BACKGROUND: Recently, it has been suspected that there is a relationship between therapy with some antibiotics and the onset of autism; but even more curious, some children benefited transiently from a subsequent treatment with a different antibiotic. Here, we speculate how aminoglycoside antibiotics might be associated with autism. PRESENTATION: We hypothesize that aminoglycoside antibiotics could a) trigger the autism syndrome in susceptible infants by causing the stop codon readthrough, i.e., a misreading of the genetic code of a hypothetical critical gene, and/or b) improve autism symptoms by correcting the premature stop codon mutation in a hypothetical polymorphic gene linked to autism. TESTING: Investigate, retrospectively, whether a link exists between aminoglycoside use (which is not extensive in children) and the onset of autism symptoms (hypothesis "a"), or between amino glycoside use and improvement of these symptoms (hypothesis "b"). Whereas a prospective study to test hypothesis "a" is not ethically justifiable, a study could be designed to test hypothesis "b". IMPLICATIONS: It should be stressed that at this stage no direct evidence supports our speculative hypothesis and that its main purpose is to initiate development of new ideas that, eventually, would improve our understanding of the pathobiology of autism

AS Mankin

C Lord

E Maestrini

H Tager-Flusberg

Hari Manev

JF Burke

M Wilschanski

MA Aberg

MT Howard

MX Guan

P Warburton

R Schroeder

Radmila Manev

RH Sandler

RS MacDonald

WD Graf

English

PubMed

Abstract Background Recently, it has been suspected that there is a relationship between therapy with some antibiotics and the onset of autism; but even more curious, some children benefited transiently from a subsequent treatment with a different antibiotic. Here, we speculate how aminoglycoside antibiotics might be associated with autism. Presentation We hypothesize that aminoglycoside antibiotics could a) trigger the autism syndrome in susceptible infants by causing the stop codon readthrough, i.e., a misreading of the genetic code of a hypothetical critical gene, and/or b) improve autism symptoms by correcting the premature stop codon mutation in a hypothetical polymorphic gene linked to autism. Testing Investigate, retrospectively, whether a link exists between aminoglycoside use (which is not extensive in children) and the onset of autism symptoms (hypothesis "a"), or between amino glycoside use and improvement of these symptoms (hypothesis "b"). Whereas a prospective study to test hypothesis "a" is not ethically justifiable, a study could be designed to test hypothesis "b". Implications It should be stressed that at this stage no direct evidence supports our speculative hypothesis and that its main purpose is to initiate development of new ideas that, eventually, would improve our understanding of the pathobiology of autism.</p

Manev Hari

Manev Radmila

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BMC Psychiatry

Aminoglycoside antibiotics and autism: a speculative hypothesis

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BioMed CentralBMC PsychiatryBMC Psychiatry 2001, 1 :5Hypothesis
Aminoglycoside antibiotics and autism: a speculative hypothesis
Radmila Manev  and Hari Manev *
Address: Department of Psychiatry, The Psychiatric Institute, The University of Illinois at Chicago, Chicago, IL 60612, USA
E-mail: Radmila Manev - RManev@psych.uic.edu; Hari Manev* - HManev@psych.uic.edu
*Corresponding author
Abstract
Background: Recently, it has been suspected that there is a relationship between therapy with
some antibiotics and the onset of autism; but even more curious, some children benefited
transiently from a subsequent treatment with a different antibiotic. Here, we speculate how
aminoglycoside antibiotics might be associated with autism.
Presentation: We hypothesize that aminoglycoside antibiotics could a) trigger the autism
syndrome in susceptible infants by causing the stop codon readthrough, i.e., a misreading of the
genetic code of a hypothetical critical gene, and/or b) improve autism symptoms by correcting the
premature stop codon mutation in a hypothetical polymorphic gene linked to autism.
Testing: Investigate, retrospectively, whether a link exists between aminoglycoside use (which is
not extensive in children) and the onset of autism symptoms (hypothesis "a"), or between
aminoglycoside use and improvement of these symptoms (hypothesis "b"). Whereas a prospective
study to test hypothesis "a" is not ethically justifiable, a study could be designed to test hypothesis
"b".
Implications: It should be stressed that at this stage no direct evidence supports our speculative
hypothesis and that its main purpose is to initiate development of new ideas that, eventually, would
improve our understanding of the pathobiology of autism.
Background
Autism is a devastating neurodevelopmental syndrome
characterized by difficulties in social interaction, prag-
matic language, and repetitive behaviors or obsessive in-
terests, which usually begins in infancy and is still largely
untreatable [1,2]. It appears that there may be a genetic
component in the predisposition to autism; there are
probably a few genes that interact and cause the autism
phenotype [3]. Recently, it has been suspected based on
an uncontrolled study that there is a relationship be-
tween therapy with various antibiotics and the onset of
autism; but even more curious, some children benefited
transiently from a subsequent treatment with a different
antibiotic, vancomycin [4]. Thus, a link between antimi-
crobial use and the onset of autistic symptoms was first
noticed by parents of children with regressive-onset au-
tism. An attempt to help these children by treatment
with vancomycin was based on the following hypothesis:
the first antimicrobial treatment led to the colonization
of the intestines by a neurotoxin-producing microbial
species that was responsible for triggering autism;
hence, improvement could be expected by treating this
Published: 10 October 2001
BMC Psychiatry 2001, 1:5
Received: 16 August 2001
Accepted: 10 October 2001
This article is available from: http://www.biomedcentral.com/1471-244X/1/5
© 2001 Manev and Manev; licensee BioMed Central Ltd. Verbatim copying and redistribution of this article are permitted in any medium for any non-
commercial purpose, provided this notice is preserved along with the article's original URL. For commercial use, contact info@biomedcentral.com
BMC Psychiatry 2001, 1:5 http://www.biomedcentral.com/1471-244X/1/5intestinal infection with vancomycin. Inspired by these
findings, we propose a speculative hypothesis on how an-
tibiotics might be associated with autism.
Presentation of the hypothesis
Modulation of RNA function by antibiotics
As important as the genetic code itself is the decoding
that takes place at ribosomes via translation of mRNA
into proteins. Antibiotics may significantly interfere with
this process [5]. Particularly important is the ability of
aminoglycosides (e.g., gentamicin) to suppress prema-
ture stop mutations in mammalian mRNA and to restore
physiological amounts of protein that otherwise could
not be translated and synthesized. This action of antibi-
otics such as gentamicin can be used for therapeutic pur-
poses in genetic diseases that arise from point mutations
which introduce premature stop codons (UAA, UAG,
UGA) into coding sequences [6,7]. For example,
aminoglycoside antibiotics are currently being consid-
ered for treatment of Duchenne's muscular dystrophy
patients who carry a nonsense mutation in the dys-
trophin gene [8] as well as for the treatment of cystic fi-
brosis (CF) patients [9]. In CF patients, mutations in the
cystic fibrosis transmembrane conductance regulator
(CFTR) gene, containing a premature stop codon, are re-
sponsible for decreased production of CFTR chloride
channels. In vitro, aminoglycoside antibiotics were
shown to be capable of restoring the appearance of func-
tional CFTR channels in mutant cells, and in a pilot study
with nine patients carrying stop mutations, local gen-
tamicin application produced improvement in a physio-
logic parameter measured in nasal epithelia [9].
Interestingly, recent studies of autism patients con-
firmed previous evidence that linked autism to a region
of chromosome 7q near the CFTR gene [10].
We now hypothesize that antibiotics could a) trigger the
autism syndrome in susceptible infants by causing the
stop codon readthrough, i.e., a misreading of the genetic
code of a hypothetical vulnerable gene, and/or b) im-
prove autism symptoms by correcting the premature
stop codon mutation in a hypothetical polymorphic gene
linked to autism.
These speculative hypotheses are inspired by the obser-
vations by Sandler et al. [4] who linked the onset of au-
tism symptoms to previous antimicrobial therapy and
the improvement of these symptoms to treatment with
vancomycin. These authors did not specify whether
aminoglycosides were used in children prior to onset of
autism in their study; they primarily focused on antimi-
crobial therapy-induced diarrhea which they thought
might relate causally to the onset of autism symptoms.
Thus, our hypothesis that aminoglycoside antibiotics
may precipitate autism in genetically susceptible indi-
viduals would be supported if a link could be established
between amynoglicosides and the onset of autism symp-
toms, or if it could be found in a post-hoc analysis of ex-
isting clinical data from a larger pool of autism patients.
Genetic susceptibility is a known factor in the occurrence
of side effects of aminoglycosides, which produce lasting,
sometimes permanent alterations despite even a tran-
sient use. For example, inherited susceptibility to
aminoglycoside ototoxicity is based on a mutation in mi-
tochondrial DNA (i.e., 12S rRNA) [11]. It is possible that
similar aminoglycoside-sensitive mitochondrial muta-
tions could be involved in autism as well; namely, an au-
tistic phenotype was recently observed in a child from a
family with the mitochondrial DNA G8363A transfer
RNA mutation [12].
Paradoxically, our hypothesis postulates that in some
cases, i.e., premature stop codon mutation in a hypothet-
ical autism-linked gene, antibiotics might be helpful in
treating autism symptoms. Sandler et al. [4] found a
transient improvement of autism symptoms in children
treated with vancomycin. Since vancomycin is poorly ab-
sorbed (and it is not an aminoglycoside), these authors
concluded that it must have produced a local effect (i.e.,
on the intestinal flora) and they proposed the existence
of a "gut-brain" connection in autism. We hypothesize
that aminoglycoside antibiotics might be helpful because
they would correct a premature stop codon mutation in a
hypothetical autism-linked gene product. This effect
could not only be achieved in the central nervous system
(CNS), i.e., for a CNS-specific RNA, but also in the pe-
riphery. For example, insulin-like growth factor (IGF-1),
a growth-promoting peptide hormone that has neuro-
trophic properties in the CNS and is synthesized in the
periphery including the intestine [13], has been shown to
cross the blood-brain barrier; when injected systemically
IGF-1 increases the proliferation and survival of neurons
in the CNS of adult rats [14]. Thus, if a similar peripher-
ally-synthesized protein plays a role in autism when mu-
tated, the premature stop codon mutation in the RNA
that is responsible for its synthesis might be susceptible
to correction by local (e.g., enteric) administration of an
effective antibiotic.
Testing the hypothesis
Relatively simple but rather extensive studies would be
required to investigate whether a link exists between
aminoglycoside use (which is not extensive in children)
and the onset of autism symptoms (hypothesis "a"), or
between aminoglycoside use and improvement of these
symptoms (hypothesis "b"). Even if a positive correlation
were found, this would be a first step, not definitive proof
of our concept. Whereas a prospective study to test hy-
pothesis "a" (e.g., investigate the effect of aminoglyco-
sides in children at risk for autism) is not ethically
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justifiable, a study could be designed to test hypothesis
"b", i.e., whether aminoglycosides could ameliorate the
clinically symptomatic disease.
Implications of the hypothesis
If a link between aminoglycoside antibiotic use and au-
tism could be clearly established, either positive or nega-
tive, further studies could be designed to elucidate the
mechanisms involved, including genetic analyses. It
should be stressed, however, that at this stage no direct
evidence supports our speculative hypothesis and that its
main purpose is to initiate development of new ideas
that, eventually, would improve our understanding of
the pathobiology of autism.
List of abbreviations
CF, cystic fibrosis
CFTR, cystic fibrosis transmembrane conductance regu-
lator
CNS, central nervous system
IGF, insulin-like growth factor
mRNA, messenger RNA
Competing interests
None declared
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A: Identifying autism susceptibility genes. Neuron

Amaral DG: Autism spectrum disorders. Neuron

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Attardi G: A biochemical basis for the inherited susceptibility to aminoglycoside ototoxicity. Hum Mol Genet

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Folstein S: Current directions in research on autism. Ment Retard Dev Disabil Res Rev

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HM: Short-term benefit from oral vancomycin treatment of regressive-onset autism.

Kerem E: A pilot study of the effect of gentamicin on nasal potential difference measurements in cystic fibrosis patients carrying stop mutations. Am J Respir Crit Care Med

Liebman SW: Baby, don't stop! Nat Genet

Modulation of RNA function by aminoglycoside antibiotics.

Mogg AE: Suppression of a nonsense mutation in mammalian cells in vivo by the aminoglycoside antibiotics G418 and paromomycin. Nucleic Acids Res

The role of insulin-like growth factors in small intestinal cell growth and development. Horm Metab Res

Z: Support for linkage of autism and specific language impairment to 7q3 from two chromosome rearrangements involving band 7q31.

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