nejm letter: Genomics, Intellectual Disability, and Autism

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Genomics, Intellectual Disability, and Autism

n engl j med 366;23 nejm.org june 7, 2012

To the Editor:

Mefford et al. (Feb. 23 issue)1 provide an excellent review of the

genomic factors in autism but do not mention that the quantitative

contribution of the enumerated genetic factors to the rates of autism is

small, as compared with the contribution of nongenomic (i.e.,

environmental) factors. In doing so, they create the false impression

that autism is mainly a genetic disorder. The recent rapid rise in

diagnoses of autism belies this concept, and a twin study2 suggests that

environmental factors play a major role in autism susceptibility whereas

genetic factors play a moderate role. Thousands of patients are

typically screened to identify genomic risk loci, and many findings fail

replication. In contrast, studies have consistently shown an association

among autism, oxidative stress, and a deficit in the plasma level of the

antioxidant glutathione. 3,4 Importantly, the metabolic effects of toxic

exposures can be treated.5 Perpetuating the myth of autism as a

primarily genetic disorder is a disservice to those who might benefit

from treatment and diverts attention from nongenetic causes.

C. Deth, Ph.D.

Northeastern University

Boston, MA

Dr. Deth reports having received research grant support from

the Autism Research Institute, Autism Speaks, the National Autism

Association, and SafeMinds. No other potential conflict of

interest relevant to this letter was reported.

1. Mefford HC, Batshaw ML, Hoffman EP. Genomics, intellectual

disability, and autism. N Engl J Med 2012;366:733-43.

2. Hallmayer J, Cleveland S, A, et al. Genetic heritability

and shared environmental factors among twin pairs with autism.

Arch Gen Psychiatry 2011;68:1095-102.

3. SJ, Melnyk S, Jernigan S, et al. Metabolic endophenotype

and related genotypes are associated with oxidative stress

in children with autism. Am J Med Genet B Neuropsychiatr Genet

2006;141B:947-56.

4. Frustaci A, Neri M, Cesario A, et al. Oxidative stress-related

biomarkers in autism: systematic review and meta-analyses.

Free Radic Biol Med 2012 April 18 (Epub ahead of print).

5. SJ, Melnyk S, Fuchs G, et al. Efficacy of methylcobalamin

and folinic acid treatment on glutathione redox status in

children with autism. Am J Clin Nutr 2009;89:425-30.

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The Authors Reply:

Deth points out that our review does not focus on the role of nongenomic

factors with regard to the causes of autism. We would note that our

assignment was to review the genomic aspects of developmental

disabilities as part of a series on genomics in medicine. We would also

note that a clear distinction between environment and genetics is an

artificial one. It is now evident that environment can affect gene

expression and that genetic variations can affect responses to

environmental stressors. Although Deth is correct in noting that few

mutations have been associated with autism, it is likely that more

subtle interactions between gene and environment play a major role in

this disorder. We suspect that he would agree, given his reference to

the association between autism and a low level of glutathione.1

C. Mefford, M.D., Ph.D.

University of Washington

Seattle, WA

Mark L. Batshaw, M.D.

P. Hoffman, Ph.D.

Washington University School of Medicine

Washington, DC

Since publication of their article, the authors report no further

potential conflict of interest.

1. SJ, Melnyk S, Jernigan S, et al. Metabolic endophenotype

and related genotypes are associated with oxidative stress

in children with autism. Am J Med Genet B Neuropsychiatr Genet

2006;141B:947-56.

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