energytxt

Lombard J (1998) Autism: a mitochondrial disorder? Autism: a mitochondrial disorder? Med
Hypotheses. 1998 Jun;50(6):497-500.
Coleman M (2005) Advances in autism research. Dev Med Child Neurol. 2005 Mar;47(3):148.
Oliveira G, Diogo L, Grazina M, Garcia P, Ataide A, Marques C, Miguel T, Borges L, Vicente AM,
Oliveira CR. (2005) Mitochondrial dysfunction in autism spectrum disorders: a population-
based study. Dev Med Child Neurol. 2005 Mar;47(3):185-9.
Heilstedt HA, Shahbazian MD, Lee B. (2002) Infantile hypotonia as a presentation of rett
syndrome. American Journal of Medical Genetics 111:238-242.
Mak SC, Chi CS, Chen CH, Shian WJ. (1993) Abnormal mitochondria in Rett syndrome: one
case report. Chung Hua I Hsueh Tsa Chih (Taipei). 52:116-9.
Eeg-Olofsson O, al-Zuhair AG, Teebi AS, al-Essa MM (1989) Rett syndrome: genetic clues
based on mitochondrial changes in muscle. American Journal of Medical Genetics 32:142-
144.
Philippart M (1986) Clinical recognition of Rett syndrome. Am J Med Genet Suppl. 1986;1:111-
8.
Chugani DC, Sundram BS, Behen M, Lee ML, Moore GJ (1999) Evidence of altered energy
metabolism in autistic children. Progress In Neuro-Psychopharmacology and Biological
Psychiatry 23:635-9.
Wallace DC (1999) Mitochondrial diseases in man and mouse. Science 283:1482-1488.
Warner TT, Schapira AH (1997) Genetic counselling in mitochondrial diseases. Current
Opinion in Neurology 10:408-412.
Reijnders L (1975) The origin of mitochondria. Journal of Molecular Evolution 5:167-76.
Gray MW (1989) The evolutionary origins of organelles. Trends In Genetics 5:294-9
Gray MW, Burger G, Lang BF. (1999) Mitochondrial evolution. Science (Mar 5, 5407) 283:1476-
1481.
DeJong R (1944) Methyl bromide poisoning. Journal of the American Medical Association 125:
702.
Cavanagh JB (1992) Methyl bromide intoxication and acute energy deprivation syndromes.
Neuropathology and Applied Neurobiology 18:575-578.
Tipton KF, Singer TP. (1993) Advances in our understanding of the mechanisms of the
neurotoxicity of MPTP and related compounds. Journal of Neurochemistry 61:1191-1206.
Schapira AH (1998) Inborn and induced defects of mitochondria. Arch Neurol 55:1293-1296.
Prezant TR, Agapian JV, Bohlman MC, Bu X, Oztas S, Qiu WQ, Arnos KS, Cortopassi GA, Jaber
L, Rotter JI, et al (1993) Mitochondrial ribosomal RNA mutation associated with both antibiotic-
induced and non-syndromic deafness. Nature Genetics 4:289-294.
Pandya A, Xia X, Radnaabazar J, Batsuuri J, Dangaansuren B, Fischel-Ghodsian N, Nance WE
(1997) Mutation in the mitochondrial 12S rRNA gene in two families from Mongolia with
matrilineal aminoglycoside ototoxicity. J Med Genet 1997 Feb;34(2):169-72
Cavanagh JB, Harding BN (1994) Pathogenic factors underlying the lesions in Leigh's
disease. Tissue responses to cellular energy deprivation and their clinico-pathological
consequences. Brain 117(Pt 6):1357-1376.
Nishino I, Spinazzola A, Hirano M (1999) Thymidine phosphorylase gene mutations in MNGIE,
a human mitochondrial disorder. Science 283(5402 Jan 29):689-692.
Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M, Berelowitz M, Dhillon AP,
Thomson MA, Harvey P, Valentine A, Davies SE, Walker-Smith JA (1998) Ileal-lymphoid-
nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children.
Lancet Feb 28;351(9103):637-41
Graf WD, Marin-Garcia J, Gao HG, Pizzo S, Naviaux RK, Markusic D, Barshop BA, Courchesne
E, Haas RH (2000) Autism associated with the mitochondrial DNA G8363A transfer RNA(Lys)
mutation. Journal of Child Neurology 15:357-361.
Fillano JJ, Goldenthal MJ, Rhodes CH, Marin-Garcia J (2002) Mitochondrial dysfunction in
patients with hypotonia, epilepsy, autism, and developmental delay: HEADD syndrome.
Journal of Child Neurology17:435-439.
Goodman W (1992) TV weekend, New York Times, March 13.
Spiker D, Lotspeich L, Hallmayer J, Kraemer HC, Ciaranello RD.Failure to find cytogenetic
abnormalities in autistic children whose parents grew up near plastics manufacturing sites. J
Autism Dev Disord. 1993 Dec;23(4):681-2.
Jensen RA. (1994) Autism and the chemical connection. J Autism Dev Disord. 1994 Dec;24(6):
785-7.
Maassen JA, Kadowaki T (1996) Maternally inherited diabetes and deafness: a new diabetes
subtype. Diabetologia 39:375-382.
Dumas P, Gueldry D, Loireau A, Chomard P, Buthieau AM, Autissier N (1985) [Effects of lead
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la Societe de biologie et de ses filiales 179:175-83.

4 - The brain and energy metabolism
Disorders like Rett syndrome and phenylketonuria are
progressive disintegrative disorders. If the core
syndrome of autism is a genetic disorder, it is not of
this type. Lombard (1998) suggested that autism
might be the result of a mitochondrial disorder [1].
This idea caught on quickly within the next few years,
with several cases uncovered [2,3]. Mitochondrial
disorders are worth further investigation, with
consideration of the brain areas most likely to be
involved. Compromise of aerobic activity should be
expected in the inferior colliculi and other nuclei in the
brainstem auditory pathway, with subsequent
disruption of maturation of the language receptive
areas of the temporal lobes. Much evidence indicates
that some cases of Rett syndrome may include
disorders of mitochondrial function [4-7].

As discussed extensively in this book, the auditory
system has metabolic demands higher than in any
other area of the brain. Intact functioning of aerobic
metabolic mechanisms is thus especially important for
neurons of the auditory system, and aerobic
metabolism is accomplished in all cells by enzyme
complexes within mitochondria.

Energy in the form of adenosine tri-phosphate (ATP)
is produced within the mitochondria, and all other
cellular functions depend upon a steady supply of
ATP. Mitochondrial enzymes convert glucose to
carbon dioxide, which is exchanged for oxygen as the
final step in the chain of reactions that generate ATP
and recycle intermediate cofactors. Chugani et al.
(1999) provided evidence from positron emission
tomography (PET) data that a disorder of energy
metabolism may be the cause of some forms of
autistic disorder [8].

Mitochondria contain 37 genes in a double-stranded
circular DNA inherited only from the mother.
Mitochondria are duplicated from the maternal egg
because sperm cells do not contain mitochondria.
The mitochondrial genes encode 13 polypeptides, 22
transfer-RNA molecules, and two RNA sequences that
make up ribosomes where peptides are assembled.
These peptides become components of the enzymes
that catalyze oxidative metabolism [9, 10].

Mitochondrial DNA is similar to that of primitive
bacteria that do not have nuclei. Mitochondria may
have evolved from infections that were of symbiotic
benefit to host cells 11, 12], although this hypothesis
is still under investigation and subject to refinement
by future research [13]. However, mitrochondrial DNA
is especially susceptible to mutagenic agents,
including antibiotic drugs. Protective histones and
enzymes that repair chromosomal DNA evolved later
in cells with nuclei. Genes within chromosomes of cell
nuclei encode additional RNA and peptide sub-units
for the mitochondrial enzyme system. Chromosomal
genes are derived from both parents, and are far less
vulnerable to mutations.

Toxic chemicals used as herbicides and pesticides
have long been known to cause neurodegenerative
disorders; DeJong (1944) reported on the
neurotoxicity of methyl bromide, which is now known
to produce a brainstem pattern of damage similar to
that caused by asphyxia [14, 15]. Tipton & Singer
(1993) and Schapira (1998) discussed other chemical
substances that have been found to be mutagenic to
mitochondrial DNA and are known to cause symptoms
similar to those of Parkinsonism and Huntington’s
chorea [16, 17]. Antibiotic medications can damage
mitochondria because of their similarity to bacterial
organisms that cause illnesses treated with these
drugs; the kidneys and auditory system are most
susceptible. Matrilineal transmission of deafness
induced by widespread use of streptomycin has been
reported [18, 19].

Inherited mitochondrial disorders lead to defects of
energy metabolism in all tissues of the body, and
often result in early death as discussed by Cavanagh
& Harding (1994) in Leigh's syndrome [20]. But
perhaps some cases of autism are caused by milder
or intermittent disorders of energy metabolism.
Nishino et al (1999) described the biochemical lesion
in mitochondrial neurogastrointestinal
encephalomyopathy (MNGIE), a disorder usually
detected between the second and fifth decades, with
oculomotor deficits and gastrointestinal dysmotility
[21]. Earlier onset of this and similar disorders should
be investigated as possible etiological factors in some
cases of autism, as gastrointestinal abnormalities
have been brought up as a possible cause of autism
in some children [22].

Graf et al. (2000) observed autism in one child from a
family with a specific mutation of mitochondrial DNA
[23]. Filiano et al. (2002) reported diverse
mitochondrial defects in children who display a
syndrome that includes muscular weakness
(hypotonia), developmental delay, epilepsy, and
autistic behaviors [24]. It can probably be predicted
that other mitochondrial disorders will be found
responsible for autism in some children.

In 1992 reports appeared in the news of a larger than
average percentage of autistic children born to
parents who grew up in the vicinity of a factory in
Leominster Massachusetts [25-27]. Parents
questioned whether improperly disposed toxic wastes
might have caused genetic damage later passed on
to their children. Inheritance of mitochondrial DNA
from mothers exposed to toxic substances should be
looked into. The effects on mothers of smoking,
alcohol and drug use, and antibiotic medications
would also have to be taken into consideration.
Incidence of other disorders known to be caused by
mitochondrial DNA damage would have to be looked
for as well, including diabetes (as discussed by
Maassen & Kadowaki 1996) and other
neurodegenerative disorders such as Parkinson’s
disease and Huntington’s chorea [28-29].

Mitochondrial mutations represent one way that
aerobic metabolism can be disrupted and lead to
impairment within the brain. Mitochondrial damage is
one way that chronic exposure to toxic substances
might lead to diminished energy and autism in
families. For example, Dumas et al. (1985) found that
lead poisoning affects mitochondria in the brains of
laboratory rats [26].

Lombard J (1998) Autism: a
mitochondrial disorder?
Coleman M (2005) Advances
in autism research.
Oliveira G et al. (2005)
Mitochondrial dysfunction in
autism spectrum disorders:
a population-based study.
Heilstedt HA et al. (2002)
Infantile hypotonia as a
presentation of rett syndrome.
Mak SC et al. (1993)
Abnormal mitochondria in
Rett syndrome: one case
report.
Eeg-Olofsson O et al. (1989)
Rett syndrome: genetic clues
based on mitochondrial
changes in muscle.
Philippart M (1986) Clinical
recognition of Rett syndrome.
Chugani DC et al. (1999)
Evidence of altered energy
metabolism in autistic
children.
Wallace DC (1999)
Mitochondrial diseases in
man and mouse.
Warner TT, Schapira AH
(1997) Genetic counselling in
mitochondrial diseases.
Reijnders L (1975) The origin
of mitochondria.
Gray MW (1989) The
evolutionary origins of
organelles.
Gray MW et al. (1999)
Mitochondrial evolution.
DeJong R (1944) Methyl
bromide poisoning.
Cavanagh JB (1992) Methyl
bromide intoxication and
acute energy deprivation
syndromes.
Tipton KF, Singer TP. (1993)
Advances in our
understanding of the
mechanisms of the
neurotoxicity of MPTP and
related compounds.
Schapira AH (1998) Inborn
and induced defects of
mitochondria.
Prezant TR et al. (1993)
Mitochondrial ribosomal RNA
mutation associated with
both antibiotic-induced and
non-syndromic deafness.
Pandya A et al. (1997)
Mutation in the mitochondrial
12S rRNA gene in two
families from Mongolia with
matrilineal aminoglycoside
ototoxicity.
Cavanagh JB, Harding BN
(1994) Pathogenic factors
underlying the lesions in
Leigh's disease. Tissue
responses to cellular energy
deprivation and their clinico-
pathological consequences.
Nishino I et al. (1999)
Thymidine phosphorylase
gene mutations in MNGIE, a
human mitochondrial
disorder.
Wakefield AJ et al. (1998)
Ileal-lymphoid-nodular
hyperplasia, non-specific
colitis, and pervasive
developmental disorder in
children.
Graf WD et al. (2000) Autism
associated with the
mitochondrial DNA G8363A
transfer RNA(Lys) mutation.
Fillano JJ et al. (2002)
Mitochondrial dysfunction in
patients with hypotonia,
epilepsy, autism, and
developmental delay: HEADD
syndrome.
Goodman W (1992) TV
weekend.
Spiker D, Lotspeich L,
Hallmayer J, Kraemer HC,
Ciaranello RD.Failure to find
cytogenetic abnormalities in
autistic children whose
parents grew up near
plastics manufacturing sites.
J Autism Dev Disord. 1993
Dec;23(4):681-2.
Jensen RA. (1994) Autism
and the chemical connection.
J Autism Dev Disord. 1994
Dec;24(6):785-7.
Maassen JA, Kadowaki T
(1996) Maternally inherited
diabetes and deafness: a
new diabetes subtype.
Dumas P et al. (1985)
[Effects of lead poisoning on
properties of brain
mitochondria in young rats]

Tonight's edition of "20/20" contains intriguing evidence of a connection between
environmental pollution and autism. "The Street Where They Lived," a report by Dr.
Timothy Johnson, the ABC News medical editor, focuses on a number of children who
suffer from some form of pervasive developmental disorder, a combination of social,
behavioral and language problems, of which autism is the best known. What links the
children is the town of Leominster, Mass., where their mothers or fathers grew up in
the 1960's.

Leominster was then home to several plastics companies that polluted air, water and
land. Suspicion centers especially on the 27 smokestacks of Foster Grant, makers of
sunglasses; they spewed a derivative of vinyl chloride, which is known to cause cancer
and other illnesses. The relationship to autism is not proved, but, as Dr. Johnson
notes, the figures are startling: a neighborhood of about 600 homes around the Foster
Grant plant have produced 42 cases of pervasive developmental disorder. That
compares with a national figure of 15 children in 10,000 who show symptoms of the
disease.

Experts remain unconvinced, but this brief report ends with a hope that the painful
story of Leominster may hold a clue to the cruel riddle of autism.