Autism spectrum disorders: a relational cause
Brief communication arising (submitted to Nature 11/10/13: not accepted)
Jones and Klin (1) showed that newborns who will later develop autism spectrum disorders (ASDs) pay normal attention to eyes, but that attention declines from 2-6 months. This shows, they say, how 'initial genotypic vulnerabilities' cause ASDs. Their results suggest, however, that ASDs are caused by insufficient practice of early eye-contact.
Though many genetic lesions are each associated with a small fraction of ASDs, association does not prove direct causation (2). When an allele directly causes a disease, e.g. Huntington's, then that allele is both necessary and sufficient to cause it. Abrahams and Geschwind showed that the genetic lesions associated with ASDs are neither necessary nor sufficient (3, see 4 for commentary). "Overall, none of the molecules or syndromes currently linked to the ASDs have been shown to selectively cause autism. Instead, each seems to result in an array of abnormal neurobehavioral phenotypes, including autism, Asperger syndrome, non-syndromic mental retardation and other neurodevelopmental abnormalities" (3 p. 348; 5 p. 1301). Each known genetic lesion seems to 'cause' a small fraction of ASDs indirectly by broadly disrupting brain development.
Illiteracy is surely associated with genetic blindness but genes do not cause illiteracy except in the trivial, indirect sense that all life depends upon genes. To treat illiteracy we need to know its direct cause (not learning to read). This principle is sometimes overlooked in genetic research. Illiteracy may be a useful model for ASDs which are known to be the developmental consequence of early failures to learn (6). That ASDs are sometimes reversed by psychotherapy (4, 7) points to learned rather than genetic pathology.
In essence Jones and Klin proposed that the newborns who would later develop ASDs had genes for normal eye-attention as well as genetic defects which would later undermine the practice of eye-contact. Thus they elaborated their genetic model to accomodate a contradictory result. But their result suggests the deficit was not genetic. There is no evidence that ASD-associated genetic defects were present in these newborns. We know that the known genetic defects are not necessary and do not selectively cause ASDs (above). Jones and Klin's model requires selective genetic causation.
There are other objections: Because ASDs may not reduce intelligence, they cannot always be caused by broad-acting genetic disruptions of brain development. Genetic causation cannot be reconciled with recent increases in autism's incidence (the evidence for increase therefore tends to be dismissed). Observed sibling associations may reflect shared environments. Finally genes are too few to specify behavior, including eye-contact: genes enable self-organizing complex adaptive systems from which specific behaviors emerge (4). Autism is very strongly associated with infant blindness, with infant cranial nerve palsy causing eye-muscle paralysis, with early institutionalization4, and with early exposure to television (8). What these conditions have in common is that each interferes with early eye-contact. The possibility that this interference might cause autism is strongly supported by the objections to genetic causation (above), and by Jones and Klin's discovery that their newborns had normal eye-contact. It follows that, for apparently normal infants who later develop ASDs, the most plausible location of the deficit is in the actions of caregivers who, within a narrow developmental window, must engage the infant in practicing eye-contact (or, for blind infants, the equivalent of eye-contact using other senses.)
The probable direct cause of ASDs, therefore, is insufficient practice of eye-contact in the first months of life. The naming of a probable direct cause is not semantics: it should affect the direction of future research. If that cause is proven, then ASDs' incidence can be reduced by public education.
References
1. Jones, W. & Klin, A. Attention to eyes is present but in decline in 2–6-month-old infants later diagnosed with autism. Nature doi:10.1038/nature12715 (2013)
2. Novella, S. Evidence in medicine: correlation and causation. Science-Based Medicine. sciencebasedmedicine.org Posted Nov 18 (2009)
3. Abrahams, B. S. & Geschwind, D. H. Advances in autism genetics: on the threshold of a new neurobiology. Nature Rev. Genet. 9, 341-355 (2008)
4. McDowell, M. J. Autism's direct cause? Failure of infant-mother eye contact in a complex adaptive system. Biological Theory 5(4), 344-356 (2011). Also at: http://cogprints.org/9124/
5. State, M. W. & Sestan, N. Neuroscience: the emerging biology of autism spectrum disorders. Science 337, 1301–1303 (2012)
6. Klin, A., Jones, W., Schultz, R.T., Volkmar, F.R. The enactive mind – from actions to cognition: lessons from autism. Phil. Trans. R. Soc., Bio. Sci. 358, 345-360 (2003)
7. McDowell, M. J. Autism, early narcissistic injury and self-organization: a role for the image of the mother's eyes? J. Analyt. Psychol. 49(4), 495-520 (2004)
8. Waldman, M., Nicholson, N. A., & Williams, J. Autism prevalence and precipitation rates in California, Oregon, and Washington counties. Arch. Ped. Adol. Med. 162(11), 1026-34 (2008)