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"...well-structured and an easy read - essential for professionals, academics and students who are interested in autism and its treatment..." (The Psychologist, Vol 17(1), Jan 2004)
This book draws together contributions from some of the leading investigators in the field of autism to consider specific problem areas in current research. Each contributor brings expertise from a different field, providing a balanced view of the whole spectrum of study of this disorder. It covers four main areas:
* Twin and family studies indicate that the heritability of the underlying liability to autism exceeds 90% and point to a multifactorial causation, involving a relatively small number of susceptibility genes. The book discusses this issue in detail, along with the problem of why some additional symptoms are associated with autism while others are not.
* New techniques are available for examining the neurobiology of autism. The book contains results from imaging studies showing the contributions of different brain regions to autism. It includes neuropathological data and examines the neuropharmacology of autism.
* There is considerable discussion concerning the fundamental psychological deficit in children with autism. There is good evidence that "Theory of Mind" deficits are associated with autism and this issue is discussed in the book, as are other competing possibilities.
* The most important practical question facing medical and psychological practitioners is how to help children with autism. The evidence relating to possible psychological or psychiatric interventions for rehabilitation of children with autism is examined in detail. Drug treatments have generally been disappointing in this field and there is one chapter devoted specifically to this problem.
The book focusses ultimately on intervention studies and so is of practical relevance to people interested in helping autistic children. In addition, it provides a very convenient summary of the principal controversies which currently exist in research on autism.
"...well-structured and an easy read - essential for professionals, academics and students who are interested in autism and its treatment..." (The Psychologist, Vol 17(1), Jan 2004)
Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK
There have been many important advances in research into the nature of autism and, as a result, our concepts of autism have undergone a radical change (Rutter 1999). At one time, the prevailing view was that autism was an unusually early variety of schizophrenia that had been caused, in large part, by so-called refrigerator parenting. It became clear that that was a wholly mistaken concept and that, instead, autism constitutes a neurodevelopmental disorder with a rather distinctive pattern of cognitive deficits, and that it is strongly genetically influenced.
Nevertheless, we are a long way from understanding the basic pathophysiology, and numerous puzzles and paradoxes remain. The aim of this symposium is to grapple with these issues, tackling the challenges from a range of different perspectives in the hope that a coming together of minds, and of different research strategies, may point the way ahead. My task is to set the scene by outlining some of these challenges in order to provoke us all to abandon the safety of our own research territory, and of the findings that are well established, in order to focus on the difficulties that are inherent in ourfavoured theories.
We need to begin with implications of the huge rise in diagnosed autism (Baird et al 2000, Chakrabarti & Fombonne 2001, Fombonne 1999). To a substantial extent, this rise is a consequence of a major broadening of the concept of autism together with better ascertainment. However, is that all? When like is compared with like, has there been a real rise in the rate of autism? If that should prove to be the case, what is the environmental factor that has brought this about (the rise is unlikely to have been genetically determined)? There have been claims that the rise is due to the use of the combined measles/mumps/rubella (MMR) vaccine but that does not seem very likely. The rise began before the introduction of MMR and it continued to rise, without any plateauing, after MMR was used with the vast majority of the population (Dales et al 2001, Farrington et al 2001, Taylor et al 1999). But, if that is not the cause, what is?
The prevailing consensus at the moment is that autism spectrum disorders constitute a continuum extending from mild autism to severe handicap. That could prove to be the case but, if so, why is it that individuals with the so-called broader phenotype do not have associated mental retardation and do not seem to have an increase in the rate of epilepsy, both being very characteristic correlates of autism (Rutter 2000)? The question has to be addressed if only because the limited genetic evidence from twin studies indicates that the broader phenotype seems to share the same genetic liability (Le Couteur et al 1996). Could there be some kind of two-hit mechanism? If so, what is it that provides impetus for the shift from the broader phenotype to major handicap?
Asperger syndrome appears to involve exactly the same qualitative deficits as those associated with autism, but, unlike autism, this has not been associated with any delay in early language development and abnormalities are usually not clearly manifest until after infancy. Of course, that is not to suggest that language development is necessarily fully normal (indeed there are good reasons to suppose that it is not) but the existence of the syndrome provides a challenge to those who have viewed the language deficits as basic. It also provides a challenge to those who have argued that autism is almost always manifest from at least the age of 18 months, if not considerably earlier (Osterling et al 2002). Of course, it may be that a careful analysis of the social and communicative behaviour of individuals with Asperger syndrome would show early abnormalities, but what is clear is that the abnormalities are usually not recognized by either parents or professionals until quite a lot later (Gilchrist et al 2001). If Asperger syndrome is synonymous with mild autism, what does this mean?
In most cases, autism involves no developmental regression or loss of skills. However, numerous studies have shown that in about a quarter of cases, there is a temporary loss of language skills usually in the second half of the second year (Kurita 1985, Rogers & DiLalla 1990). This is often accompanied by a change in social interaction and a loss of pretend play, but it is not usually accompanied by a loss of motor, or other, skills. So far, evidence suggests that there is nothing distinctive about autism that is accompanied by regression. Interestingly, regression seems to be as common in autism when it occurs in two or more members of the same family (Parr et al 2003), with the implication that regression is neither more nor less common when it is likely that there is a strong genetic liability. What, therefore, does the regression mean?
Over the years, evidence has accumulated that the clinical picture of autism in early childhood is seen in several atypical circumstances. Thus, for example, it was described in children with congenital rubella, the follow-up indicating that, although the children tended to remain severely handicapped, the autistic features lessened (Chess 1977). Autistic-like syndromes have also been described in congenitally blind children (Hobson et al 1999), and in children who have suffered severe institutional deprivation (Rutter et al 1999). Careful analysis suggested that the picture is in some respects slightly atypical and, at least in the case of the institution-reared children, the autistic features tend to diminish as the children grow older. What do these findings tell us about the nature of autism or the cause of the syndrome? Some may be tempted just to dismiss the descriptions as representing phenocopies but there is still the need to account for the emergence of the picture strongly resembling autism.
There is then the further question of the overlap with semantic-pragmatic language disorders (Bishop 2000). It is clear that the two cannot be regarded as entirely synonymous because by no means all children with semantic-pragmatic language disorder show the features of autism (Bishop & Norbury 2002). The follow-up of the sample of boys with severe developmental disorder of receptive language, first seen in early childhood has brought out two further findings that need taking into account. First, although the children with language disorder did not appear at all autistic when young, at least half of them showed substantial social impairment early and mid-adult life (Howlin et al 2000). Second, the adults who had shown this severe developmental disorder of receptive language, were found to have impairments in 'theory of mind' skills at follow-up (Clegg 2002). It is not known, of course, whether the impaired 'theory of mind' skills had been present in early childhood but it seems likely that they must have been. If so, why were they not showing autistic features when young?
One further epidemiological finding requires highlighting. Autism is very much more common in males than females. The ratio is usually given as about 3 or 4:1, but evidence from recent epidemiological studies suggest that the male preponderance is very much greater in the case of autism that is not accompanied by severe mental retardation (Baird et al 2000). As we shall hear, hypotheses have been put forward to account for this sex ratio in autism. However, it is not self evident that the explanation will be found in a feature that is specific to autism. It is noteworthy that a similar marked male preponderance is found in most neurodevelopmental disorders such as dyslexia, attention deficit disorder with hyperactivity, and developmental language disorders (Rutter et al 2003). Is this just coincidence or is there some common factor that is responsible for the male preponderance across this range of disorders? They are all associated with cognitive deficits of one kind or another that are evident in the preschool period. This is quite different from what is seen with female preponderant psychopathological disorders such as depression or eating disorders, which typically have an onset in adolescence and are not accompanied by any marked cognitive deficits. Does this provide a clue as to a causal explanation? Do we need to consider epigenetic mechanisms and, if so, what might they be? Is it likely that prenatal differences in sex hormone pattern have been influential?
Another well established clinical finding concerns the tendency for autism to be associated with increased head size (Lord & Bailey 2002). Probably, this arises after birth and possibly, too, is associated with an increased head size in other members of the family. If the emergence of increased head size after birth is confirmed, what does this imply with respect to the neural processes that are responsible?
As the pioneering studies of Hermelin and O'Connor (1970) demonstrated, it has long been evident that autism is associated with an unusual pattern of cognitive deficits. During the 1980s and 1990s, attention particularly focused on what came to be called 'theory of mind' deficits - meaning an impairment in mentalizing skills that enabled children to use context to assess what another person was likely to be thinking. However, impairments in executive planning, the use of central coherence, and in facial processing have also been found (Hobson 1993, Lord & Bailey 2002, Medical Research Council 2001). It may certainly be accepted that deficits in social cognition constitute an intrinsic part of autism. Nevertheless, questions remain. What are the interconnections, if any, among these various deficits? If theory of mind skills are so crucial, why is autism manifest such a long time before theory of mind skills can be clearly demonstrated? Of course, the answer could lie in cognitive precursors of theory of mind but, if so, what is the explanatory power of theory of mind as such? Even infants are highly social, and so should the explanation be sought in some aspect of social relationships, rather than cognition, as Hobson has suggested? How might these highly specific cognitive deficits account for the language delay and mental retardation that are so commonly associated with autism (Rutter & Bailey 1993)? What accounts for the savant skills or special cognitive talents that occur in a substantial minority of individuals with autism (Hermelin 2001)? Conversely, if these are closely associated with the specific cognitive deficits, why are such talents not found in most individuals with autism? How might the cognitive deficits account for the repetitive stereotyped behaviours that are so characteristic of autism? I have spent quite some time outlining the epidemiological and clinical background because these are the findings that require explanation.
Let me turn now to the genetic findings. The findings suggest that genetic factors account for over 90% of the population variance in the underlying liability (Folstein & Rosen-Sheidley 2001, Rutter 2000). In view of the new evidence indicating that the prevalence of autism is considerably higher than used to be believed, there must be some caution about the precise heritability, because it will be affected to some extent by the assumptions made about the general population base rate. Nevertheless, even if the true rate of autism is as high as 0.6%, the rate in siblings would still be at least 10 times that. The marked fall of rate between monozygotic and dizygotic pairs, together with the fall off in the broader phenotype from first degree to second degree relatives, suggests that it is likely that some three to 12 genes are involved in the susceptibility to autism, and that there is a synergistic interaction among the susceptibility genes (Pickles et al 1995). But, what are the effects of each of these genes? Do they provide a vulnerability to autism as such or, rather, do they involve susceptibilities for individual components of autism (Bradford et al 2001, Folstein et al 1999)? If they do operate on different components, why is not the rate of each component very much higher than the rate of the syndrome as a whole?
Of course, there are no epidemiological studies that provide precise estimates of each component but such evidence as there is provides no indication that the rates are high. Also, one might expect that individual members of families with a proband showing autism might have only single elements, because they are likely to have only a few of the susceptibility genes. Findings suggest that, although that is sometimes the case, familial loading is mainly for a combined pattern that is similar to autism in quality, although much milder in degree. The history of medical genetics indicates that it must be expected that autism will prove to be genetically heterogeneous. To some extent, we know that it is heterogeneous because of the associations with tuberous sclerosis and with the fragile X anomaly (Lord & Bailey 2002, Medical Research Council 2001). Nevertheless, it is not yet quite clear why either of these conditions predisposes to autism.
If autism is genetically heterogeneous, we have to ask whether the heterogeneity is indexed by clinical variability. Of course, it need not be. The findings on concordant monozygotic pairs show that there is huge clinical variability in the manifestations of autism and of the associated cognitive impairment, even when one may assume that the genetic liability is the same (Le Couteur et al 1996). It is also known that even single gene conditions such as Rett syndrome or tuberous sclerosis show surprisingly wide clinical expression (Sharbazian & Zogbi 2001). What is not known, however, is what causes such variable expression. When variable expression is not properly understood even with single gene disorders, elucidation is likely to prove even more challenging with a multifactorial disorder such as autism.
In sorting out genetic heterogeneity, there must be consideration of the possibility of either multiple mutations of the same gene, as found in Rett syndrome or multiple different genes, as is the case with tuberous sclerosis. As already noted, although the heritability of autism is very high, it does appear to be a multifactorial disorder in which environmental factors also play a role in the overall susceptibility. What are those environmental susceptibility factors? Of course, these may not necessarily involve specific environmental hazards. Thus, they could reflect developmental perturbations of one kind or another (Rutter 2002). The increase in the rate of minor congenital anomalies is perhaps consistent with this suggestion. Recently, it has been argued that the rate of twinning in autism is much increased (Greenberg et al 2001) but it seems likely that this is an artefact of ascertainment.
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Introduction: autism - the challenges ahead (M. Rutter).
Epidemiology and early identification of autism: research challenges and opportunities (T. Charman).
Implications of the broader phenotype for concepts of autism (A. Bailey and J. Parr).
Strategies for autism candidate gene analysis (G. Barnby and A. Monaco).
How might genetic mechanism operate in autism? (S. Folstein, et al).
X-linked genes and the neural basis of social cognition (D. Skuse).
The neuropathology of the autism spectrum disorders: what have we learned? (M. Bauman and T. Kemper).
Microbiology and immunology of autism spectrum disorders (W. Lipkin and M. Hornig).
What do imaging studies tell us about the neural basis of autism? (C. Frith).
The Amygdala, autism and anxiety (D. Amaral and B. Corbett).
Cognition in autism: one deficit or many? (F. Happé).
Autism and specific language impairment: categorical distinction or continuum? (D. Bishop).
Why have drug treatments been so disappointing? (J. Buitelaar).
Can early interventions alter the course of autism? (P. Howlin).
Early intervention and brain plasticity in autism (G. Dawson and K. Zanolli).
Summing up (M. Rutter).
Index of contributors.