1 -  Autism's multiple etiologies
Autism has multiple etiologies, predispositions, or
associated medical conditions.  Some of these
conditions are summarized in table 1 and also listed
as headers for references [1-16].  Autism is not the
only outcome of any of these.  All of the associated
disorders must however affect a common vulnerable
brain system under some special circumstance to
result in autism.  The medical conditions associated
with autism include anatomical anomalies as in
tuberous sclerosis or neurofibrotamosis.  Temporal
lobe involvement in tuberous sclerosis is associated
with more cases of autism than tubers in other brain
areas [7b].  How development of the temporal lobes
might be curtailed by other disorders associated with
autism should therefore be considered.

The temporal lobes, like other higher cortical areas
are not fully myelinated or mature until after the third
or fourth postnatal year [17a].  Maturation of the
cerebral cortex depends on integrity of the
subcortical structures that transmit sensory and
autonomic signals to these higher centers of
cognitive processing.  Maturation of the auditory
language circuits in the temporal lobes must be
dependent upon integrity of the brainstem auditory
pathway, which is myelinated and functional by 29
gestational weeks in the human fetus [17b].

More rare genetic causes of autism are being
reported on a regular basis, and the hunt for "autism
genes" is the focus of much current research, but it
seems unlikely to me that a unique genetic flaw (or
predisposition) that underlies all or most cases of
autism will be found.  It is illogical to try to link factors
like prenatal infections or exposure to alcohol and
drugs during gestation to genetic conditions or
predispositions.  It is just as illogical to presume that
genetic predispositions contribute to complications at
birth.  Birth has always been recognized as difficult
and dangerous.  Experiments with monkeys on the
effects of asphyxia at birth were undertaken to try to
better understand the hazards of birth, and to
minimize these hazards.  The monkeys subjected to
asphyxia at birth had no genetic predisposition for
the resulting brain damage.

How the brain is affected by all of the conditions
associated with autism should be the focus of
research.  How infections, alcohol, mercury, lead,
toxic chemicals, and oxygen insufficiency affect the
brain is known and recorded in the medical literature.
 Auditory nuclei in the brainstem have repeatedly
been found vulnerable.  The inferior colliculi are most
severely involved with any factor that leads to a
catastrophic disruption of aerobic metabolism,
whether by a poisonous substance, suffocation,
circulatory arrest, or an especially virulent infection
[18-23].

Unfortunately much of the evidence reported in the
past is ignored by many researchers, because they
tend to limit searches for background information to
the past five, ten, or twenty years.  Important data,
like those on brain damage caused by asphyxia at
birth, are all but lost in the dustbin of forgotten
history; and these experiments can never be
repeated because of restrictions on use of laboratory
animals.

Oxygen insufficiency during childbirth is most
frequently associated with cerebral palsy, although
discussed now much less often in the medical
literature than in legal journals [24].  Myers (1972)
found that prolonged partial hypoxia resulted in
cerebral palsy, whereas resuscitation after a period
of eight minutes or more of total asphyxia damaged
only brainstem structures, most notably the inferior
colliculi [25].  It is proposed here that autism is more
likely the result of brainstem lesions, and in particular
that language development may be disturbed due to
impairment of the brainstem auditory pathway.

The inferior colliculus is at the top of a rank-order of
brainstem nuclei of high metabolic rate [26].  Myers
referred to the brainstem pattern of damage as
affecting a monotonous rank-order of subcortical
nuclei.  He was seeking to produce a primate model
of cerebral palsy, and the brainstem pattern did not
match the expected outcome.  Figure 1, showing the
prominent damage in the inferior colliculi, is from
Myers paper, which does provide an excellent
analysis of metabolic events that lead to brain
damage.

The highly active subcortical centers are more
susceptible to damage during a sudden and total
disruption of oxygen delivery.  Under hypoxic
conditions (partial restriction of oxygen) protective
mechanisms ensure delivery of whatever oxygen is
available first to the brainstem nuclei of high
metabolic rate, at the expense of the cerebral cortex
and other less metabolically active structures.

Autonomic functions like breathing and heartbeat are
controlled from brainstem centers, and these take
priority for survival over higher cognitive function.  
That the auditory system has the highest metabolic
rate in the brain makes it special; this cannot be
denied, and deserves every effort to try to
understand why.

Autism is found among children with disorders like
phenylketonuria (PKU) in which abnormal and toxic
metabolites are produced by faulty enzymes. These
endongenous toxins can damage the blood-brain
barrier, then enter and disrupt metabolism in
neurons, and impairment might be expected to be
most severe in the brainstem nuclei of high metabolic
rate, as happens with asphyxia.

Disorders of mitochondria, where aerobic production
of energy takes place, are also associated with
autism; and all metabolic processes are dependent
upon adenosine tri-phosphate (ATP), the
end-product of aerobic metabolism [16].  The
brainstem nuclei of high metabolic rate might also be
expected to be most severely affected in
mitochondrial disorders.
                Damage in the inferior
colliculi caused by asphyxia at birth
17. Maturation of the brain
  1. Yakovlev PI and Lecours A-R
    (1967) The myelogenetic
    cycles of regional maturation
    of the brain.
  2. Moore JK et al. (1995). Time
    course of axonal myelination
    in the human brainstem
    auditory pathway.

18. Effects of alcohol

19. Infections
  1. Jereb M et al. (2005) Herpes
    simplex virus infection limited
    to the brainstem.
  2. Shotland LI et al. (2003)
    Audiologic manifestations of
    patients with post-treatment
    Lyme disease syndrome.

20. Lead

21. Mercury

22. Toxic substances
  1. Husain K et al. (2003)
    Carboplatin-induced oxidative
    injury in rat inferior colliculus.
  2. Cavanagh JB & Nolan CC
    (1993) The neurotoxicity of
    alpha-chlorohydrin in rats and
    mice: II. Lesion topography
    and factors in selective
    vulnerability in acute energy
    deprivation syndromes.

23. Anoxia
  1. Windle WF (1969) Brain
    damage by asphyxia at birth.
  2. Janzer RC & Friede RL (1980)
    Hypotensive brain stem
    necrosis or cardiac arrest
    encephalopathy?

24. Legal versus medical
literature

25. Cerebral palsy following
prolonged partial hypoxia

26. Brainstem nuclei of
high metabolic rate
References on etiologic factors
associated with autism 1-16
Etiologic Conditons Associated with Autism
Disorders                                                 Citations
Metabolic/Constitutional:
1.   Neurolipidosis

2.  Tuberous Sclerosis



3.  Neurofibromatosis


4.  Phenylketonuria (PKU)


5.  Fragile X Syndrome

6.  Seizure Disorder


7.  Leber's Congenital Amaurosis


8   Adenylosuccinate Lyase Defect



9.  Lactic Acidosis



10. Krebs Cycle Defects

11. Moebius Syndrome



12.  Intestinal Inflammation
Creak (1963), Darby (1976)

Fisher et al (1986), Bolton & Griffiths (1997), Webb et  
al. (1996), Griffiths & Martland (1997), Crino et al.
(1999)

Gaffney et al. (1997a, b, 1988, 1989),  Folstein & Rutter
 (1988), Gillberg & Coleman (1996)

Lowe et al. 1980, Williams et al. 1980, Chen & Hsiao
1989, Miladi et al. 1992, Leuzzi et al. 1995)

Brown et al. (1982), Folstein and Rutter (1988)

Bailey et al. (1998), Chugani et al. (1996),  DaSilva et
al. (1997)

Rogers & Newhart-Larson (1989), Malamud (1959)


Jaeken & Van den Berghe (1984), Jaeken et al. (1988),
Barshop et al (1989), Van den Berghe et al. (1997),
Fon et al. (1995)

Coleman and Blass (1985), Philippart (1986),
Lombard (1998)


Shaw et al. (1995)

Moebius (1888), Gilles (1963), Gillberg & Steffenburg
(1989), Miller et al. (1998)


Wakefield et al. 1998
Prenatal Exposure to Drugs:
1.  Alcohol


2.  Valproic Acid


3.  Thalidomide
Nanson 1992, Harris et al. 1995, Aronson et al. 1997,
Church et al. 1997

Christianson et al. (1994), Williams & Hersh (1997),
Williams et al. (2001)

Stromland et al. (1994)
Infectious Encephalitis:
Desmond et al. (1970),  Chess (1971), Townsend et al.
(1975), Weil et al. (1975), Chess et al. (1978)

DeLong et al. (1981), Gillberg (1986),  Greer et al.
(1989), Gillberg (1991), Ghaziuddin et al. (1992)

Domachowske et al. (1996)

DeLong et al (1981),  Thivierge (1986), Barak et al.
(1999)
1.  Prenatal Rubella


2.  Herpes Simplex


3.  Epstein-Barr Virus

4.  Other Viral Infections
Obstetric Suboptimality:
1.  In Twins

2.  Meconium Aspiration

3. Respiratory depression

4.  Newborn encephalopathy
Folstein & Rutter (1977), Steffenburg et al. (1989)

Matsuishi et al. (1999)

Glasson et al. (2004)

Badawi et al. (2006)
Non-genetic Predispositions for Autism:
1.  Prenatal exposure to alcohol and/or other drugs
  1. Nanson JL (1992) Autism in fetal alcohol syndrome: a report of six cases.
  2. Harris SR et al. (1995) Autistic behaviors in offspring of mothers abusing
    alcohol and other drugs: a series of case reports.
  3. Aronson M et al. (1997) Attention deficits and autistic spectrum problems
    in children exposed to alcohol during gestation: a follow-up study.
  4. Church MW et al. (1997) Hearing, language, speech, vestibular, and
    dentofacial disorders in fetal alcohol syndrome.
  5. Christianson AL et al. (1994) Fetal valproate syndrome: clinical and
    neuro-developmental features in two sibling pairs.
  6. Williams PG & Hersh JH (1997) A male with fetal valproate syndrome and
    autism.
  7. Williams G et al. (2001) Fetal valproate syndrome and autism: additional
    evidence of an association.
  8. Stromland K et al. (1994) Autism in thalidomide embryopathy: a
    population study.

2.  Infectious encephalitis
  1. Desmond MM et al. (1969) Congenital rubella encephalitis. Effects on
    growth and early development.
  2. Chess S (1971) Autism in children with congenital rubella.
  3. Chess S et al. (1978) Behavioral consequences of congenital rubella.
  4. Townsend JJ et al. (1975) Progressive rubella panencephalistis: Late
    onset after congenital rubella.
  5. Weil et al. (1975) Chronic progressive panencephalitis due to rubella
    virus simulating subacute sclerosing panencephalitis.
  6. deLong GR et al. (1981) Acquired reversible autistic syndrome in acute
    encephalopathic illness in children.
  7. Gillberg C (1986) Brief report: onset at age 14 of a typical autistic
    syndrome. A case report of a girl with herpes simplex encephalitis.
  8. Gillberg IC (1991) Autistic syndrome with onset at age 31 years: herpes
    encephalitis as a possible model for childhood autism.
  9. Ghaziuddin M et al. (1992) Brief report: autism and herpes simplex
    encephalitis.
  10. Greer MK et al. (1989) A case study of the cognitive and behavioral
    deficits of temporal lobe damage in herpes simplex encephalitis.
  11. Domachowske JB et al. (1996) Acute manifestations and neurologic
    sequelae of Epstein-Barr virus encephalitis in children.
  12. Thivierge J. (1986) A case of acquired aphasia in a child.
  13. Barak Y et al. (1999) Autistic subjects with comorbid epilepsy: a possible
    association with viral infections.
  14. Sweeten TL et al. (2004) Brief report: autistic disorder in three children
    with cytomegalovirus infection.

3.  Lead poisoning
  1. Cohen DJ et al. (1976) Pica and elevated blood lead level in autistic and
    atypical children.
  2. Accardo P et al. Autism and plumbism. A possible association.
  3. Eppright TD et al. Attention deficit hyperactivity disorder, infantile autism,
    and elevated blood-lead: a possible relationship.

4.  Seizure disorder/ neurologic damage
  1. Chugani HT et al. (1996) Infantile spasms: III. Prognostic implications of
    bitemporal hypometabolism on positron emission tomography.
  2. daSilva EA et al. (1997) Landau-Kleffner syndrome: metabolic
    abnormalities in temporal lobe are a common feature.

5.  Perinatal complications
  1. Lobascher ME et al. (1970) Childhood autism: an investigation of
    aetiological factors in twenty-five cases.
  2. Levy S et al. (1988) A comparison of obstetrical records of autistic and
    nonautistic referrals for psychoeducational evaluations.
  3. Steffenburg S et al. (1989) A twin study of autism in Denmark, Finland,
    Iceland, Norway and Sweden.
  4. Lord C et al. (1991) Pre- and perinatal factors in high-functioning females
    and males with autism.
  5. Ghaziuddin M et al. (1995) Obstetric factors in Asperger syndrome:
    comparison with high-functioning autism.
  6. Bolton PF et al (1997) Obstetric complications in autism: consequences
    or causes of the condition?
  7. Matsuishi T et al (1999) Brief report: incidence of and risk factors for
    autistic disorder in neonatal intensive care unit survivors.
  8. Bodier C et al. (2001) Autisme et pathologies associées. Étude clinique
    de 295 cas de troubles envahissants du developpment [Autism and
    associated pathologies. Clinical study of 295 cases involving
    development disorders].
  9. Juul-Dam N et al (2001) Prenatal, perinatal, and neonatal factors in
    autism, pervasive developmental disorder-not otherwise specified, and
    the general population.
  10. Greenberg DA et al. (2001) Excess of twins among affected sibling pairs
    with autism: implications for the etiology of autism.
  11. Wilkerson DS et al. (2002) Perinatal complications as predictors of
    infantile autism.
  12. Hultman CM et al. (2002) Perinatal risk factors for infantile autism.
  13. Zwaigenbaum L et al (2002) Pregnancy and birth complications in autism
    and liability to the broader autism phenotype.
  14. Glasson EJ et al (2004) Perinatal factors and the development of autism:
    a population study.
  15. Larsson HJ et al. (2005) Risk factors for autism: perinatal factors,
    parental psychiatric history, and socioeconomic status.
  16. Newschaffer CJ & Cole SR (2005) Invited commentary: risk factors for
    autism--perinatal factors, parental psychiatric history, and socioeconomic
    status.
  17. McInnes LA et al. (2005) A genetic study of autism in Costa Rica: multiple
    variables affecting IQ scores observed in a preliminary sample of autistic
    cases. BMC Psychiatry. 2005 Mar 21;5(1):15.
  18. Gillberg C. & Cederlund M. (2005). Asperger syndrome: familial and pre-
    and perinatal factors.
  19. Badawi N et al. (2006) Autism following a history of newborn
    encephalopathy: more than a coincidence?
  20. Maimburg RD, Vaeth M. Perinatal risk factors and infantile autism.

Genetic/Metabolic Predispositions for Autism:
6.  Neurolipidosis
  1. Creak M (1963) Childhood psychosis: A review of 100 cases.
  2. Darby JK (1976) Neuropathologic aspects of psychosis in children.

7.  Tuberous sclerosis
  1. Fisher W et al. (1986) Tuberous sclerosis and autism.
  2. Bolton PF & Griffiths PD (1997) Association of tuberous sclerosis of
    temporal lobes with autism and atypical autism.
  3. Webb DW et al. (1996) Morbidity associated with tuberous sclerosis: a
    population study.
  4. Griffiths PD & Martland TR (1997) Tuberous Sclerosis Complex: the role
    of neuroradiology.
  5. Crino PB & Henske EP (1999) New developments in the neurobiology of
    the tuberous sclerosis complex.
  6. Bolton PF et al. (2002) Neuro-epileptic determinants of autism spectrum
    disorders in tuberous sclerosis complex.

8.  Neurofibromatosis
  1. Gaffney GR et al. (1989) Forebrain structure in infantile autism.
  2. Gaffney GR et al. (1987a) Midsagittal magnetic resonance imaging of
    autism.
  3. Gaffney GR et al. (1987b) Cerebellar structure in autism.
  4. Gillberg C & Coleman M (1996). Autism and medical disorders: a review
    of the literature.

9.  Phenylketonuria (PKU)
  1. Lowe TL et al. (1980). Detection of phenylketonuria in autistic and
    psychotic children.
  2. Williams RS et al. (1980) Autism and mental retardation: Neuropathologic
    studies performed in four retarded persons with autistic behavior.
  3. Chen CH & Hsiao KJ (1989) A Chinese classic phenylketonuria
    manifested as autism.
  4. Miladi N et al. (1992) Phenylketonuria: an underlying etiology of autistic
    syndrome. A case report.
  5. Leuzzi V et al. (1995) Biochemical, clinical and neuroradiological (MRI)
    correlations in late-detected PKU patients.

10. Fragile X syndrome
  1. Brown WT et al. (1982) Autism is associated with the fragile-X syndrome.
  2. Folstein SE & Rutter ML (1988) Autism: familial aggregation and genetic
    implications.

11. Chromosomal disorders
  1. Cohen D et al. (2005) Specific genetic disorders and autism: clinical
    contribution towards their identification.

12. Leber's Congenital Amaurosis
  1. Rogers SJ & Newhart-Larson S (1989) Characteristics of infantile autism
    in five children with Leber's congenital amaurosis.
  2. Malamud N (1959) Heller's disease and childhood schizophrenia.

13. Adenylosuccinate Lyase Defect
  1. Jaeken J & Van den Berghe G. (1984) An infantile autistic syndrome
    characterised by the presence of succinylpurines in body fluids.
  2. Jaeken J et al. (1988) Adenylosuccinase deficiency: an inborn error of
    purine nucleotide synthesis.
  3. Barshop BA et al. (1989) Kinetic studies of mutant human
    adenylosuccinase.
  4. Van den Berghe G et al. (1997) Inborn errors of the purine nucleotide
    cycle: adenylosuccinase deficiency.

14. Lactic Acidosis
  1. Coleman M & Blass JP (1985) Autism and lactic acidosis.
  2. Philippart M (1986) Clinical recognition of Rett syndrome.
  3. Lombard J (1998) Autism: a mitochondrial disorder?

15. Krebs Cycle (aerobic metabolism) Defects
  1. Shaw W, Kassen E, Chaves E (1995) Increased urinary excretion of
    analogs of Krebs cycle metabolites and arabinose in two brothers with
    autistic features.

16. Mitochondrial Disorders
  1. Fillano JJ et al. (2002) Mitochondrial dysfunction in patients with
    hypotonia, epilepsy, autism, and developmental delay: HEADD syndrome.
  2. Graf WD et al. (2000) Autism associated with the mitochondrial DNA
    G8363A transfer RNA(Lys) mutation.
Table 1 - Medical Conditions Associated with Autism
Table 1
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1.   Neurolipidosis
2.  Tuberous Sclerosis
3.  Neurofibromatosis
4.  Phenylketonuria (PKU)
5.  Fragile X Syndrome
6.  Seizure Disorder
7.  Leber's Congenital Amaurosis
8   Adenylosuccinate Lyase Defect
9.  Lactic Acidosis
10. Krebs Cycle Defects
11. Moebius Syndrome
12.  Intestinal Inflammation
Metabolic/Constitutional:
Prenatal Exposure to Drugs:
1.  Alcohol
2.  Valproic Acid
3.  Thalidomide
Infectious Encephalitis:
1.  Prenatal Rubella
2.  Herpes Simplex
3.  Epstein-Barr Virus
4.  Other Viral Infections
Obstetric Suboptimality:
1.  In Twins
2.  Meconium Aspiration
3.  Respiratory depression
4.  Newborn encephalopathy
Medical conditions & autism
References on factors that  affect
the auditory system 17-26
top
(Full references in
alphabetic bibliography)
Full references in alphabetic
bibliography (& later chapters)

Figure 1 -  Damage in the
inferior colliculi of an infant
monkey, caused by a brief
episode of total asphyxia at
birth.  From Myers (1972).
Figure 1:
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