Aminoglycoside antibiotics and autism: a speculative hypothesis: 2001

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Some of the few unvaccinated children I know, have antibiotics in their

history while in utero or after delivery by breastmilk or given to them

directly

Sheri

http://en.wikipedia.org/wiki/Aminoglycoside

Aminoglycosides are a group of antibiotics that are effective against

certain types of bacteria. They include amikacin, gentamicin, kanamycin,

neomycin, netilmicin, paromomycin, streptomycin, tobramycin and apramycin.

Aminoglycosides that are derived from Streptomyces genus are named with the

suffix -mycin, while those which are derived from Micromonospora are named

with the suffix -micin. This nomenclature system is not specific for

aminoglycosides, as vancomycin is a glycopeptide antibiotic and

erythromycin, clarithromycin, azithromycin are macrolides - all of which

differ in their mechanism of actions. Note that the suffixes '-micin' and

'-mycin' do not contain the letter 'a' and should be pronounced " my-sin "

not " my-ah-sin " as is commonly heard.

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Hypothesis

Aminoglycoside antibiotics and autism: a speculative hypothesis

Radmila Manev email and Hari Manev email

Department of Psychiatry, The Psychiatric Institute, The University of

Illinois at Chicago, Chicago, IL 60612, USA

author email corresponding author email

BMC Psychiatry 2001, 1:5doi:10.1186/1471-244X-1-5

The electronic version of this article is the complete one and can be found

online at: http://www.biomedcentral.com/1471-244X/1/5

Received: 16 August 2001

Accepted: 10 October 2001

Published: 10 October 2001

© 2001 Manev and Manev; licensee BioMed Central Ltd. This is an Open Access

article: verbatim copying and redistribution of this article are permitted

in all media for any purpose, provided this notice is preserved along with

the article's original URL.

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 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.

Background

Autism is a devastating neurodevelopmental syndrome characterized by

difficulties in social interaction, pragmatic language, and repetitive

behaviors or obsessive interests, 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

between 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

antimicrobial use and the onset of autistic symptoms was first noticed by

parents of children with regressive-onset autism. 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 intestinal infection with vancomycin. Inspired by these

findings, we propose a speculative hypothesis on how antibiotics 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 premature

stop mutations in mammalian mRNA and to restore physiological amounts of

protein that otherwise could not be translated and synthesized. This action

of antibiotics such as gentamicin can be used for therapeutic purposes 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 considered for treatment of

Duchenne's muscular dystrophy patients who carry a nonsense mutation in the

dystrophin gene [8] as well as for the treatment of cystic fibrosis (CF)

patients [9]. In CF patients, mutations in the cystic fibrosis

transmembrane conductance regulator (CFTR) gene, containing a premature

stop codon, are responsible for decreased production of CFTR chloride

channels. In vitro, aminoglycoside antibiotics were shown to be capable of

restoring the appearance of functional CFTR channels in mutant cells, and

in a pilot study with nine patients carrying stop mutations, local

gentamicin application produced improvement in a physiologic parameter

measured in nasal epithelia [9]. Interestingly, recent studies of autism

patients confirmed 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

improve autism symptoms by correcting the premature stop codon mutation in

a hypothetical polymorphic gene linked to autism.

These speculative hypotheses are inspired by the observations by Sandler et

al. [4] who linked the onset of autism 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

antimicrobial 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 individuals would be supported if a link could be established

between amynoglicosides and the onset of autism symptoms, or if it could be

found in a post-hoc analysis of existing 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 transient use. For example,

inherited susceptibility to aminoglycoside ototoxicity is based on a

mutation in mitochondrial DNA (i.e., 12S rRNA) [11]. It is possible that

similar aminoglycoside-sensitive mitochondrial mutations could be involved

in autism as well; namely, an autistic 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 hypothetical 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 absorbed (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 periphery. For example, insulin-like

growth factor (IGF-1), a growth-promoting peptide hormone that has

neurotrophic 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

peripherally-synthesized protein plays a role in autism when mutated, 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 hypothesis " a " (e.g., investigate the effect of aminoglycosides in

children at risk for autism) is not ethically 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 autism could be clearly

established, either positive or negative, 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 regulator

CNS, central nervous system

IGF, insulin-like growth factor

mRNA, messenger RNA

Competing interests

None declared

References

1. Lord C, Cook EH, Leventhal BL, Amaral DG: Autism spectrum disorders.

Neuron 2000, 28:355-363. PubMed Abstract | Publisher Full Text | OpenURL

Return to text

2. Tager-Flusberg H, ph R, Folstein S: Current directions in

research on autism.

Ment Retard Dev Disabil Res Rev 2001, 7:21-29. PubMed Abstract |

Publisher Full Text | OpenURL

Return to text

3. Maestrini E, A, Monaco AP, A: Identifying autism

susceptibility genes.

Neuron 2000, 28:19-24. PubMed Abstract | Publisher Full Text | OpenURL

Return to text

4. Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP, Vaisanen

ML, MN, Wexler HM: Short-term benefit from oral vancomycin treatment

of regressive-onset autism.

J Child Neurol 2000, 15:429-435. PubMed Abstract | OpenURL

Return to text

5. Schroeder R, Waldsich C, Wank H: Modulation of RNA function by

aminoglycoside antibiotics.

EMBO J 2000, 19:1-9. PubMed Abstract | Publisher Full Text | OpenURL

Return to text

6. Burke JF, Mogg AE: Suppression of a nonsense mutation in mammalian

cells in vivo by the aminoglycoside antibiotics G-418 and paromomycin.

Nucleic Acids Res 1985, 13:6265-6272. PubMed Abstract | OpenURL

Return to text

7. Mankin AS, Liebman SW: Baby, don't stop!

Nat Genet 1999, 23:8-10. PubMed Abstract | Publisher Full Text | OpenURL

Return to text

8. MT, Shirts BH, Petros LM, Flanigan KM, Gesteland RF, Atkins

JF: Sequence specificity of aminoglycoside-induced stop condon readthrough:

potential implications for treatment of Duchenne muscular dystrophy.

Ann Neurol 2000, 48:164-169. PubMed Abstract | Publisher Full Text |

OpenURL

Return to text

9. Wilschanski M, Famini C, Blau H, Rivlin J, Augarten A, Avital A,

Kerem B, 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 2000, 161:860-865. PubMed Abstract |

Publisher Full Text | OpenURL

Return to text

10. Warburton P, Baird G, Chen W, K, s BW, Hodgson S,

Docherty Z: Support for linkage of autism and specific language impairment

to 7q3 from two chromosome rearrangements involving band 7q31.

Am J Med Genet 2000, 96:228-234. PubMed Abstract | Publisher Full

Text | OpenURL

Return to text

11. Guan MX, Fischel-Ghodsian N, Attardi G: A biochemical basis for the

inherited susceptibility to aminoglycoside ototoxicity.

Hum Mol Genet 2000, 9:1787-1793. PubMed Abstract | Publisher Full

Text | OpenURL

Return to text

12. Graf WD, Marin- J, Gao HG, Pizzo S, Naviaux RK, Markusic D,

Barshop BA, Courchesne E, Haas RH: Autism associated with the mitochondrial

DNA G8363A transfer RNA(Lys) mutation.

J Child Neurol 2000, 15:357-361. PubMed Abstract | OpenURL

Return to text

13. Mac RS: The role of insulin-like growth factors in small

intestinal cell growth and development.

Horm Metab Res 1999, 31:103-113. PubMed Abstract | OpenURL

Return to text

14. Aberg MA, Aberg ND, Hedbacker H, sson J, sson PS: Peripheral

infusion of IGF-I selectively induces neurogenesis in the adult rat

hippocampus.

J Neurosci 2000, 20:2896-2903. PubMed Abstract | Publisher Full Text

| OpenURL

Return to text

Pre-publication history

The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1471-244X/1/5/prepub

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Vaccination Information & Choice Network, Nevada City CA & Wales UK

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