- Bliss, Michael (1982) The discovery of insulin. Chicago: University of Chicago Press.
- Güttler F (1984) Phenylketonuria: 50 years since Folling's discovery and still expanding our
clinical and biochemical knowledge. Acta Paediatrica Scandinavica 73:705-716.
- Nanson JL (1992) Autism in fetal alcohol syndrome: a report of six cases. Alcoholism, Clinical
and Experimental Research 16:558-565.
- Harris SR, MacKay LL, Osborn JA (1995) Autistic behaviors in offspring of mothers abusing
alcohol and other drugs: a series of case reports. Alcoholism, Clinical and Experimental
Research 19:660-5.
- Aronson M, Hagberg B, Gillberg C (1997) Attention deficits and autistic spectrum problems in
children exposed to alcohol during gestation: a follow-up study. Developmental Medicine and
Child Neurology 39:583-7.
- Church MW, Eldis F, Blakley BW, Bawle EV (1997) Hearing, language, speech, vestibular, and
dentofacial disorders in fetal alcohol syndrome. Alcoholism, Clinical and Experimental
Research 21:227-237.
- Christianson AL, Chesler N, and Kromberg JGR (1994) Fetal valproate syndrome: clinical
and neuro-developmental features in two sibling pairs. Developmental Medicine and Child
Neurology 36:357-369.
- Williams PG & Hersh JH (1997) A male with fetal valproate syndrome and autism.
Developmental Medicine and Child Neurology 39:632-634.
- Williams G, King J, Cunningham M, Stephan M, Kerr B, Hersh JH. (2001) Fetal valproate
syndrome and autism: additional evidence of an association. Developmental Medicine and
Child Neurology 43:202-206.
- Stromland K, Nordin V, Miller M, Akerstrom B, and Gillberg C (1994) Autism in thalidomide
embryopathy: a population study. Developmental Medicine and Child Neurology 36:351-356.
- Steinhausen H-C, Willms J, and Spohr H-L (1994). Correlates of psychopathology and
intelligence in children with fetal alcohol syndrome. Journal of Child Psychology and
Psychiatry 35:323-331.
- Roebuck TM, Mattson SN, Riley EP (1998) A review of the neuroanatomical findings in children
with fetal alcohol syndrome or prenatal exposure to alcohol. Alcoholism, Clinical and
Experimental Research 22:339-44
- Coleman PD, Romano J, Lapham L, Simon W (1985) Cell counts in cerebral cortex of an
autistic patient. Journal of Autism and Developmental Disorders 15:245-255.
- Rodier PM, Ingram JL, Tisdale B, Nelson S, Romano J (1996) Embryological origin for autism:
developmental anomalies of the cranial nerve motor nuclei. Journal of Comparative Neurology
370:247-261.
- Kemper TL, Bauman M (1998). Neuropathology of infantile autism. Journal of Neuropathology
fcand Experimental Neurology 57:645-652.
5 - Toxic substances and infection
Autism is a brain disorder, and the brain (not genes)
should be the primary focus of research. At least 30
years before nucleic acid base pairs were known or
steps for their transcription to polypeptides
determined, the discovery of insulin saved many lives
and prevented much suffering [1]. Likewise,
discovery of abnormal urinary metabolites in
phenylketonuria led to dietary treatment long before
anyone had the idea to look for mutations in the
genes for peptides assembled into the enzyme that
converts phenylalanine to tyrosine [2]. Autism has
many etiologies, including many genetic disorders,
and it appears there is a particular area or system of
the brain vulnerable to all of these. Vulnerable
regions of the brain are what should be of greatest
interest.
Nanson (1992), Harris et al. (1995), Aronson et al.
(1997), and Church et al. (1997) all reported autism
or autistic behaviors in children with prenatal
exposure to alcohol [3-6]. Christianson et al. (1994),
Williams & Hersh (1997), and Williams et al (2001)
found autistic disorder in children whose mothers
used valproic acid for seizure control during
pregnancy [7-9]. Stromland et al. (1994) found four
cases of autism in a follow-up investigation of 100
people who had been exposed during gestation to the
highly teratogenic drug thalidomide [10].
The neuropathology of disorders like fetal alcohol
syndrome or embryopathy caused by teratogenic
drugs early in gestation can therefore clearly involve
the same brain systems responsible for autism. But
fetal alcohol syndrome is defined in part by specific
cranio-facial abnormalities, and thalidomide causes
deformity of the limbs. Physical deformities of the
limbs or face are not characteristic of the core
syndrome of autism. Thus if the core syndrome of
autism is caused by a prenatal factor, it has to be an
event that occurs beyond the period when
differentiation of limbs and facial features takes place.
On the other hand, investigations such as those of
Steinhausen et al. (1994) and Roebuck et al. (1998)
show that prenatal exposure to alcohol does not
always lead to full-blown fetal alcohol syndrome, and
there may be some children whose autism is the
result of prenatal exposure to alcohol or other drugs
[11, 12]. The mother of the case investigated by
Coleman et al. (1985) and Rodier et al. (1996) was
hospitalized for alcohol and amphetamine addiction
after the birth of her child, but said she could not
remember if she had this problem during pregnancy
[13, 14]. Maternal use of alcohol and drugs should
be determined in every case of autistic disorder,
especially in research studies investigating genetic
factors in families with two or more affected children.
The core syndrome of autism (Kanner autism) is
neither progressive nor the result of chronic exposure
to a toxic substance during gestation. It is more
characteristic of impairment caused by injury or
infection within a limited period, most likely during late
prenatal or early neonatal development. In
examination of the brains of nine individuals with
autism, Kemper and Bauman (1998) found
abnormalities in the brainstem and cerebellum. In
particular, Kemper and Bauman described how
neurons (called climbing fibers) within the inferior
olivary complex of the brainstem influence
development of Purkinje cells in the cerebellum, and
pointed out that disruption of this developmental
sequence would place time of injury around the 30th
week of gestation [15].
Prenatal rubella infection is thought to be most
dangerous during the first three months of
pregnancy, but if the time of infection were later, or
the virus persisted in maternal tissues and passed to
the fetus later in gestation, the climbing fibers from
inferior olive to cerebellum might be the most
prominently affected. It is clear that prenatal rubella
infection and prenatal exposure to alcohol are
associated with some cases of autism; these then are
factors that affect the same brain areas impaired in
autism of unknown cause. There are likely many
other perinatal factors that will be found; among
these, trauma and anoxia at birth deserve to be
investigated as extensively as genetics or exposure to
toxic substances.
- Bliss, Michael (1982) The
discovery of insulin.
- Güttler F (1984)
Phenylketonuria: 50 years
since Folling's discovery and
still expanding our clinical and
biochemical knowledge.
- Nanson JL (1992) Autism in
fetal alcohol syndrome: a
report of six cases.
- Harris SR et al. (1995) Autistic
behaviors in offspring of
mothers abusing alcohol and
other drugs: a series of case
reports.
- Aronson M et al. (1997)
Attention deficits and autistic
spectrum problems in
children exposed to alcohol
during gestation: a follow-up
study.-7.
- Church MW et al. (1997)
Hearing, language, speech,
vestibular, and dentofacial
disorders in fetal alcohol
syndrome.
- Christianson AL et al. (1994)
Fetal valproate syndrome:
clinical and neuro-
developmental features in two
sibling pairs.
- Williams PG, Hersh JH (1997)
A male with fetal valproate
syndrome and autism.
- Williams G et al. (2001) Fetal
valproate syndrome and
autism: additional evidence of
an association.
- Stromland K et al. (1994)
Autism in thalidomide
embryopathy: a population
study.
- Steinhausen H-C et al. (1994).
Correlates of psychopathology
and intelligence in children
with fetal alcohol syndrome.
- Roebuck TM et al. (1998) A
review of the neuroanatomical
findings in children with fetal
alcohol syndrome or prenatal
exposure to alcohol.
- Coleman PD et al. (1985) Cell
counts in cerebral cortex of an
autistic patient.
- Rodier PM et al. (1996)
Embryological origin for
autism: developmental
anomalies of the cranial nerve
motor nuclei.
- Kemper TL, Bauman M
(1998). Neuropathology of
infantile autism.