REVIEWIntersubjectivity, Affective Neuroscience, and the Neurobiologyof Autistic Spectrum Disorders: A systematic review
Kenneth J.Aitken

K.Aitken Consultancy; Greater Glasgow Primary Healthcare Trust, United Kingdom(Received for publication on November 14, 2006)(Revised for publication on December 7, 2007)(Accepted for publication on December 7, 2007)

Abstract: Intersubjectivity is an approach to the study of social interaction viewed froma perspective which rejects the view that reducing any such analysis to study at the levelof the individual is adequate to address the issues of social functioning. It also stresses
the view that social processes cannot be reduced to cognitive ones - most of the importantquestions in the study of developmental psychopathology deal with issues which have commonality with many other species and are patent well before the ontological emergence of‘cognitive’ abilities. In this paper we review the evidence in this area, and discuss a range ofissues relevant to autistic spectrum disorders. We focus in particular on social interaction;
the role of the Intrinsic Motive Formation and recent work on mirror neurons in autism; genetic and teratogenic factors in the genesis of autism; and the role of a number of biologicalfactors in pathogenesis - tryptophan; vitamin B12; sterol metabolism; glutamate and GABA;
and the Fragile-X expansion. (Keio J Med 57 (1) : 15－36, March 2008)
Key words: intersubjectivity, mirror neuron, autistic spectrum disorder, intrinsic motive formation,
sodium valproate, misoprostal, thalidomide, tryptophan, vitamin B12, sterol, glutamate,
gamma amino butyric acid, Fragile-X

1. Introduction
Biomedical research increases exponentially and wholeareas are often closed fields to many clinicians only a
few years after finishing their training. Genomics1 andproteomics2, 3 to take two examples, have changed out of
all recognition over the past decade, while disciplines
like genetic epidemiology4 are only now taking recognizable form.
Many problems face those who try to assimilate research findings into clinical practice - topics seem to become ever more discrete with relevance to clinical practic often seeming remote.
This paper draws together ideas from various researchareas and clinical specialities typically regarded as independent and unrelated. One aim is to demonstrate thatthese topics are fundamentally interrelated and that aninterdisciplinary programme of work is required to address and adequately answer many of the questions
raised through this recognition of the complexity of theautistic spectrum disorders.
Autism is diagnosed on the presence of overlappingdifficulties in communication, social functioning and rigidity of routines (often referred to as the autistic triad of
impairments), together with abnormalities of early development. No features are necessary and many combinations are independently sufficient, thus the basis for aclinical diagnosis in two individuals may be very different. It is unsurprising, therefore, that there are a wide
range of independently sufficient factors which may resultin diagnosis.5, 6 Specific endo- and behavioural phenotypes have begun to emerge, with many diagnostic subgroups such as Asperger syndrome, Rett syndrome, andChildhood Disintegrative Disorder. It is highly unlikelythat autistic behaviour will prove to have a common
pathogenesis, and equally surprising if any treatment /intervention is successful with the whole autistic population. This paper provides evidence that autism consists ofa number of different biological entities. A clearer under-This paper is based on an invited lecture given to the Keio Medical Society, the Pediatric Department of Keio Hospital and the FOUR WINDS Association for
Infant Mental Health, on 25th June 2006 (1472nd Meeting).
Corresponding Author: Kenneth J. Aitken, Ph.D. 57 Leamington Terrace, Edinburgh, EH10 4JS, Scotland. E-mail: drken.aitken@btinternet.com
15

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standing of these conditions is critical to successful intervention and management.
Autism is a condition which seems to arouse complex
and often contradictory responses both from those involved in its diagnosis and management7 and not leastfrom parents and affected individuals themselves.8,9 The
intention here is to provide access to key research and toallow those reading this material to pursue these ideas
further should they wish to, and to draw their own conclusions.
The pharmaceutical industry has highlighted autism asa priority target for drug development. 1 0 The risingprevalence figures have led to autism rivaling Alzheimers disease in terms of “illness years”.11
No single model is adequate to explain the causes ofautism. The different components of the ‘autistic triad’seem to be largely independent.1 2 Happe, Ronald andPlomin using this notion have shown that within the general twin population (using the Childhood Asperger
Screening Test with those in the Twins Early Development Study) these three aspects of functioning do not sigificantly co-vary13 but appear to operate as independent
genetic factors.
There are, however, sufficient commonalities to justify
the continuing use of the term autism at our current levelof understanding. Certain conditions (such as fragile X
syndrome, where much of the neurobiology is now wellunderstood) may help to inform our understanding ofother types of autistic disorder.
This paper covers general ideas on developmental processes, particularly the relevance of a move from individual to dyadic systems levels of analysis of infant behaviour and development; it provides some general information on autism, developing a model of autism basedon the dyadic level of analysis, and how this is amenable
to analysis; it discusses the commonalities across thosewith autism from the perspective of developmental psychopathology; and presents differences between several
patterns of autistic presentation. The scope of this review,has been limited, omitting areas such as basic clinicalneurochemistry where recent systematic reviews arereadily accessible.14
One final caveat concerns the generality of conclusions
drawn here concerns ethnic differences in genetic makeup and their possible implications for our understandingof autism. We are aware of ethnic differences in genetic
factors which affect a wide range of aspects of humanbehaviour from athletic prowess,1 5 to differences in theprevalence of the DRD4-7 allele repeats correlating withprevalence of Attention-Deficit Hyperactivity Disorder.16
Similar ethnic differences may account for inconsistencies in the clinical literature on autistic spectrum disorders as with the recent findings of differences between
US and Italian families in the association between PON1
abnormalities and autism2 4 and the failure to find evi-

Aitken KJ: Intersubjectivity, Affective Neuroscience and ASD

dence of an association between the 5-HTT serotonintransporter gene polymorphism and autism in Japanesecases17 despite such findings in other populations.18
2. Social Development and the Neurobiology of the
Self and Other
We traditionally draw a boundary for analysis at thelevel of the individual. In Western thought, this comesfrom the tradition started by Rene Descartes, of beginning from one’s own personal thoughts and captured byhis phrase ‘Cogito ergo sum’ (I think therefore I am).
This artificial boundary is ultimately unhelpful in looking at the social as it divorces individual function fromits necessary ontogenetic context.
The English Psychoanalyst Donald Winnicott statedthat when we try to look at the infant we are inevitably
looking at the infant and a caregiver. It is impossible tolook at the infant alone.19 This viewpoint is equally valid when we look at the factors in what has come to becalled “affective”20 or “social” neuroscience.21 Development in emotional interactions are contingent for eachindividual on their partner’s emotional communicationand cannot be looked at in isolation.22
Parallelling developing interest in the biosocial, thepast 25 years have also seen a steady increase in the development of interest in the biological underpinnings to
the developmental psychopathologies.23, 24
We cannot restrict our study to the biologically bounded individual infant, we have to look at the infant in his/her social context. At the very minimum, this involves
the infant and his/her primary caregiver. The process isalso a reflexive one - looking at the behaviour of a caregiver outside the context of the dyad is equally limited.
Each member requires the other (see Figure 1).
The idea of a pre-formed infant nurtured in the mother’s womb has been present in Western thinking since
antiquity. The notion was typically that the infant was ahomunculus present in either the egg or in the spermatozoa. For the latter view, the womb simply provided anenvironment in which the foetus could grow. Early studies by Hartsoeker2 5 and others seemed, at the time, toconvincingly support the view that the infant grew fromthe sperm.
The complex skills of the newborn are attuned to social
interaction with facility for behaviours such as interactional synchrony; imitation; and seeking eye contact onmaternal speech (for reviews, see Ref.26,27). The infant
is not nearly as well developed in respect of its non-social abilities - for example, visual acuity for social phenomena (as when used in the imitation of tongue protrusion) is far more precise than for non-social stimuli (suchas preferential looking).28
Detailed analysis of the infant behaviours seen in such
early dyadic processes has been carried out at least since
the observations of Dietrich Tiedemann2 9 over two cen-

Keio J Med 2008; 57 (1): 15 － 36

17

Fig. 1 Protoconversation between mother and infant. Synrhythmic regulation of mutual psychological engagement by exchange of
expressions of interest and emotional feelings. (From: 24)

turies ago. Observational methods are easier to systematize, operationally define and validate with electronic
recording, enabling detailed micro-analysis and inter-rater reliability checks. This approach has been pioneeredin the work of researchers like Daniel Stern; Colwyn
Trevarthen; and Heidi Als.
Babies are born with the ability to ensure that they arelikely to be cared for and nurtured by those around them.
This social attunement ensures their survival. The infant
tailors use of such abilities to the responses obtained
from their social environment - the same infant can produce higher levels of tactile and vocal communication toa blind caregiver, while using more animated facial expressions and non-tactile movements with a sighted caregiver.30
It is well known that the maturation of the brain in part
depends on the quality of its early experience.3 1 There
are predictable periods of rapid development and predictable periods of developmental stasis - human social
and neural development are non-linear processes.32
There is now clear evidence that modifying early experience can enhance brain development in premature human infants.33 Various mechanisms have been proposed
for this process.34 A critical aspect is that infants are intimately involved in generating and enriching the mutualsocial experience which drives this process. The effectsof factors such as caregiver mental health limit the environment through which this is canalized.24, 26, 35
Psychosocial factors are crucial in the neurological development of both the normal and the developmentallydifferent infant.35

3. Mirror Neurons and Social Understanding
A recent development in our understanding of the biological mechanisms for social responsiveness comesfrom our understanding of the neurobiology underpinning both self-referential processes and what have beentermed ‘mirror neurons’.36
Studies which have looked at activation during tasks
that require self-reference and tasks that do not indicate
coordination in the activity of areas involved in self-referenced sensory, motor, emotional and proprioceptive
processes during the former but not the latter.37 Similarly, there is now a considerable literature on the brain systems activated during tasks such as imitation and perspective-taking in normal subjects.38
Mirror neurons are activated specifically when we areengaging in or thinking of being involved in activities,or, when we observe others engaging in activities and are
inferring why an action is being carried out.
“...premotor mirror neuron areas―areas active during
the execution and the observation of an action―previously thought to be involved only in action recognition
are actually also involved in understanding the intentionsof others.” (Iacoboni, Molnar-Szakacs, Gallese, Buccino,
Mazziotta & Rizzolatti 2005).39
In fMRI activation tasks in normal controls, recognitionof emotion is associated with increased activation in various structures, but particularly in paracingulate, anterior
and posterior cingulate and amygdala. In contrast the ability to infer and attribute mental states was associated withincreased activation in lateral orbito-frontal cortex, middle
frontal gyrus, cuneus and superior temporal gyrus.40

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Aitken KJ: Intersubjectivity, Affective Neuroscience and ASD

abFig. 2 The above figure, reproduced from Trevarthen, Aitken, Vandekerckhove, Delafield-Butt & Nagy 200624 illustrates, on the left,
a , that the mechanisms involved in the development of attachment, care and emotional contact combine successively physiologicalor amphoteronomic processes, and the special direct psychological communications which we define as synrhythmic. The right handfigure, b, shows graphically the range of processes and the basic neurochemistry involved in the functioning of the Intrinsic Motive
Formation or IMF.

4. The Intrinsic Motive Formation (IMF)
Trevarthen and Aitken have developed the idea of asystem which is the neural basis to social abilities, that isfunctional and accessible from birth and is thus not verbally mediated, and that has a high degree of phylogenetic preservation.26, 41, 42
These papers develop a model which bases affect on a
range of neural structures that are functional prior to thedevelopment of expressive or receptive language in theinfant. These structures, their neurochemistry and theirbroad roles are detailed in table 2 below. They rely on
structures in the limbic system43 and the emotional motor system44 of the vertebrate nervous system. Ergotropic
and trophotropic are terms use here to describe respectively 1) effortful behaviours which enable connection
with / avoidance of social stimulation in the environmentand 2) behaviours which result in physical nurturance /care / procreation.
The discontinuous nature of development is based on
the alternating ascendancy at any point in time of ergotropic and trophotropic processes.35
5. What about autism ?
Kanner’s initial description of autism47 was as “a biologically provided disturbance of affective contact”. For
Kanner, autism was a condition which was a biologicaldisorder of the individual child.
Today it is clear, through studies of perinatally institu-

tionalized Roumanian children, that although extreme
psychological deprivation alone cannot result in autism,4 8 there are autistic-like behaviours in many who
are subjected to extreme early deprivation. A proportionof those in such early care fulfill behavioural criteria for
autism which ameliorate steadily over time in post-adoptive placement.4 9 It is of course possible that some ofthose placed in such care were also at biological risk ofdeveloping an ASD in any event.
The typical age at diagnosis for autistic disorder in the
UK and USA is between 2 and 3 years of age. When
identified at this age, studies do not discriminate within
the ASD spectrum but have reasonable overall prospective validity.50
The current World Health Organization diagnostic classification system (ICD-10) and the American Psychiatric
Association’s system (DSM-IV Tr) have employed similar criteria since 1994, the previous systems having had
major differences.5 1, 5 2 There are still differences between accepted measures used in diagnosis and a clear
agreed protocol for diagnosis using standardized tools issome way off.5 3 In the clinical context, scales such as
the ADI-R and ADOS do not adequately discount otherpossible conditions, and more broadly based tools suchas the DISCO (Diagnostic Interview for Social and Communication Disorders)54 may be more helpful for clinicaluse.

Keio J Med 2008; 57 (1): 15 － 36

19

Table 1 Emotion systems, (after Panksepp, 1998a45; 1998b46) (+ = excitatory; - = inhibitory)
Affective Behavior
SEEKING
Exploratory Behaviour

PLAY, JOY,SOCIAL
AFFECTION

RAGE
Affective Attack
FEAR

Distributed Neural Networks
ERGOTROPIC
Ventral tegmental Area (VTA) todorsolateral hypothalamus toperiaqueductal gray (PAG),
with diffuse mesolimbic andmesocortical “extensions”.
Nucleus accumbens as basal
ganglia processor for emotional“habit” systems.
Parafascicular/centromedian thalamus,
dorso-medial thalamus
dorso-medial thalamus, posterior thalamus,
projecting to more dorsal PAG(the septum is inhibitory for play;
the role of other basal forebrain andhypothalamic systems is not clear)
Medial amygdala to bed nucleus of
stria terminalis (BNST) to anterior andventromedial and perifornical hypothalamic
to more dorsal PAG.
Central & lateral amygdala to anterior and medial
hypothalamic to more dorsal PAG to nucleus reticularis
pontine caudalis.

SEXUALITY

TROPHOTROPICBNST and corticomedial amygdala to preoptic andventromedial hypothalamus to lateral and more
ventral PAG to lateral and more ventral PAG

NURTURANCE,
MATERNAL
CARE

Anterior cingulate to BNST topreoptic hypothalamic to VTA
to more ventral PAG

SEPARATION
DISTRESS,SOCIALBONDING

Anterior cingulate/anterior thalamus to
BNST/ventral septum to
midline & dorsomedial thalamus todorsal preoptic hypothalamic tomore dorsal PAG(close to circuits for physical pain)

Neuromodulators

DA (+);
glutamate (+);
neuropeptides
neuro-tensin;
CCK

Glutamate (+)
Opioids (+) (Modest)/(- Major)
ACh (muscarinic +)ACh (nicotinic -)DA (-)NE (-)
5-HT (-)
Substance P (+)
ACh (+)
glutamate (+)
Glutamate (+)
ACTHneuropeptides(DBI, CRF, CCK, alpha MSH, NPY)
Steroids (+);
vasopressin;
oxytocin;
LH-RH;CCK.
Oxytocin (+)
prolactin (+)
Dopamine (+)
Opioids (+)
Opioids (+/-)
oxytocin (-/+)
prolactin (-/+)
CRF (+) for sep.
distress
ACh (-)The hypothesis of a maturing IMF is that there is continuous CNS maturation but that the processes dictate when this is reflected in overt,
ergotropic behaviours and when in largely covert trophotropic actions.

6. Are there any early warning signs of autism which
can be reliably identified ?
There is a higher rate of pre- and peri-natal risk factors(such as abnormal growth rate both in utero and after
birth; enlarged head at birth; bleeding in pregnancy andlow Apgar scores) in those who go on to receive an autism diagnosis.5 5, 5 6 Some 5% of the variance in headcircumference can be explained on the basis of the
HOXA1 A218G G allele.57
Collaborative Programs of Excellence in Autism(CPEA) studies are beginning to demonstrate associations, with biomedical factors, for example, between re-

gressive onset autism and Familial Autoimmune Thyroid
Disease.58
Ongoing prospective studies such as the MoBa Autism
Birth Cohort (ABC) study5 9 and the CHARGE Study6 0
will help to identify early signs of autism, perhaps linked
to specific biobehavioural phenotypes.
7. Are there differences in Early Motor developmentin those who go on to receive a diagnosis ?
Philip and Oznat Teitelbaum have analysed early videotapes of children who were subsequently diagnosed
with of autism.6 1 Differences in early motor develop-

20

ment - particularly in early motor abilities like rollingover and protective reflexes and in facial expressions
such as the ‘Moebius mouth’ (typically an indication of aproblem with cranial nerves VI and VII) were apparent.
This work compared ASD children to earlier descriptive
accounts of normal development.62 This is not an ideal
basis for clinical comparison as the children were notdrawn from comparable populations.
In a study of home movie recordings of subsequently
diagnosed autistic children, Adrien and colleagues63 described a number of behavioural abnormalities in thefirst two years of life - abnormalities of eye contact, limited and variable emotional expression, attention deficits
and limited initiation of communication, together withabnormalities of motor development.
Osterling and Dawson (1994)64 on an analysis of firstbirthday party videotapes were able to discriminate subsequently diagnosed autistic children on various criteria
including showing objects to others, orienting to theirown name, looking at others faces and pointing. Thissuggested that there were potential social risk features
which were evident well before the 18 month age at
which the CHAT screening was done. Later research by
the same group has again found variation in early presentation, with a subgroup failing to manifest obvious
behavioural signs of early developmental risk.65
Sandra Maestro and colleagues have examined early
videotapes of 40 such children and found clear evidenceof abnormalities within the first year of life in 87.5%(35) with a small subgroup (the remaining 12.5%) showing no behavioural differences. This group used a standardized rating scale of early behaviour - the Behavioural Summary Evaluation Scale.66
8. Are there structural or functional differences in theautistic brain ?
Gross anatomic and cytoarchitectonic differences in
autism are now well recognized.67, 68
Neuroanatomical differences being reported in many
structures including the amygdala;6 9 more generally of
medial temporal lobe structures including amygdala, hippocampus and entorhinal cortex.70 The elegant and detailed neuropathology studies of Bauman and Kemper71
have shown a range of anatomical differences, particularly in prefrontal cortex; limbic and cerebellar structures. There may be subtle regional reductions in hippocampal volume.72
There are reported differences in the structure of thecerebellum in some cases,7 3, 7 4 associated with reduced
numbers of Purkinje cells.75 There may be a causal link
between these abnormalities and autistic symptomology.7 6, 7 7 Similar features are described in the “cerebellar
cognitive affective syndrome”(CCAS).7 8 In CCAS, agroup of patients with frank neurological damage confined to the cerebellum, a wide range of non-motor func-

Aitken KJ: Intersubjectivity, Affective Neuroscience and ASD

tions are impaired which include blunting of affect; dysprosodia; executive dysfunction and working memory
problems.
A number of studies suggest that the brain is typicallylarger in autism at birth (albeit with a high degree ofoverlap with the general population), with a subsequentslowing in brain growth compared to normal.79, 80
Some studies suggest underconnectivity between brain
areas, involving abnormal development of the corpus
callosum81 and of connectivity between dorsolateral prefrontal cortex and hippocampus8 2 or anterior cingulate,ventral striatum and anterior thalamus.83
One study has suggested differences in the functional
activation of the primary language areas in able autists
with reduced activation in Broca’s area (left inferior
frontal) and increased activation in Wernicke’s area (lefttemporal) during language processing tasks.8 4 Anotherstudy showed abnormal fMRI activation of the amygdala
and fusiform gyrus to cartoon faces and reduced activation to normal faces in one autistic subject obsessive
about cartoon characters when compared to normal controls.85
9. What about early social communication in autism ?
Baron-Cohen, Allen and Gillberg (1992)86 studied 41
children at high-risk for developing autism (siblings born
into families with previously diagnosed autistic offspring). At 18 months, these children were screened using a tool called the Checklist for Autism in Toddlers(CHAT). This was administered partly by observationand partly by parental questioning. Abnormalities were
found in eye contact, pretend play, protodeclarative
pointing (pointing to show), social play and social interest in the four children who went on to receive a diagnosis of autism. The first three features were seen in all
subsequently diagnosed cases. This was a prospective
screening study in a group known to be at high risk ofdeveloping autism so could not be used to infer the likely
occurrence of such features as risk factors in the general
population. A population study was required to ascertain
false positive and false negative rates (how many children would be classified as high-risk who would subsequently develop normally and how many subsequently
affected children would be missed).
In a subsequent population based study,8 7 the teamscreened 16,235 children at 18 months from 10 healthdistricts in South London. Their initial screening identified 10 children who were predicted on their CHAT
scores to be likely autistic children. All were found to be
autistic when followed up several years later.
In the followup screening, a further 40 cases who had
passed the CHAT were identified. Thus 80% of theirsubsequently diagnosed cases had had normal eye contact, protodeclarative pointing and / or play at 18 months.
These early prognostic indicators did not seem to be asKeio J Med 2008; 57 (1): 15 － 36

21

useful as initially thought either because they are of limited sensitivity or because there is a group who show later emergence of autistic behaviour. It would be interesting to know how many of the high-risk children in theoriginal 1992 paper have gone on to show any ASD features in subsequent years.
A number of subsequent studies have used refinementsof the CHAT scale such as the M-CHAT8 8, 8 9 and theCHAT-2390 in attempts to improve sensitivity and specificity.
As indicated above, various groups have examined early video material of subsequently diagnosed children. To
date, this source of data is limited as it is retrospective, is
not systematically collected, and is collected by parents.
These factors introduce a number of biases - socioeconomic skewing as more affluent families are more likely
to collect this type of material; selective recording, as
parents of those with an ASD are more likely to exhibit
similar difficulties and could thus choose to record different types of material - the child’s interest in mobiles
rather than in people, for example. Video material being
collected in some of the prospective research studies
now underway will allow this material to be validated.59
Initiatives are underway to try to develop earlier
screening tools such as the SEEK which has been trialled
for 8 month screening focussing on aspects of early behaviour such as sleep rhythm; eating rhythm; social interaction; eye contact; body contact and bodily tonus.91

tions on the strength of conclusions which can be drawn
from virtually all of the epidemiological studies todate.see, eg:5 9, 1 0 0 -1 0 3 Most studies are on clinic populations or of areas with apparently anomalous rates while
few are true population studies.
One of the most recent UK studies gives a prevalence
for all ASDs of over one in 86 live births, and one in 257
for childhood autism.104 A further recent paper from Japan gives a rate of one in 62 live births for the prevalence of ASDs for a cohort of Japanese children born inthe early 1990s.105
It remains uncertain whether there is a true rise in incidence (the actual numbers of new cases), however there
is a definite rise in reported prevalence (the number ofcases being identified).

10. Are there differences in Mirror Neurons in Autism ?
There has been speculation over possible mirror neuron defects in autism for some time9 2 and evidence isemerging of anatomical differences in the areas implicated in mirror neuron function.9 3 These differences are,however, part of more general differences also reflected
in other brain areas involved in emotional recognitionand social understanding. A somewhat different perspective suggests a general problem of underconnectivity between cortical areas.81
Several studies address mirror neuron function in autism and related disorders, documenting functional differences in both Asperger syndrome94 and ASD.95
There is a fundamental problem in “intentional attunement” in autism.96 There appears to be a lack of coordination in the activity of areas involved in sensory, motor, emotional and proprioceptive processes.97 A reduction in spindle cells (also known as Von Economo neurons) may be involved in the empathy deficits seen in
autism. These cells, found in the anterior cingulate are
involved in emotional understanding9 8 and function abnormally in autism.99

13. Do we have a model for how social understanding
in autism takes place ?
Various models of the social deficits in autism havebeen proposed. I will briefly elaborate on one psychological model which has clear parallels to the interestingfindings on mirror neuron dysfunction describedabove.41
The process of normal interpersonal interaction relies
on conveying information and on internal models to process and interpret the feelings, intent and likely future
actions of self and other. Where aspects of the process
are impaired ― through sensory or motor deficit or
through a lack of an internal model of self / other - interaction will be affected.
In autism, it appears that the ability to interpret others
is selectively impaired.
Such a deficit has implications for therapy. A range ofinterventions can be viewed as operating by simplifying
B’ in Figure 3 to make interaction with the autistic individual easier to understand. The ‘Option’ approach, forexample, provide a situation where the other person becomes easier to interact with through providing a situation in which the autistic child can successfully interact
using the belief that A = B’. Structured approaches suchas Applied Behavior Analysis (ABA) simplify the behaviour of others by the use of limited vocabulary, frequent

11. Prevalence of Autistic Spectrum Disorders
With a few notable exceptions there are major limita-

12. Outcome in Autistic Spectrum Disorders
There are a number of reviews of outcome in autistic
spectrum disorders.106
Speech and language problems at 2.5 years appear to
be a strong predictor of subsequent neuropsychiatric disorder (ADHD or ASD) but not to be syndrome specificwith regard to prognosis.107
Diagnoses such as Rett syndrome and Childhood Disintegrative Disorder have poorer developmental outcome
and a degenerative timecourse. Certain medical co-morbidities such as epilepsy are also associated with increased morbidity and mortality.108

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Aitken KJ: Intersubjectivity, Affective Neuroscience and ASD

Non-Autistic
Person
A

B'

A

A'

B

B

Fig. 3 A diagram of autistic interaction

repetition and the use of the same repertoire by all significant caregivers (thus making B’ more predictable).
The common factor underpinning successful early intervention approaches appears to be making the world
appear simpler and more predictable. Other approaches
can introduce patterning and predictability using methods from music therapy or by introducing ‘rhythmic intention52’ (see: Jaqueline Robarts section on music therapy in).
14. Is Autism a Genetic Condition ?
The view that autism is largely a single but polygenic
genetic condition came from early twin studies that appear to support this view.1 0 9 Bailey et al found a 60%
MZ concordance for narrowly defined autistic disorderand a 0% concordance in DZ pairs. High and stable concordance rates in identical twins and lower rates in nonidentical twins were used to argue for a polygenic model.11 0 Increasingly, general objections have been raised
to the view that MZ-DZ concordance differences are adequate to address such issues.111 Various objections totwin data specifically in autism research have beenraised including the higher rate of autistic traits in maletwins when compared to non-twin controls,11 2 and thesuggestion in some studies that twinning may be an associated risk factor per se.113 ; but see also: 114
Concordance appears to have fallen in identical twinpairs and risen in non-identical twin pairs, leading one

group to draw the following conclusion:“Our data suggest that heritability estimates from previous studies may have overestimated the role of genetics and underestimated the role of environmental factors
in the etiology of autism.” (Croen, Grether & Hallmayer2002)1 1 5
A recent advance in our conceptualization of neurodevelopmental disorders in general has been the recognition of ‘Behavioural Phenotypes’.116
Genetic analysis is starting to provide answers to why
particular individuals are affected and may benefit fromparticular approaches. There are also recommendations
from a number of quarters concerning the importance ofidentifying ‘syndromal’ autism, or pathogenesis specificclinical presentations which help to identify patients who
warrant further laboratory and imaging studies.117
There are many recognized clinical conditions which
are associated with ASDs at a greater than expected frequency.
There are also a large number of gene markers whichfrom linkage studies are over-represented in the autistic
population but where we are currently unsure of theirfunctional significance (see Ref.118 for a discussion ofmany of the weaker associations).
A wide range of conditions which have been describedin individuals with ASD diagnoses have distinct behav-

Keio J Med 2008; 57 (1): 15 － 36

ioural and physical phenotypes, mostly associated with
developmental disability/learning problems. Many arelinked to other co-morbid problems such as ADHD
symptomology; sensory deficits; immune dysfunction or
epilepsy.
The principal conditions are listed here:
15q11-q13 duplication; chromosome 2q deletion; XYY
syndrome;10p terminal deletion; 45,X/46,XY mosaicism; 22q13 deletion syndrome; Aarskog syndrome;
Adenylosuccinate lyase deficiency; Adrenomyeloneuropathy; Angelman syndrome; Apert syndrome; ARX
gene mutations; Autism secondary to lymphoproliferative syndrome (ALPS); Bannayan-Riley-Ruvalcalba syndrome; Basal cell nevus syndrome; Biedl-Bardet syndrome; CATCH 22; CHARGE syndrome; Coffin-Lowry
syndrome; Coffin-Siris syndrome; Cohen syndrome;
Cole-Hughes macrocephaly syndrome; Congenital adrenal hyperplasia; Cowden syndrome; De Lange syndrome; DiGeorge syndrome; Down syndrome; Duchenne’s disease; Ehlers-Danlos syndrome; Fragile X syndrome; Fragile X permutation (partial methylation defects); GAMT deficiency (guanidinoacetate methyltransferase deficiency); Goldenhar syndrome; HEADD syndrome; Hyper IgE syndrome with autism; Hypomelanosis of Ito; Hypothyroidism; Joubert syndrome; Kleine
Levin syndrome; Lujan-Fryns syndrome; macrocephaly/
autism syndrome also defined above as Cole-Hughes
macrocephaly syndrome; Moebius syndrome; Myhre
syndrome; Neurofibromatosis type 1; Noonan syndrome;
Ornithine carbamyltransferase deficiency; Oculocutaneous albinism; Orstavik 1997 syndrome; Phenylketonuria;
Pituitary deficiency; Prader-Willi syndrome; Proteus
syndrome; Rett syndrome; Rett syndrome (Hanefeld
variant); Rubenstein-Taybi syndrome; Schindler’s disease; Smith-Lemli-Opitz syndrome; Smith-Magenis syndrome; Sotos syndrome; Steinert myotonic dystrophy;
Timothy syndrome; Tourette syndrome; Trichothiodystrophy; Tuberous sclerosis; Turner’s syndrome; Unilateral cerebellar hypoplasia syndrome; Velo-cardio-facial
syndrome (also see CHARGE syndrome); Williams syndrome; Xeroderma pigmentosa.
A number of overgrowth syndromes with associatedneurodevelopmental difficulties have been reported
which may also present with autistic/autistic-like symptomology.
These include the following:
Weaver syndrome (this may be synonymous with Sotos syndrome also now localized to 5q35); Simpson-Golabi-Behmel syndrome Type 1; hemihyperplasia; SturgeWeber syndrome; and PEHO syndrome (Progressive Encephalopathy with Edema, Hypsarrythmia and Optic Atrophy).
In addition to the described clinical phenotypes whichhave been reported in association with autism, there aremany genes associated with autistic diagnosis through23

linkage studies.11 9, 1 2 0 Such studies have been carriedout through the analysis of large case series or of archived genetic material. The reported associations with
LOD scores of 2.2 or greater are tabulated below (dataadapted from Ref.1,5,119,121 for justification of thiscutoff, see Ref.122).
There are currently few areas of overlap between linkage sites and associated conditions―the homeobox sites
DLX1/2 and HOXB1 on chromosomes 2 and 17 and theserotonin transporter SLC6A4 on chromosome 17 currently looking the most promising.
Gene mapping of complex disorders such as autism isproceeding rapidly. Understanding the biological and behavioural mechanisms by which these have effects in theprocess poses greater difficulties.6, 139 It is the epigenetic
regulation of gene function that is core to our understanding of mechanism.140
Associations between such linkage sites and specificbehavioural phenotypes are coming to light. A recent paper suggests a link between a chromosome 2q linkagesite - D2S116 and delayed onset of phrase speech in autistic disorder (MLS 2.86),141 while MLS in the total autistic disorder group is only 1.3.136
Known genetic causes account for around 12% of cases.142 Recent findings on the prevalence of factors suchas DHCR7 mutations, and a recently described variant of
the MET receptor tyrosine kinase143 suggest that further
genetic factors may be important in a higher proportionof cases. Based on the epidemiological data so far collected, perhaps in as many as 65% of cases. The majorityof such factors are not screened in routine clinical practice. It seems likely that the vast majority of those with
autistic disorders will be found to have pathogenically
relevant genetic factors. Given what we know of the few
conditions that have been investigated, many genetic differences seem likely to vary by ethnicity.
The extent to which genetic factors increase susceptibilities to environmental effects and the extent to whichthese are sufficient in the absence of any environmental
factors is, for most, an open question. Environmental exposures may result in autistic behaviour primarily in genetically susceptible individuals.
15. Do we know of non-genetic biological causes of autism ?
There are apparent peaks for exposure to environmental stressors at 25-28 weeks post conception associatedwith a heightened liklihood of the development of autism.144
The recent rise in reported prevalence (see Ref.102,145
for discussion), the changes in reported MZ/DZ concordance rates (see above), increased susceptibility to autistic traits in male twins compared to the general population,112 and public concerns over various environmental
exposures146, 147 have led to a developing research focus

24

Aitken KJ: Intersubjectivity, Affective Neuroscience and ASD
Table 2 Gene positions with linkage to ASD diagnoses

Chr
1
2
DLX1/2
DLS1/2
3
4
5
6

7

9
11
13
15
16

17

19
21
X

1p13.2
1q21-22
1q22
1q23.3
1q42.2
2q31.1Marker(at or near)
D1S1675
D1S1653
D1S2721
D1S484
D1S1656
D2S21881
12
2
3
4 (but see 16)

MLS Group Candidate(multipoint LOD score)
2.63+?
2.63
2.88
3.58
3.06
4.80

2q31.1
3p24.1
3p25.3
3q22.1
3q26.32
4q23
4q27
4q32.3
5p13.1
5p13.1
6q14.3
6q16.3
7q21.2
7q22.1
7q32.1-34
7q34-36.2
7q36.1
7q36
9p22.2
9q34.311p11.2-13
13q12.3
13q22
13q32.1-32.3
15q21.2
16p13
16p13.2
17p11.2
17q11.2
17q11.2
17q11.2
17q11.2
17q21.2
17q21.32
17q24.3
19p
19p13.11
19p13.12
19p13.12
21q21.1
Xq21.33
Xq25
Xq

D2S355
D3S2432
D3S3691
D3S3045 - D3S1736
D3S3715/D3S3037
D4S1647
D4S3250
D4S2368
D5S2494
D5S2494
D6S1270
D6S283
D7S1813
D7S477
D7S530-D7S684
D7S1824-D7S3058
D7S483
D7S1824
D9S157
D9S1826
D11S1392/D11S1993
D13S217/12229
D13S800
D13S793-D13S1271
CYP19
D16S3102
D16S407
D17S1298-D17S1299
D17S1294-D17S798
D17S1294
D17S1800
HTTINT2
D17S1299
D17S2180
D17S1290-D17S1301
D19S433
D19S930
D19S714
D19S714
D21S1437
DXS6789
DXS1047
DXS1047

3 (but see 16)
2
5
6
1
3
3
2
7
8
3
9
10
4 (but see 17)
11
6
12
1
4
4
7
10
10
2
4
4
4
6
13
5
7
4
5
14
6
8
5
8
3
12
1
8
8

3.32
3.32
2.22
3.10
4.81
2.87
2.73
2.82
2.54
2.55
2.61
2.23
2.2
3.55
3.55
2.98
2.37
3.66?
3.11
3.59
2.24
2.3
2.3
2.86
2.21
2.93
2.22
2.22
4.3
2.85
2.83
2.34
2.26
4.41
2.84
[3.36]
2.77
2.53
2.31
3.4
2.54
2.67
[2.27]

PositionScan

on environmental factors. A number of large studies are
now underway which should help to address and resolve
the issues,59 such as the CHARGE study.60
That environmental factors may compound a genetic
vulnerability - for example, that various PCBs can multiply glutamate based potentiation five fold in vitro1 4 8 isclearly a plausible factor. A recent, well-controlled Australian study found that by age 5 years the risk of ASD

Gene Locus

PON1
RELN
WNT2
EN2
EN2

BDNF

SLC6A4SLC6A4SLC6A4SLC6A4SLC6A4
HOXB1
HOXB1

following neonatal encephalopathy was 5% as opposed
to 0.8% in a randomly selected control group.149
There are many findings suggestive of an association
between oxidative stress and autism,1 5 0 particularly incases associated with loss of previously acquired language skills.151

Keio J Med 2008; 57 (1): 15 － 36

16. Teratogenic Exposures
Sodium Valproate, one of the safest antiepileptic
agents, is a compound that acutely interrupts neuralmigration in animal models, and when taken during
pregnancy it can result in autism. In a recent series, 8.9%of those exposed in utero to sodium valproate were subsequently diagnosed with autistic disorder or Asperger
syndrome.152
As many epileptic women may conceive whilst on
medication and may be unaware of the potential risk it isimportant that this is part of pre-conceptual advice towomen of child-bearing age on sodium valproate prophylaxis. The lesser risks associated with other antiepileptic medications may be an important consideration for
epileptic women wishing to have children.
Misoprostal is an abortifascient which, in babies subsequently carried to term, results in an iatrogenicallyinduced cranial nerve VI and VII palsy. It is associatedwith the subsequent diagnosis of autistic disorder in approximately 1/3 of cases.1 5 3 The effects of misoprostal
are equivalent in nature and extent to those seen in thegenetic form of Moebius syndrome. In both conditions,
there is a significant association of the neurological features with autistic disorder.
Thalidomide, a medication which was used in Europe
as treatment for ‘morning sickness’ during pregnancy
also resulted in a significant number of autistic children,
if taken during a critical time window of pregnancy(20-24 days post-conception), also resulting in associatedear and digit anomalies in those affected by autistic disorder and suggesting a critical time window in embryogenesis.154, 155
17. Viral pathogeneses
Animal models demonstrate the biological plausabilityof viral pathogeneses of ASD.1 5 6
In autism, exposure to a range of viral agents has beensuggested as having played a possible causal role, including Cytomegalovirus;157 Herpes encephalitis;158 Human immunodeficiency virus;159 Rubella160 and Measles(SSPE and OCDD).161
It is important to stress that research in this area is notrobust. Demonstration of cases where viral exposure andautism co-occur does not prove causality without greater
knowledge of factors such as community levels of exposure and ASD prevalence within such communities.
18. Can a knowledge of biological differences in pathogenesis have relevance to management ?
There are many disparate approaches being advocatedfor the biological management of ASDs, some of whichhave become the subject of much controversy - secretinand chelation therapies being two amongst many such25

‘alternative/adjunctive’ approaches. A plausible theoretical basis for interventions can often be constructed, butthere is only limited / anecdotal evidence of abnormalities in the parameter of interest in the autistic populationand even less of clinical benefit from addressing suchdifferences (see Ref.106,162,163 for reviews).
Those who take a strictly ‘Evidence-Based’ approach
have to admit that there is a paucity of adequate evidence
for all approaches, whether conventional or alternative,
and a laissez-faire approach is easy to adopt and justify.
This situation should not be used to argue for maintenance of a status quo, but rather to stimulate adequate research (adequate in the sense of being sufficient to affectclinical practice if it were to demonstrate positive effects).
The UK Medical Research Council Research Review1 6 4 highlighted a range of potentially promisinglines for further research in the area of dietary treatments. There is now an extensive literature on gastrointestinal problems in autism.1 6 5, 1 6 6 As the various biological factors involved in gastrointestinal function are
identified, as with the MET receptor tyrosine kinase,1 4 3
the nature and role of such involvement will be clarified.
A number of differences between those with ASDs andthe control populations against which they are often
matched may be important in interpreting any biologicalfindings which are reported. For example, creatinine levels are often used as a standard reference against which
abnormalities in other biochemical products are compared. Recent research has indicated that creatinine levels may be significantly reduced in the ASD population.1 6 7 This difference may be genetic in origin - a
GAMT deficiency,1 6 8 for example, would lead to lowlevels of creatine, and consequently to lowered creatinine levels. Such a difference may be important in interpreting the results of studies such as the recent paper on
differences in urinary porphyrin levels that may be ofclinical relevance.169 Results should be reported making
allowances for and pointing out any such group differences found.
18.1. Abnormalities of Tryptophan Metabolism
As early as 1986 there was published research suggesting a link between abnormal tryptophan metabolism andseverity of problems in children with autism.1 7 0 This
group demonstrated that free plasma tryptophan levels
were elevated in autistic children compared to both childand adult controls and that levels correlated positively intheir autistic sample (n = 37) with both activity level andrated severity of psychiatric symptomology. Subsequently, McDougle and colleagues have demonstrated that bydepleting tryptophan in adult autistic subjects they could
induce marked changes in behaviour - significant increases in behaviors such as whirling, flapping, pacing,banging and hitting self, rocking, and toe walking could

26

be induced (p < .05) and these were not seen in casematched controls.171
A potential pathological role for abnormal tryptophan
metabolism in the development of autism and epilepsy
has been described.172 One aspect of abnormal metabolism of tryptophan could be the induction of cortical dysplasia, predisposing to a higher risk of both autism andepilepsy.
A recent genetic study has shown a polymorphism of
the tryptophan 2-3 dioxygenase gene in a significant
subgroup of autistic patients from 196 multiplex families,1 7 3 effectively blocking one catabolic pathway fortryptophan metabolism to kynurenine and increasing theavailability of tryptophan for the production of serotonin.
This suggests that a subgroup may be centrally hyperserotonaemic.
Differences in the brain expressed form of tryptophanhydroxylase (TPH2) have also been reported as occurring at a modestly elevated level in a subgroup of the autistic population.1 7 4 This suggests that there may be afurther subgroup who are centrally hyposerotonaemic.
These genetic differences in tryptophan metabolism
may account for the variable response reported in theclinical literature to SSRIs.175
As tryptophan is the dietary precursor to a wide rangeof biologically active substances such as serotonin, melatonin, and kynurenine, the role of this metabolic pathway
in autism deserves more detailed analysis.
18.2. Methylmalonic Acidaemia, Vitamin B12 (methylcobalamin) and cobalt levels
Methylmalonic acidaemia (MMA) was first describedin children in 1967 and had previously been described in
adults with pernicious anaemia. It results from a deficiency of either methylmalonyl-CoA mutase (the principal factor in converting Methylmalonyl-CoA to Succinyl-CoA) or of adenosine cobalamin, an essential cofactor derived from vitamin B12 (cobalamin). MMA is abranched-chain organic aciduria like Maple syrup urine
disease (MSUD), isovaleric acidaemia (IVA) and propionic aciduria (PA).1 7 6There are well recognised neurological-psychiatric sequelae of impaired intracellular synthesis of adenosylcobalamin and methylcobalamin (cobalamin C disease)which is an inborn error of metabolism.177
Vitamin B-12 deficiency can arise for various reasons
including mother adhering to a vegan diet during pregnancy and while breastfeeding,1 7 8 or through strict adherence to a vegan diet.179
A genetic basis to some forms of vitamin B-12 dependent methylmalonic acidaemia has now been identified.180 Imerslund-Gräsbeck disease is an autosomal recessive problem with B12 absorption, coupled with proteinurea.181
Abnormalities of methylation are described in autism

Aitken KJ: Intersubjectivity, Affective Neuroscience and ASD

and, when present, can be ameliorated by the use of a
combination of folinic acid, betaine and methylcobalamin.182
Metabolic endophenotypes183 may be associated withtransmethylation and transsulfuration of methionine,demonstrating abnormal rates of allele frequency or
gene-gene interactions in the following:
reduced folate carrier (RFC 80G > A);transcobalamin II (TCN2 776G > C);catechol-O-methyltransferase (COMT 472G > A);
methylenetetrahydrofolate reductase (MTHFR
677C > T and 1298A > C);
glutathione-S-transferase (GST M1).
18.3. Abnormal Sterol Metabolism and the case of
SLOS
Abnormalities of short chain fatty acid metabolism
have been hypothesised as being involved in some formsof autistic spectrum disorder. Abnormal long chain acylCoA dehydrogenase (LCAD), for example has beenfound in an autistic patient with consequent defects inthe beta-oxidation of branched and unsaturated fatty acids, with reduced synthesis of omega-3 DHA and abnormal cholesterol metabolism.184
Bell has described abnormal erythrocyte cell membrane phospholipids - in particular reduced levels ofhighly unsaturated fatty acids (HUFAs) in an ASD sample, specifically after cold storage, suggesting a possible
more rapid breakdown of these compounds in those with
ASDs and particularly in those who presented with regressive autism than in those with ‘classical’ autism.185
One small study1 8 6 has shown an increased level ofamino-glycerophospholipids in the plasma of 14 autistic
children compared to their sibling controls, also suggesting abnormal erythrocyte membrane composition.
A small double-blinded group-matched randomized
placebo-controlled pilot study of omega-3 fatty acids in
autistic children provides evidence for a significant effect on hyperactivity and stereotypy in this population.187
Smith-Lemli-Opitz syndrome (SLOS) is a defect in the
final stage of cholesterol biosynthesis, due to an inborn
error of the gene for 3 beta-hydroxysteroid Delta7-reductase (DHCR7). It results in multiple congenital anomalies.188
One well constructed study has found a high rate ofautistic behaviour in those with SLOS.1 8 9 A further recent study found approximately 3/4 of a sample of children with SLOS qualified for an ASD diagnosis on parental interview, direct observation and a diagnostic behaviour checklist.190
From unselected blood samples from multiplex autistic
families, although none demonstrated cholesterol levels
consistent with a severe abnormality of sterol metabo-

Keio J Med 2008; 57 (1): 15 － 36

lism such as SLOS, 19/100 samples analysed showed
levels below the 5th centile indicating that such abnormalities are more common within this population.191
Similarly, a recent study compared excretion levels of
8-hydroxy-2-deoxyguanosine (8-OHdG) and 8-isoprostane-F2alpha (8-iso-PGF2alpha). Comparing 33 autistic
children to 29 healthy group-matched controls a groupdifference was found, however the autistic distribution
was bimodal and a small subgroup of the autistic children showed a far more marked elevation over controls.192
SLOS is more common in populations of Central European origin. The first study to look at carrier frequency
in the general population was recently completed in Poland,193 and screened for the two most common DHCR7
mutations, which together account for some 65.2% of
Polish cases. This study found an incidence of SLOS ofsome 1 in 2,300 to 1 in 3,937. This suggests SLOS is oneof the most common recessive genetic disorders, and, if
replicated, would make it the most prevalent genetic basis to autism, exceeding the prevalence in fragile-X.
In a study of a genetic mouse model of SLOS similarly
lowered levels of serum and tissue cholesterol were
found with impaired response to glutamate by frontal
cortical neurons.194
A more recent mouse model of SLOS1 9 5 produced
mice with the following structural CNS differences commissural deficiencies, hippocampal abnormalities,
and, perhaps most interestingly, hypermorphic development of serotonergic neurons. The same group have goneon to look at the immunohistochemistry of these differences, particularly as they affect commisural and hippocampal axonal guidance pathways.196
18.4. Glutamate and Gamma-Amino Butyric Acid
Glutamate and Gamma-amino butyric acid (GABA)
have received limited attention in the study of autistic
spectrum disorders. Researchers have only recently begun to investigate the role of these factors in the pathogenesis and development of autism and the potential implications for treatment.
Glutamate is the principal excitatory amino acid transmitter found in vertebrate nervous systems. An imbalance between excitatory and inhibitory transmitter systems provides a reasonable theoretical model for certain
presentations of autism.197 The physiological effects ofglutamate are ubiquitous.1 9 8 GABA is converted fromglutamate by the enzyme glutamic acid decarboxylase(GAD). Pyridoxal phosphate (vitamin B6) is an essential
co-enzyme in this process. GAD is the rate-limiting stepin the synthesis of GABA and reduction in GAD activity
would thus lead to excess levels of glutamate. There aresome preliminary results suggesting that autism may be
associated with abnormal GABA A receptor genes onchromosome 4199 and with a defect in the metabotropic

27

glutamate receptor 8 at chromosome 7q13.200
Examination of brain levels of GAD in five autistic
and eight control subjects at postmortem found that thisenzyme was reduced by 48-61% in parietal and cerebellar areas of the brain in individuals with autism compared to controls.201 As the “excitotoxic” effects of glutamate interfere with neuronal development, and havetheir maximal effect during the second year of human
life,202 it seems plausible that such a difference in glutamate metabolism may be implicated in the brain differences reported in the ASDs. A further recent study ofadult autistic serum levels of glutamate also provides
support for the involvement of abnormal glutamergic
neurotransmission in autism.203
In addition to being the period of maximal effects ofglutamate on neural maturation, the middle of the second
year is the time when parents typically first note concerns over development in subsequently diagnosed autistic children.204
A further postmortem study of 10 autistic and 23 groupmatched control brains found a range of neurogenetic
differences, particularly of interest here being thatmRNA levels of excitatory amino acid transporter 1 andglutamate receptor AMPA 1 were elevated, specificallyin cerebellum, while AMPA type glutamate receptor density was significantly reduced, also selectively in cerebellum.205
The interactions between glutamate, GABA, and theother neurotransmitter systems involved in brain development such as serotonin and dopamine are complex237
and not yet fully understood (see Ref.15,207 for recent
reviews of the neurochemistry).
Various environmental factors such as chronic stressincrease circulating glutamate levels, 2 0 8 activating
N-methyl D-aspartate (NMDA) receptors and increasing
liklihood of cell death.209
Anti-glutamergic agents are receiving increasing attention for their potential role in the management of autism(see Ref.210 for review). Glutamatergic overactivity isalso associated known to be associated with increased
risk of seizures.2 11 It is well recognized that seizure
problems are more common in the autistic population,212
with more severely impaired individuals having a greater
likelihood of also having seizures,213 however the potential link between these various aspects has yet to be systematically explored.
Researchers have found abnormalities of cellular development in the limbic system and cerebellum at
postmortem71, 214 consistent with abnormal antenatal development of these structures.
We now have evidence for differences in the GABA
receptor pathways (as indicated by the abnormal GAD
levels reported above), in the ionotrophic glutamate receptor system (as indicated by the the AMPA 1 differences above) and metabotropic glutamate receptors (as28

we will see in the following section).
Glutamate abnormalities appear to occur in autism at ahigher than expected rate. These may be primary, andgenetic in origin, driven by secondary factors such as
anxiety, or a compound of such effects.
18.5. Fragile-X syndrome and autism (AFRAX)
Recent developments in AFRAX provide perhaps themost exciting developments in biological understandingof ASD, linking genetics, proteomics and neurochemistry to the effects of the biological environment on development.
Fragile-X syndrome (FXS) results from a triplet gene
expansion at chromosome Xq27.3 of the FMR1 (Fragile-X Mental Retardation 1) gene coding Fragile-X Mental Retardation Protein (FMRP) (see Ref.215). FXS is
caused by inactivation of the gene and the reduction orabsence of FMRP. The transcription process is partly
controlled by Nrf-1 and Sp1 and is not regulated by
DNA methylation alone.2 1 6 The CGG (cytosine-guanine-guanine) sequence involved in production of FMRP
repeats some 6-55 times in the general population, in
mothers of affected individuals the same sequence copies some 55-230 times (previously called a ‘pre-mutational’ expansion). In diagnosed individuals some 230 to1000 copies are typically seen.217 The condition affects
the X chromosome in boys who will have inherited their
Y chromosome from their father and their affected X
chromosome from their mother. De novo mutation anduniparental isodisomy with patrilineal inheritance arepossible but neither has been reported to date.
The full mutation form of the Fragile-X expansion isreported as affecting some 1 in 3,717 to 1 in 8,918 of thecaucasian male population.218 There appear to be ethnic
differences in prevalence - the Afro-American male population being reported as having a prevalence rate of 1 in
1,289 to 1 in 2,545.219 A recent Taiwanese study foundonly one query positive and 6 premutational cases in
10,046 neonates.220 With a full Fragile-X mutation, 21%of all cases, and 25.9% of males exhibit autistic behaviour and an inverse correlation between severity of autistic symptomology and level of FMRP.221
FMRP is localized in dendrites and reduced in synapses by activation of the glutamate receptor mGluR5.2 2 2
mGluR5 can be detected during embryonic development,223 and is most prominent in zones of active neurogenesis.2 2 4 Its expression rises through the first two
postnatal weeks then falls.225
Neuroanatomically FXS results in an excess of long,thin dendritic spines seen in both human CNS autopsy
tissue from affected individuals2 2 6 and knockout mouse
CNS tissue.2 2 7 Dendritic anomalies are seen in various
disorders associated with learning problems, with the nature, location and extent of these defects seemingly disorder-specific.2 2 8, 2 2 9 In Fragile X, the effects of the

Aitken KJ: Intersubjectivity, Affective Neuroscience and ASD

FMRP defect is to produce an abnormality of dendritic
spine morphology.230 In certain brain areas, expressionof FMRP mRNA is regulated by brain-derived neurotrophic factor.231
FXS has a well recognized physical and behavioural
phenotype.232 Seizure problems affect 10-20% of cases,
with complex partial seizures being most common.233
FXS is associated with autism at well above chancelevels.2 3 4, 2 3 5 Cases where autism has been found inchildren with pre-mutational expansions2 3 6 strengthen
the idea of a common underlying pathophysiology toboth the Fragile-X-specific physical and behavioural
phenotype and autism. This may lead to better understanding of the neurobiological mechanisms that produce
and maintain autistic symptomology.
Three recent developments have stimulated interest in
Fragile-X syndrome:237
1) The recognition that grandfathers of those affected
by Fragile X syndrome often presented in later life with
Fragile X-associated tremor/ataxia syndrome (FXTAS)(see Ref.238 for review), the condition has also been reported in carrier sisters who have preferential activationof the premutational X allele.239
There is also a possible link between pre-mutational
expansion and risk of autism with several cases being reported240 ― this suggests that pre-mutational expansions
may not be benign but convey risk in pre-mutationalmales.
Recent studies have shown that inclusion of untranslated FMR1 messenger RNA results in the inclusion bodies
seen in the glial cells and neurons in the hippocampus
and cerebral cortex of pre-mutational male.241
2) There is strong evidence for premature ovarian failure in female carriers of a pre-mutational expansion.2 4 2There is a particular neuropsychological profile in somefemale carriers with problems of selective attention.2 4 3There is, in addition, a small effect of carrier status andof the size of premutational expansion on verbal IQ in
female carriers, explaining some 4% of the variance.244
and3) Following on from the previous section, the main
effect of the fragile-X expansion is interference withmetabotropic glutamate receptor-coupled pathways (specifically those involving mGluR5).245 The mGluR5 theory was first proposed in 2004246 and has quickly established support from animal and human studies. A recent
finding is that mGluR5 receptors respond to glutamate
preferentially, but also to cysteine, aspartate and asparagine.247
mGluR5 antagonists such as 2-methyl-6(phenylethynyl)pyridine (MPEP) can, in vitro at least, block
many of the effects resulting from absence of FMRP.248
Brain areas, including the cerebellum and limbic system have high numbers of glutamate receptors. Researchers have theorized that overactivity of glutamate

Keio J Med 2008; 57 (1): 15 － 36

may result in ‘‘ excitotoxicity’’ and cause aberrant neuronal development.249 In mice, FMR1 deletion affects thedevelopment of various neural structures with abnormal
mGluR1 dependent long term depression in hippocampus250 and in cerebellum.251 If the glutamergic system ishyperfunctional, it is likely that neuronal growth andconnectivity would be damaged during critical periods ofearly development.
There is currently much interest in the development ofpharmacological treatments targeted at addressing boththe abnormal dendritic formation seen at postmortem in
the FRAX brain252 and also in the knockout mouse model of human FMR1.2 5 3 There is exaggerated long term
depression of responses caused by the absence of feedback inhibition of mGluR5-induced dendritic translation
by FMRP. Long term depression eliminates alpha-amino3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)
receptors from the synapse.2 5 4 The interactions in thissystem are complex, involving a range of other factors
including DARPP-32 phosphorylation which is regulated
by glutamate.255
There appear to be multiple roles for FMRP. from theheterogeneity of expression of FMRP granules in response to oxidative stress and the variability of co-localization of FMRP and T-cell internal antigen (TIA-1), a
stress granule marker protein.256
In the drosophila dfmr1 knockout model,257 many behavioural abnormalities mirror those seen in human fragile X patients.2 5 8 Of potential importance is that manyof these differences can be corrected through the use ofglutamate antagonists.2 5 9 Certain antagonists such as
MPEP show reversal of the fragile X physical and behavioural phenotype in animal knockout models andmay hold promise in human treatment.260
The role of mGluR5 in learning and memory has been
extensively studied.261 From the animal research to date,there are two splice variants - mGluR5a and mGluR5b,
with the b variant predominating in the adult brain, andmGluR5 mRNA being found predominantly in hippocampus, amygdala, caudate-putamen and cortex.
There has been a steadily growing interest in metabotropic glutamate receptors as a potential target for pharmacotherapy.262
The biology of glutamatergic differences in Fragile-X
syndrome is now becoming well understood. The resultsof treatment studies in animal models are highly encouraging. Human trials of an mGluR5 antagonist (STX107)
are to begin in the USA in 2007 (see: Seaside Therapeutics).
19. References
1.
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Gupta A.R. & State M.W: Advances in the Genetics of Autism,
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Junaid M.A. & Pullarkat R.K. Proteomic approach for the eluci-

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31: 557－560
3. Rohlff C. & Hollis K. Modern Proteomic Strategies in the Studyof Complex Neuro-Psychiatric Disorders, Biol Psychiatry 2003;
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4. http://www.greenelab.columbia.edu/
5. Newschaffer C.J. Fallin D. & Lee N.L. Heritable and Nonheritable Risk Factors for Autism Spectrum Disorders. Epidemiologic Reviews 2002; 24: 137－153.
6. Herbert M.R. Russo J.P. Yang S. Roohi J. Blaxill M. Kahler S.G.
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