Posts tagged autism
The epigenetics of Autism: Oxytocin factor and implications for schizophrenia

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Autism is a hard disorder to nail down genetically- single nucleotide polymorphisms (SNPs) or even multiple locus genetic effects are not able to account for the large genetic component to the disorder. In recent times, Copy number variations (CNVs) has come to the forefront of Autism research , suggesting that microdeletions, duplications etc may account for some cases. Another new , till now unsuspected mechanism that has recently been implicated in autism is epigenetic mechanism of increased methylation in promoter regions that has the effect of silencing/reducing the expression of genes involved to a certain extent. The recent study by Gregory et al, is just such a step in the right direction, which will hopefully bring us closer to the truth.
The study is available in full at BMC Medicine site and is accompanied by a must read commentary that explains a lot of things and puts the finding in context.
In a nutshell, the study authors used CNV determining methods to discover that a deletion of OXTR (oxytocin receptor) gene was presnet in an autistic subject and was not de novo , but the deletion was inherited from his mother. One of the affected siblings of the autistic subject, who too was autistic, on the other hand did not have a deletion, but had increased methylation of the OXTR. this led the study authors to revisit their genomics data and look at adta across all autistic subjects and controls and discover that indeed, in other autistics too the OXTR had increased methylation. Then they looked for expression of OXTR in peripheral blood cells and temporal cortex and found that indedd in autistics, as compared to controls, there was reduced expression of OXTR. This strongly suggest that the epigentic changes that lead to autism (the efffect of OXTR suppression) happen quite early in the devlopmenet and might happen in utero.
Before I elaborate on my take home from the study, there are some excerpts (as I know you didn’t read the originals)
Classic autism comprises a spectrum of behavioral and cognitive disturbances of childhood development. The core autism phenotype includes deficits in social interaction, language development and patterns of repetitive behaviors and/or restricted interests. The population prevalence of the spectrum of autism disorders is estimated to range between 1/300 [1] to 1/100 (http://www.nschdata.org/), with a male: female ratio of 4:1 [2,3]. The disorder has been shown to be highly heritable with the relative risk for siblings being approximately 2% to 8%, much higher than that of the general population [4]. To date, only a small percentage of autism cases (<10%) have been ascribed to single gene disorders such as fragile X syndrome, tuberous sclerosis [5] and Rett syndrome [6]. Numerous approaches including genetic linkage, genome-wide association, candidate gene association and gene expression analysis have been used to identify the additional genes
implicated in the development of autism [7,8]. However, the heterogeneous nature of autism and autism spectrum disorders has limited their success.An additional approach to identify genes involved in autism is to characterize copy number variants (CNVs), that is, chromosomal deletions and duplications, that are known to be present within at least 5% of individuals with idiopathic autism [9]. Autism CNVs have been shown to involve almost all chromosomes [10,11], with the most frequently observed alteration localizing to chromosome 15q11-13 [12-23]. A number of different methods have been used to characterize autism related CNVs, including but not limited to, cytogenetic Gbanding [14,23,24], metaphase fluorescence in situ hybridization (FISH) [22], Southern blotting [18], loss of heterozygosity (LOH) analysis [15-17,19], quantitative polymerase chain reaction (PCR) [25] and, more recently, genotyping and representational oligonucleotide microarray analysis (ROMA) [26].
Here we describe the use of genome-wide tilepath microarrays and array comparative genomic hybridization (CGH) to identify CNVs in a dataset of 119 unrelated probands from multiplex autism families [27]. The genomic profiles of our autism dataset were compared to the array CGH profiles of 54 phenotypically normal individuals, to previously published CNVs present within the database of genomic variants [28] and to the Autism Chromosome Rearrangement Database (http://projects.tcag.ca/autism/). The most significant finding thus far from our analysis is a heterozygous deletion of the oxytocin receptor gene (OXTR) (MIM accession no.: 167055) in an individual with autism and his mother with putative obsessive-compulsive disorder (OCD). We further investigated the relationship between OXTR and autism by carrying out epigenetic analysis of the promoter region of OXTR. We show that the gene is hypermethylated in independent cohorts with autism as compared to controls, in both peripheral blood mononuclear cells (PBMCs) and the temporal cortex. Additionally, our analysis of expression levels of OXTR in the temporal cortex shows decreased levels of expression in individuals with autism as compared to controls matched for age and sex.These data suggest that OXTR and the oxytocin signaling pathway play an important role in the etiology of autism and autism spectrum disorders and implicate epigenetic misregulation of OXTR in this complex disease.
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Epigenetic control of autism susceptibility is a recent concept and most certainly a topic of great interest in the field. Over the past decade, researchers have uncovered suggestive links between epigenetics and autism, for example, autism is associated with duplications of 15q11-13 (especially maternally inherited), an imprinted region in the genome where DNA methylation status has been linked to Prader-Willi syndrome (PWS) and Angelman syndrome (AS) [66]; mutation within a gene that encodes a methyl-DNA-binding protein (MECP2, (MIM accession no.: 300005)) is the causative agent of Rett syndrome [67]; and mutation of this same gene has been associated with both autism and AS populations [55]. Nagarajan et al. have shown that 79% of autism cases have a decrease in MECP2 expression in the frontal cortex and that an increase in aberrant DNA methylation correlates with this decrease in MECP2 expression [68]. These data implicate epigenetic dysregulation as a mechanism for the development of autism and justify the examination of DNA methylation of autism candidate genes, such as OXTR identified in this study.
Now from the accompanying (more accessible) commentary:
The article by Gregory et al. published this month in BMC Medicine, reports on genomic and epigenetic alterations of OXTR, the gene encoding the receptor for oxytocin. The involvement of this gene was suggested by its deletion in an autistic patient. The subsequent analysis of a group of unrelated autistic subjects did not show an OXTR deletion, but rather hypermethylation of the gene promoter, with a reduced mRNA expression.
These findings address two major points of the current debate on the etiology and pathogenesis of autism: the role of oxytocin, known to be involved in modeling human behavior, and the possible involvement of epigenetic mechanisms. The nature of this epigenetic dysregulation is unknown but, if proved to be true, might explain the failure to identify sequence alterations in a host of candidate genes. Practical implications of these findings may be forthcoming, however not before extension and validation on a larger scale have confirmed their value.
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The second issue raised by Gregory et al. deals with the epigenetic inhibition of OXTR expression in ASD. Such epigenetic modification, at least as reported so far, does not seem to be sequence based but rather of a different, as yet unknown nature. This might explain why researchers have been looking for decades for genetic mutations in ASD and yet have found almost none. An epigenetic mechanism would justify the ‘unusual’, non-Mendelian familial aggregations of ASD. In this respect, even the family with OXTR deficiency reported by Gregory et al. shows an unusual genotype-phenotype correlation, in that the same phenotype is caused by alterations of the same gene but due to different molecular defects (deletion versus hypermethylation).Also, the possibility that in most ASD patients there might be an epigenomic instability is of interest in consideration of the fact that it has been shown that the epigenetic status in early fetal development can be reprogrammed by maternal behavior in a reversible way [34]. Therefore, other environmental factors, yet to be discovered, might also be able to reprogram the epigenotype of the embryo.
I hope the fact that epigenetic changes may happen during pregnancy line of reasoning does not lead to the harmful and without-any-basis vaccination is cause of autism arguments. On the other hand I had covered earlier how Autism is more likely if mother was exposed to valproate during pregnancy or the child soon after birth. What if valproate is instrumental in an epigenetic fashion in leading to more or less methylation and gene expression. It is well known that valproate and valporic acid is given as treatment for psychosis/bipolar. In a similar vein, I am inclined to stick my neck out and claim that in schizophrenics/psychotics , the OXTR should be more expressed : perhaps more methylation, duplications etc . However I am checked in my musings by these studies that claim that negative symptoms of schizophrneia may be associated with reduced oxytocin activity in the brain. Yet, all said and done I would like to see a study that analyzes for epigenetic mechanisms in schizophrneia especially at the OXTR locus. Although the negative symptoms like social withdrawal of schizophrenia may lead to the opposite hypothesis regarding schizophrenia and oxytocin correlation, I am inclined to believe that schizophrenics (at least those suffering from positive symptoms predominantly) are too much oxytocin guided , trusting and socially too much involved in others type of people.
Gregory, S., Connelly, J., Towers, A., Johnson, J., Biscocho, D., Markunas, C., Lintas, C., Abramson, R., Wright, H., Ellis, P., Langford, C., Worley, G., Delong, G., Murphy, S., Cuccaro, M., Persico, A., & Pericak-Vance, M. (2009). Genomic and epigenetic evidence for oxytocin receptor deficiency in autism BMC Medicine, 7 (1) DOI: 10.1186/1741-7015-7-62
Gurrieri, F., & Neri, G. (2009). Defective oxytocin function: a clue to understanding the cause of autism? BMC Medicine, 7 (1) DOI: 10.1186/1741-7015-7-63
Hat tip to @Boraz for tweeting about this study.
Autism, Schizophrenia and CNV in 16p11.2

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There is a letter published in the advance online edition of Nature Genetics, that reports that microduplication of genes in the region 16p11.2 are associated with the risk of schizophrenia in a large cohort. It has been earlier shown that microdeletions in the same region confer the risk of Autism.Thus, it seems that the region codes for genes too much of which causes schizophrenia and too little autism. Here is the abstract of the study:
Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 times 10-5, OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 times 10-7), bipolar disorder (P = 0.017) and autism (P = 1.9 times 10-7). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 times 10-13). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).
Here is what medical news today (via which I found this article) has to say about the findings:
An international team of researchers led by geneticist Jonathan Sebat, Ph.D., of Cold Spring Harbor Laboratory (CSHL), has identified a mutation on human chromosome 16 that substantially increases risk for schizophrenia.
The mutation in question is what scientists call a copy number variant (CNV). CNVs are areas of the genome where the number of copies of genes differs between individuals. The CNV is located in a region referred to by scientists as 16p11.2. By studying the genomes of 4,551 patients and 6,391 healthy individuals, Sebat’s team has shown that having one extra copy of this region is associated with schizophrenia. The study appears online today ahead of print in the journal Nature Genetics.
Schizophrenia and autism: two sides of the same coin?“This is not the first time that the 16p11.2 region has caught our eye,” says Sebat. It was previously spotted in a 2007 study with Professor Michael Wigler at CSHL — a deletion of the identical region was identified in a girl with autism. Studies by several other groups have shown that losing one copy of 16p11.2 confers high risk of autism and other developmental disorders in children.
Taken together these studies suggest that some genes are shared between schizophrenia and autism, according to Sebat and colleagues. “In some ways, we might consider the two disorders to be at opposite ends of the same neurobiological process” says Shane McCarthy, Ph.D., the lead author of the study, “and this process is influenced by the copy number of genes on chromosome 16.” One hypothesis is that the loss of 16p11.2 leads to the deprivation of key genes involved in brain development, while an extra copy of this region might have the opposite effect.
A correlation between 16p11.2 mutations and head size
It is not known what biological processes are affected by the copy number of 16p11.2, Sebat notes. He believes, however, that the team may have stumbled on to an important clue. By studying the clinical records of patients, they discovered that patients with deletions of the region differ significantly in head size from those with duplications of the same region. Sebat reports, “Head circumference of patients with the deletion were larger than average by more than one standard deviation. Head circumference was slightly below average in patients with the duplication.” These findings, he notes, are consistent with some previous studies that have observed a trend towards larger brain size in autism and an opposite trend toward smaller brain size in schizophrenia.
All this nicely fits in with what I have been proclaiming from the rooftops from the early days of this blog: that autism and Schizophrenia are opposites on the same continuum and the genes involved should also be the same. More copy numbers leading to propensity towards psychosis while lesser number or deletions associated with autistic traits. One more puzzle piece fits in and now we know why the brain size differences exist in autistic and schizophrenic persons and what the poetntial function (mentalizing) of region 16p11.2 may be.
McCarthy, S., Makarov, V., Kirov, G., Addington, A., McClellan, J., Yoon, S., Perkins, D., Dickel, D., Kusenda, M., Krastoshevsky, O., Krause, V., Kumar, R., Grozeva, D., Malhotra, D., Walsh, T., Zackai, E., Kaplan, P., Ganesh, J., Krantz, I., Spinner, N., Roccanova, P., Bhandari, A., Pavon, K., Lakshmi, B., Leotta, A., Kendall, J., Lee, Y., Vacic, V., Gary, S., Iakoucheva, L., Crow, T., Christian, S., Lieberman, J., Stroup, T., Lehtimäki, T., Puura, K., Haldeman-Englert, C., Pearl, J., Goodell, M., Willour, V., DeRosse, P., Steele, J., Kassem, L., Wolff, J., Chitkara, N., McMahon, F., Malhotra, A., Potash, J., Schulze, T., Nöthen, M., Cichon, S., Rietschel, M., Leibenluft, E., Kustanovich, V., Lajonchere, C., Sutcliffe, J., Skuse, D., Gill, M., Gallagher, L., Mendell, N., Craddock, N., Owen, M., O’Donovan, M., Shaikh, T., Susser, E., DeLisi, L., Sullivan, P., Deutsch, C., Rapoport, J., Levy, D., King, M., & Sebat, J. (2009). Microduplications of 16p11.2 are associated with schizophrenia Nature Genetics DOI: 10.1038/ng.474
UPDATE: I just revisited my 20th may 2008 post on the matter and realized how prophetic my musings were. Reproducing part of it below the fold for the benefit of newbies to this blog:
CNVs on the other hand present a different model of disease. One can have one or more types of CNVs (deletions, duplications, multiple duplications etc) associated with the same genetic code sequence and this in my view would lead to spectrum like diseases where one may find variations along a continuum on a particular trait- based on how many copies of the genetic sequence one has. One would remember that I adhere to a spectrum based view of schizophrenia/psychosis and also a spectrum based view of Autism. Moreover I believe that Schizophrenia and Autism are the opposite ends of the spectrum, whose middle is normalcy and that the appropriate traits may have to do with social brain, creativity etc.
now as it happen previous research has also found that CNVs are also found to a higher extent in autistics. Moreover, research has indicated that the same chromosomal regions have CNVs in both Autism and Schizophrenia. To me this is exciting news. Probably the chromosomal region (neurexin related is one such region) commonly involved in both schizophrenia and autism is related to cognitive style, creativity and social thinking. Qualitatively (deletions as opposed to duplications) and quantitatively (more duplications) different type of CNVs may lead to differential eruption of either Schizophrenia or Autism as the same underlying neural circuit gets affected due to CNVs, though in a different qualitative and quantitative way.
A brief history of autism

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A mouse trap reader, using skribit, asked me to write a blog post about the history of madness; that is a dauting task, as she herself mentioned that Foucault wrote an entire book on the subject; so though I promise to write that post, in the meantime here is a post about the history of Autism. After this , the next in series would be a brief history of Schizophrenia.

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References to schizophrenia can be found since time immemorial, though the actual term and diagnosis is recent. It is believed that the people haunted by Furies of ancient Greek were actually schizophrenics suffering from delusions and hallucinations. As I contrast Autism and Schizophrenia it is apt that I start here; for similar to the rich historic al tradition, Autism can be equated with the ,blessed Fools’ of old Russia, “who were revered for their unworldiness. The apparent insensitivity to pain, bizarre behaviour, innocence, and lack of social awareness that these “Blessed Fools” showed, suggest that they may have had autism. ” (Happe). Similarly in almost all cultures one can find anecdotes and folktales about foolish boys (note that it is a boy and not a girl as autism has always been more prevalent in boys) who take what their mother said too literally- word for word , rather than figuratively and metaphorically or idiomatically.
The modern diagnosis of autism starts with Leo Kanner. Kanner published his first paper about autistic children in 1943, the full text of which can be found here. Some excerpts from the paper, which has many case studies , should help:
Since 1938, there have come to our attention a number of children whose condition differs so markedly and uniquely from anything reported so far, that each case merits – and, I hope, will eventually receive – a detailed consideration of its fascinating peculiarities.
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The outstanding, “pathognomonic,” fundamental disorder is the children’s inability to relate themselves in the ordinary way to people and situations from the begining of life. Their parents referred to them as having always been “self-sufficient”; “like in a shell”; “happiest when left alone”;“acting as if people weren’t there”; “perfectly oblivious to everything about him”; “giving the impression of silent wisdom”; “failing to develop the usual amount of social awareness”;“acting almost as hypnotized.”T his is not, as in schizophrenic children or adults, a departure from an initially present relationship; it is not a “withdrawal”from formerly existing participation. There is from the start an extreme autistic aloneness that, whenever possible, disregards, ignores, shuts out anything that comes to the child from the outside. Direct physical contact or such motion or noise as threatens to disrupt the aloneness is either treated “as if it weren’t there”or, if this is no longer sufficient, resented painfully as distressing interference.
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Eight of the eleven children acquired the ability to speak either at the usual age or after some delay. Three (Richard, Herbert, Virginia) have so far remained “mute.”In none of the eight “speaking” children has language over a period of years served to convey meaning to others. They were, with the exception of John F., capable of clear articulation and phonation. Naming of objects presented no difficulty; even long and unusual words were learned and retained with remarkable facility. Almost all the parents reported, usually with much pride, that the children had learned at an early age to repeat an inordinate number of nursery rhymes, prayers, lists of animals, the roster of presidents, the alphabet forward and backward, even foreign-language (French) lullabies. Aside from the recital of sentences contained in the ready-made poems or other remembered pieces, it took a long time before they began to put words together. Other than that, “language”consisted mainly of “naming,”of nouns identifying objects, adjectives indicating colors, and numbers indicating nothing specific.
Their excellent rote memory, coupled with the inability to use language in any other way, often led the parents to stuff them more and more verses, zoologic and botanic names, titles and composers of Victrola record pieces, and the like. Thus, from the start, language-which the children did not use for the purpose of communication-was deflected in a considerable measure to a self-sufficient, semantically and conversationally valueless or grossly distorted memory exercise.
…When sentences are finally formed, they are for a long time mostly parrot-like repetitions of heard word combinations. They are sometimes echoed immediately, but they are just as often “stored”by the child and uttered at a later date. One may, if one wishes, speak of delayed echolalia. Affirmation is indicated by literal repetition of a question. “Yes”is a concept that it takes the children many years to acquire. They are incapable of using it as a general symbol of assent. Donald learned to say “Yes”when his father told him that he would put him on his shoulders if he said “Yes.”This word then came to “mean”only the desire to be put on his father’s shoulders. It took many months before he could detach the word “Yes”from this specific situation, and it took much longer before he was able to use it as a general term of affirmation.
The same type of literalness exists also with regard to prepositions. Alfred, when asked, “What is this picture about?”replied:”People are moving about.”
John F. corrected his father’s statement about pictures on the wall; the pictures were “near the wall.” Donald T., requested to put something down, promptly put it on the floor. Apparently the meaning of a word becomes inflexible and cannot be used with any but the originally acquired connotation.
But the child’s noises and motions and all of his performances are as monotonously repetitious as are his verbal utterances. There is a marked limitation int he variety of his spontaneous activies. The child’s behavior is governed by an anxiously obsessive desire for the maintenance of sameness that nobody but the child himself may disrupt on rare occasions. Changes of routine, of furniture arrangement, of a pattern, of the [form] in which every-day acts are carried out, can drive him to despair. When John’s parents got ready to move to a new home, the child was frantic when he saw the moving men roll up the rug in his room. He was acutely upset until the moment when, in the new home, he saw his furniture arranged in the manner as before. He looked pleased, all anxiety was suddenly gone, and he went around affectionately patting each piece. Once blocks, beads, sticks have been put together in a certain way, they are always regrouped in exactly the same way, even though there was no definite design. The children’s memory ws phenomenal in this respect. after the lapse of several days, a multitude of blocks could be rearranged in precisely the same unoganized pattern, with the same color of each block turned up, with each picture or letter on the upper surface of each block facing in the same direction as before. The absence of a block or the presence of a supernumerary block was noticed immediately, and there was an imperative demand for the restoration of the missing piece. If someone removed a block, the child struggled to get it back, going into a panic tantrum until he regained it, and then promptly and with sudden calm after the storm returned to the design and replaced the block.
The children’s relation to people is altogether different. Every one of the children, upon entering the office, immediately went after blocks, toys, or other objects, without paying the least attention to the persons present. It would be wrong to say that they were not aware of the presence of persons. But the people, so long as they left the child alone, figured in about the same manner as did the desk, the bookshelf, or the filing cabinet. When the child was addressed, he was not bothered. He had the choice between not responding at all or, if a question was repeated too insistently, “getting it over with”and continuing with whatever he had been doing. Comings and goings, even of the mother, did not seem to register. Conversation going on in the room elicited no interest. If the adults did not try to enter the child’s domain, he would at times, while moving between them, gently touch a hand or a knee as on other occasions he patted the couch. But he never looked into anyone’s face. If an adult forcibly intruded himself by taking a block away or stepping on an object that child needed, the child struggled and became angry with the hand or the foot, and became angry with the hand or the foot, which was dealt with perse [?] and not as a part of a person. He never addressed a word or a look to the owner of the hand or foot. When the object was retrieved, the child’s mood changed abruptly to one of placitidy. When pricked, he showed fear of the pin but not of the person who pricked him.
Note already that all the currently accepted DSM-IV characteristics of Autism like communicative difficulties, social difficulties and stereotyped or repetitive behavior are already well delineated by Kanner. Here one has to pause and note that autism and autistics were used from the social aloofness first observed and documented in schizophrenics by Kreplin and we seem to have come a full circle now by positing that Autism and schizophrenia are opposites on a continuum. It is also heartening to note that Kanner was also way ahead of his times by focusing on the deficit in ‘mentalizing’ in autistic kids.
Just a year after, Hans Asperger , published his paper on ASD kids, and it is remarkable that despite not knowing about each others papers they came with similar terminology (autistic ) to describe the children and agreed on more points than they disagreed on.
Asperger published the first definition of Asperger Syndrome, in 1944. In four boys, he identified a pattern of behavior and abilities that he called “autistic psychopathy”, meaning autism (self) and psychopathy (personality disease). The pattern included “a lack of empathy, little ability to form friendships, one-sided conversation, intense absorption in a special interest, and clumsy movements.” Asperger called children with AS “little professors” because of their ability to talk about their favorite subject in great detail. It is commonly said that the paper was based on only four boys.
Asperger and Kanner agreed as well as disagreed on many things:
Hans Asperger deserves credit for some very striking insights into autism: some insights which Kanner (1943) lacked and which it has taken us many years of research to rediscover. Before considering these particular observations of Asperger’s, it is worth noting the many features on which the two physicians agreed.
Kanner’s and Asperger’s descriptions are surprisingly similar in many ways, especially when one remembers that each was unaware of the other’s ground-breaking paper. Their choice of the term “autistic” to label their patients is itself a striking coincidence. This choice reflects their common belief that the child’s social problems were the most important and characteristic feature of the disorder. The term “autistic” comes from Bleuler (1908), who used the word (from the Greek “autos” meaning “self”) to describe the social withdrawal seen in adults with schizophrenia. Both Kanner and Asperger believed the social handicap in autism to be innate (in Kanner’s words) or constitutional (as Asperger put it), and to persist through life into adulthood. In addition, Kanner and Asperger both noted the children’s poor eye contact, their stereotypies of word and movement, and their marked resistance to change. The two authors report the common finding of isolated special interests, often in bizarre and idiosyncratic objects or topics. Both seem to have been struck by the attractive appearance of the children they saw. Kanner and Asperger make a point of distinguishing the disorder they describe from schizophrenia, on the basis of three features: the improvement rather than deterioration in their patients, the absence of hallucinations, and the fact that these children appeared to be abnormal from their earliest years, rather than showing a decline in ability after initially good functioning. Lastly, both Kanner and Asperger believed that they had observed similar traits—of social withdrawal or incompetence, obsessive delight in routine, and the pursuit of special interests to the exclusion of all else—in the parents of many of their patients.
There are three main areas in which Asperger’s and Kanner’s reports disagree, if we believe that they were describing the same sort of child. The first and most striking of these is the child’s language abilities. Kanner reported that three of his 11 patients never spoke at all, and that the other children did not use what language they had to communicate: “As far as the communicative functions of speech are concerned, there is no fundamental difference between the eight speaking and the three mute children” (Kanner 1943). While phonology (as demonstrated in accurate echolalia) and vocabulary were often excellent, Kanner concluded that of his 11 cases “In none …has language…served to convey meaning”. The picture in all is of a child with profound communicative difficulties and delay; in seven of the 11 cases so profound that deafness was initially suspected (but ruled out). Asperger, by contrast, reported that each of his four case study patients (and, by implication, most of the unspecified number of such children he treated) spoke fluently. Although two of his patients showed some delay, this was followed in both cases by a rapid mastery of language, and it is difficult to imagine any of his cases having been mistaken for deaf. All four cases, by the age of examination (between 6 and 9 years old), spoke “like little adults”. Asperger notes their “freedom” and “originality” in language use, and reports that two of his four cases had a tendency to tell “fantastic stories”.
Asperger’s description also conflicts with Kanner’s on the subject of motor abilities and co-ordination. Kanner (1943) reported clumsiness in only one case, and remarks on the dexterity of four of his patients. He concluded that “several of the children were somewhat clumsy in gait and gross motor performance, but all were very skilful in terms of finer muscle coordination”—in line with their success on the Seguin form board (in which dexterity plays a part) and their ability to spin objects. Asperger, by contrast, described all four of his patients as clumsy, and recounted their problems not only with school sports (gross co-ordination), but also with fine motor skills such as writing. This feature is part of a larger contrast in Asperger’s and Kanner’s beliefs. Kanner believed the autistic child to have a specific impairment in social understanding, with better relations to objects than to people: while his children showed “excellent, purposeful and ‘intelligent’ relations to objects” their “relations to people [were] altogether different”. Asperger, on the other hand, believed that his patients showed disturbances in both areas: “the essential abnormality in autism is a disturbance of the lively relationship with the whole environment” (Asperger 1944, translated in Frith 1991b).
The last area of disagreement in the clinical pictures painted by Asperger and Kanner is that of the child’s learning abilities. Kanner believed that his patients were best at learning rote fashion, but Asperger felt that his patients performed “best when the child can produce spontaneously”, and suggests that they are “abstract thinkers”. (Happe)
We now know that many of the insights of Asperger were correct especially for those suffering from high-functioning autism or Asperger’s syndrome.
A dark period of autism research was the ‘refrigerator mother‘ hypothesis , which posited based on a psychogenic theory that autism was due to bad parenting. The seeds of this theory can be traced back to Kanner, but Bruno Bettelheim gave it a prominence. this theory as now been widely debunked and discredited and caused undue suffering and guilt to a generation of parents.
Leading researchers in the field after these have been Uta Frith, Leslie, Happe and Simon-Baron-Cohen with his ‘mind-blindness’ theory.
Before concluding please visit the DSM criteria and reassess them as now autism, at least by me and many leading researchers, is conceptualized more as a continuum disorder. Hope the DSM-V has a continuum framework for autism.
Kanner L (1968). Autistic disturbances of affective contact. Acta paedopsychiatrica, 35 (4), 100-36 PMID: 4880460
The downside of cognitive enhancement
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Jonah Lehrer, has an article in this week’s Nature News, (find a PDF here) , regarding 30 or so cognitively enhanced mice strains that have been bred and genetically engineered. As Lehrer very elaborately documents, all these have enhanced LTP as an intervening mechanism that leads to improvements in learning and memory. Most of the genes involved affcet the LTP mechanism in one way or the other to breed super mnemonist mice. However, from the time of Luria, t has been well known that those who have enhanced memory also suffer from some of its disadvantages and that the ability to forget is also very important.
Little is known about the side effects and tradeoffs of both the current usage or the drugs in development, but initial clues offered by smart mice raise concerns. The Hras strain developed in Silva’s lab might be good at learning, but its fear response for a relatively benign stimulus would be counterproductive for a wild mouse. Its enhanced memory is both a blessing and a burden. Silva cites other strains of smart mice that excel at solving complex exercises, such as the Morris water maze, but that struggle with simpler mazes. “It’s as if they remember too much,” he says — possibly taking in irrelevant information such as the position of windows or lights but missing the big clues.
Farah sees a parallel between these mice and one of the few case studies of an individual with profoundly enhanced memory. In the early 1920s, the Russian neurologist Alexander Luria began studying the learning skills of a newspaper reporter called Solomon Shereshevsky, who had been referred to the doctor by his editor. Shereshevsky had such a perfect memory that he often struggled to forget irrelevant details. After a single read of Dante’s Divine Comedy, he was able to recite the complete poem by heart. Although this flawless memory occasionally helped Shereshevsky at work — he never needed to take notes — Luria also documented the profound disadvantages of such a capacious memory. Shereshevsky, for instance, was almost entirely unable to grasp metaphors, as his mind was so fixated on particulars. When he tried to read poetry, for example, “the obstacles to his understanding were overwhelming”, Luria wrote in his book The Mind of a Mnemonist. “Each expression gave rise to a remembered image; this, in turn, would conflict with another image that had been evoked.”
For Luria, Shereshevsky’s struggles were a powerful reminder that the ability to forget is as important as the ability to remember. Enhancing human memory in individuals without severe cognitive defects might prove counterproductive.
It is interesting to pause here and note that many savants who have excellent memory are also autistic and that schizophrenics on the opposite end of the spectrum are characterized by too much reliance of metaphors and too much generalizations and abstractions. Further Martha Farah notes the following:
Many scientists are concerned that the animal models of enhanced cognition might obscure subtle side effects, which can’t be studied in rodents or primates. Farah is currently looking at the trade-off between enhanced attention — she gives human subjects a mild amphetamine — and performance on creative tasks. Other researchers have used computer models to show that memory is actually optimized by slight imperfections, as they allow one to see connections between different but related events9. “The brain seems to have made a compromise in that having a more accurate memory interferes with the ability to generalize,” Farah says. “You need a little noise in order to be able to think abstractly, to get beyond the concrete and literal.”
Again, one can easily see the correlations with Autism and Schizophrenia- one end marked by too narrow a focus , while the other marked by too much noise and divergent creativity. I would have been happy to incorporate the more LTP as autistic and less LTP as schizophrenics, but it flies in face of my earlier findings regarding experience dependent plasticity in autism and schizophrenia where the conclusions were just the revers. Yet, it is clear that synaptic plasticity is a majo mechanism involved in the autism/psychosis differentiation. Do let me know if you can reconcile the new findings with the older ones to come up with the right LTP and psychosis/autism relationship.
More From TheMouseTrap
- The ABCD of Psychology and Happiness
- Mind perception of others: opposing effects of having Autism/Psychosis
- Autism and white Matter/Myelination: the opposite of creativty/psychosis phenotype?

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