Individuals with autism or Asperger syndrome come with many problems. They are diagnosed because of their poor social relations, including all forms of human communication.
26 Formation continue / For tbildung Vol. 14 No. 6 2003
Individuals with autism or Asperger syn-
drome come with many problems. They are
diagnosed because of their poor social re-
lations, including all forms of human com-
munication. They also have restricted inte-
rests and inappropriate, rigid patterns of
behavior. They may have abnormal respon-
ses to sensor y stimuli. In the case of au-
tism, these children have major language
abnormalities, including muteness or se-
vere delays obvious by three years of age.
The majority of children called autistic are
classified as retarded when they reach
school age, although this is not always
accurate. Individuals with Asperger syn-
drome are less obvious as young children
because their language usually is not de-
layed, but contains odd characteristics
such as being ver y formal with a peculiar
voice; they usually are not classified as re-
tarded. Both children with autism and
Asperger syndrome may be savants. Most
of the subgroups within the autism/Asper-
ger syndrome are predominantly male.
The autistic/Asperger children may have
many associated problems. A dif ficult one
is food faddism, such as food refusal, food
fads and pica. Unusual sleep patterns
haunt their parents. The children can be
aggressive toward others or continually in-
jure themselves.
However in spite of the suf fering of these
children and their families, a cer tain ha-
phazardness can be obser ved in the ap-
proach to medical therapies for individuals
with such serious brain problems. This is
due to the fact that if ever there was a field
of medicine that was in a state of major
confusion and contradictions, it is autism/Asperger today. This has happened in
spite of a generation of careful standardi-
zation of criteria. The results from major
centers with reputations for excellence of-
ten contradict each other regarding which
areas of neuroanatomy are af fected as de-
duced from brain imaging, what kind of pa-
thology underlies this symptom complex
and exactly what is the electrophysiology.
The accepted pattern of publication in me-
dicine of a first study being confirmed by
a second one does happen, but is still un-
usual. There is even a dispute regarding
whether the patients should receive a me-
dical work-up in the first place in order to
establish a rational approach to treatment.
Badly needed are some guidelines for clini-
cians, researchers and parents – a frame-
work inside which to reorder the older in-
formation and place new studies. This pa-
per attempts to address this problem and
proposes one such framework.
Norman Geschwind, a brilliant behavioral
neurologist of the twentieth centur y, intro-
duced the concept of the cerebral discon-
nection syndromes as central to the clas-
sic syndromes of behavioral neurology
1).
For example, the signature syndromes of
the brain, such a Wernicke’s aphasia or
Broca’s aphasia, were originally based on
repor ts of the ef fect of lesions in a loca-
lized brain area. But it is unlikely that
neuropsychiatric disorders are limited to a
single anatomical location; they reflect the
dysfunction of one or more neural circuits
which pass through several dif ferent areas
of the brain
2). Research studies document
that the complex behavioral domains are
coordinated by large-scale distributed net-
works and damage to any network compo-nent can impair behavior in the relevant do-
main
3). Focal brain lesions that inter fere
with these processing streams lead to Ge-
schwind’s disconnection syndromes, such
as apraxia, prosopagnosia, color anomia,
amnesia etc.
Regarding the behavioral symptoms of au-
tism, there is evidence of inter ference of
the behavior domain circuits all the way
from the prefrontal cor tex down to the ce-
rebellum. It appears that the pathways can
be interrupted at a number of dif ferent
anatomical levels or at a variety of synaptic
sites. But autism is more than a discon-
nection of functional existing pathways.
Based on evidence from functional MRI
and other imaging studies
4) 5) 6) , abnormal
neural pathways may have been formed
during prenatal neurodevelopment in
many children with autistic symptoms. The
information about behavioral circuits has
been gathered from the many dif ferent di-
seases that have autistic symptoms in
their spectrum (Table 1, Table 2, Table 3,
Table 4).
Some of these studies closely match chan-
ges in the neural circuits as described in
the cerebellar cognitive af fective syndro-
me, which is based on a study of diseases
confined to the cerebellum.
7)The major pa-
thological studies in autism which included
the Purkinje cells of cerebellum actually do
replicate each other showing a decreased
density of these cells in most cases
8) 9) 10)
– in an exception to the rule of failed rep-
lication of autism studies. One such neu-
ral circuit is the dentato-thalamo-cor tical
pathway which has been found impaired in
a number of studies in autism
11). It is pos-
A framework for autism
27 Formation continue / For tbildung Vol. 14 No. 6 2003
sible that this pathway will stand the test
of time as one of the circuits that is dys-
functional in some individuals with autistic
symptoms.
The process of cor tical ontogeny in the hu-
man is complex with each of the events of
brain development having its own critical
period, a time period before or after bir th
during which a par ticular set of enabling
factors is essential for normal cor tical de-
velopment. Take the example of the neuro-
trophins, a categor y of related growth-pro-
moting substances that are essential for
normal cor tical development and plasti-
city by being a factor in the regulation of
synaptogenesis and synaptic transmis-
sion
12). In a study of archived neonatal
blood of children who later were diagnosed
as autistic, Nelson and colleagues foundver y elevated levels of cer tain neurotro-
phins and also cer tain neuropeptides –
BDNF, NT4/5, VIP and CGRP – in 99% of
the children with autism compared to con-
trols
13). The Rett syndrome gene MECP2
has been shown to regulate expression of
BDNF and maternal infections also af fect
BDNF expression in the fetus
14). The study
by Nelson and colleagues was found si-
milar elevations of the neurotrophins and
neuropeptides in 97% of the children with
later mental retardation, including those
with Down syndrome. It is great interest
that no measure distinguished the children
with autism from those with mental retar-
dation. This study could be construed as
additional evidence that the autistic syn-
drome, like the mental retardation syn-
dromes, begins prior to bir th in the over-
whelming number of cases.In fact the autistic syndrome shares many
of the characteristics of the mental retarda-
tion syndrome. They both impair the brain
in almost all cases during the gestational
neurodevelopmental time frame and they
are both present at bir th but not clinically
apparent. Although both syndromes have
•Chromosome 15q11–13 syndrome
•Infantile autistic bipolar disorder
(IABD)
•Miles-Hillman subgroup
of nonstigmatized phenotypes
•Majority «still undiagnosed»
• Transient until improved:
Zappella dysmaturational
syndrome with familial complex tics
• Transient until further deterioration:
The Rett Complex• Toxic fetal encephalopathies:– alcohol, cocaine, lead, thalidomide, valproate
• Perinatal toxicity:– ROP (retinopathy of prematurity)
• Infectious fetal encephalopathies:– rubella, herpes simplex
• Space-occupying lesions:– cysts, brain tumors
• Genetic and MAS/MR disease entities:
– Angelman syndrome – Leber congential amaurosis
– Anorexia nervosa – Lujan-Fryan syndrome
– CATCH 22 – Moebius sequence
– Charge Association – Neurofibromatosis 1
– Cohen syndrome – Neuroaxonal dystrophy
– Cole-Hughes macrocephaly syndrome – Noonan syndrome
– Cowden syndrome – Smith-Magenis syndrome
– DeLange syndrome – Sotos syndrome
– Down syndrome – Steinert’s myotonic dystrophy
– Ehlers-Danlos syndrome – Tourette syndrome
– Fragile X syndrome – Tuberous sclerosis complex
– Goldenhar syndrome – Turner syndrome
– Hypomelanosis of Ito – Williams syndrome
– Joubert syndrome
Table One: The majority
of patients have core autistic
symptoms long term
Table Two:The majority
of patients have transient
symptoms of autism
Table Three:The minority of patients have autistic symptoms
Table Four:Metabolic
disorders which sometimes
have autistic symptoms
– Adenylosuccinate lyase deficiency
– Cytosolic 5’ nucleotidase
abnormality
– Metachromatic leukodystrophy
– Mucopolysaccharidosis
– Peroxisomal disorders
– Phenylketonuria
– Pyridoxine-dependency syndrome
– Succinic semialdehyde
dehydrogenase deficiency
28 Formation continue / For tbildung Vol. 14 No. 6 2003
a percentage of children who develop epi-
lepsy, the autistic syndrome actually has
a higher prevalence of children with seizure
disorders than a population with severe
mental retardation
15). Low-functioning child-
ren with autism do not have the same neu-
ropsychological profile as youngsters clas-
sified as retarded; never theless, IQ is the
single best predictor of outcome in both
16).
It is not unreasonable to suppose that, like
mental retardation, the autistic syndrome
probably is another syndrome of many dif-
ferent underlying disease entities. If autism
is such a diverse syndrome, then each me-
dical center working with autistic patients
is likely to be studying a dif ferent mix of un-
derlying disease entities; this would ac-
count for the failure of these centers to re-
plicate each others work.
Thus, in summar y as a working frame-
work, autism/Asperger might be consi-
dered a syndrome of many disease enti-
ties whose behavioral symptoms occur due
to malfunction of the distributed beha-
vioral neural networks. This malfunction is
due to aberrant prenatal neurodevelop-
ment, leading either to 1) abnormally for-
med neural circuits or to 2) dysfunction of
network components of standard neural
pathways.
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Mar y Coleman, New York
mar ycolemanmd@yahoo.com
Informations complémentaires
Auteurs
Mary Coleman , New York
