female ratio. The number of people known to have autism has increased dramatically since the 1980s, at least partly due to changes in diagnostic practice; the question of whether actual prevalence has increased is unresolved.

• According to National Survey of Children’s Health, by the Autism and Developmental Disabilities Monitoring (ADDM) network, the estimated annual incidence of ASD world wide is 1 child in every 110 children.^[1] 
• The estimated annual incidence of autism in the United states of America is similar to the world estimate, that 1 in 91 children aged 3 to 17 years. 
• These numbers are similar to regional data
  • In Massachusetts, the incidence of ASD in 2005 was 1 per 108 in children less than 3 years of age.

• The estimated annual prevalence of is 100– 200 per 100,000 for autism and close to 600 per 100,000 for ASD.^[2][3]
• PDD-NOS is the vast majority of ASD, Asperger’s is about 30 per 100,000 and the remaining ASD forms are much rarer.^[4]

• Males are more commonly affected by ASD than females.^[5]
• The male to female ratio is approximately 4.3 to 1.

• The ASD sex ratio is greatly modified by cognitive impairment, it may be close to 2:1 with mental retardation and more than 5.5:1 for HFA.

• The national estimates for the prevalence of ASD in Australia ranged from 121 to 357 per 100,000 for children aged 6–12 years.^[6]

• The annual estimate of ASD in Denamark is estimated to be 137 per 100,000.^[7]
• A 2003 study reported that the cumulative incidence of autism in Denmark began a steep increase starting around 1990, and continued to grow until 2000, despite the withdrawal of thiomersal- containing vaccines in 1992.
  • For example, for children aged 2–4 years, the cumulative incidence was about 5 new cases per 100,000 children in 1990 and about 45 new cases per 100,000 children in 2000.

• The incidence and changes in incidence with time are unclear in the UK.^[8]
• The reported autism incidence in the UK rose starting before the first introduction of the MMR vaccine in 1989.^[9]
• The estimated annual incidence of ASD is 2.98 per 10,000 person.^[10]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Common risk factors in the development of autism include male gender, advanced maternal and paternal age, low birth weight, hypoxia during childbirth, and family history schizophrenia.

Common risk factors in the development autism include:

• Male gender: boys are at higher risk for autism than girls.^[1]
• Prenatal and perinatal risk factors:
  • Advanced maternal age
  • Advanced paternal age
  • Low birth weight
  • Gestation duration
  • Hypoxia during childbirth^[2]
• Family history schizophrenia^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The American Academy of Pediatrics recommends that all children be screened for ASD at the 18- and 24-months using autism-specific formal screening tests.

The American Academy of Pediatrics recommends that all children be screened for ASD at the 18- and 24-months using autism-specific formal screening tests.^[1][2]

Screening tools for ASD include:^[3]

• Modified Checklist for Autism in Toddlers (M-CHAT)
• The Early Screening of Autistic Traits Questionnaire
• The First Year Inventory; initial data on M-CHAT and its predecessor CHAT.

Following signs emphasizes the screening of a child for ASD without delay:

• No babbling by 12 months.
• No gesturing (pointing, waving goodbye, etc.) by 12 months.
• No single words by 16 months.
• No two-word spontaneous phrases (not including echolalia) by 24 months.
• Any loss of any language or social skills, at any age.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [3]

ASD is a chronic illness with core features persisting throughout life, although presentation may vary according to the age, level of maturity, environment. Infants are affected most severely. There is developmental delay and regression of language. Indifference and lack of interest (which is commonly found in ASD) may also seem like a delay in behavior. Some individuals may have a higher level of functioning despite social awkwardness (called savants). Autism patients may develop many syndromes and exhibit signs and symptoms of the respective syndrome, leading to complications. Higher socioeconomic status, acquisition of language skill at an early age, higher IQ and absence of underlying genetic or metabolic disorder are all associated with better outcomes in patients suffering from autism.

ASD is a chronic illness with core features persisting throughout life, although presentation may vary according to the age, level of maturity, environment. Infants are affected most severely. There is developmental delay and regression of language. Indifference and lack of interest (which is commonly found in ASD) may also seem like a delay in behavior. Some individuals may have a higher level of functioning despite social awkwardness (called savants). These children usually present later as they appear otherwise intelligent. Frustration, anxiety and depression affect future relationships even if the child becomes willing to socially interact. During adolescence hyperactivity may improve and ritualistic behaviors decrease, but the patient may be affected by other comorbidities.

• Autism can be associated with other disorders that affect the brain, such as:

• Fragile X syndrome
• Mental retardation
• Tuberous sclerosis

• Some people with autism will develop seizures.

• The stresses of dealing with autism can lead to social and emotional complications for family and caregivers, as well as the person with autism.

• There is no cure for autism. Appropriate and timely intervention may lead to better outcomes and return to normal or near normal social functioning.
• Most children with autism lack social support, meaningful relationships, future employment opportunities or self-determination.^[1]
• Symptoms associated with autism may gradually improve with age.^[2]
• Few high-quality studies address long-term prognosis.^[3]
• Early acquisition of language skills (by age 6 years), IQ > 50, and having a socially acceptable skill all predict better outcomes; independent living is unlikely with severe autism.^[4]
• A 2004 British study of 68 adults who were diagnosed before 1980 as autistic children with IQ above 50 found that 12% achieved a high level of independence as adults, 10% had some friends and were generally in work but required some support, 19% had some independence but were generally living at home and needed considerable support and supervision in daily living, 46% needed specialist residential provision from facilities specializing in ASD with a high level of support and very limited autonomy, and 12% needed high-level hospital care.^[5]
• A 2005 Swedish study of 78 adults pointed out that patients having a lower IQ, had a lower rate of achieving independence.^[6]
• A 2008 Canadian study of 48 young adults diagnosed with ASD as preschoolers found outcomes ranging through poor (46%), fair (32%), good (17%), and very good (4%); only 56% had ever been employed, most in volunteer, sheltered or part time work.^[7]
• Patients harboring the 22q13 deletion have absent or severely delayed speech. They exhibit only minor facial dysmorphism; thin, flaky toenails (78%); large, fleshy hands (68%); large feet; prominent, poorly formed ears (65%); and other characteristics which are not visually apparent: hypotonia (97%); normal to accelerated growth (95%); increased tolerance to pain (86%); seizures (unknown percentage); strabismus; anomalies of the spine; poor central vision.^[8]

The following features and characteristics are associated with a better prognosis in patients affected with autism:^[9]

• Absence of cognitive impairment
• No underlying genetic or metabolic disorder
• Early diagnosis and optimum intervention
• Upper socio-economic class
• Higher levels of parental education

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