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Multiple factors have been identified, but a unifying cascade of events is still elusive
Autism is a developmental disability with onset in infancy. Its clinical
presentation is characterised by impairments in reciprocal social
interaction and in communication with others, and by a preference for
repetitive, stereotyped behaviours. Our understanding of the clinical
picture of autism has changed dramatically over the past decade
thanks to a much greater appreciation of the possible range of
behaviours seen at different ages and degrees of functioning. Another
key change has been the appreciation that several closely related
"disorders" exist that share these same essential features but differ
on specific symptoms, age of onset, or natural history. These
disorders, which include Asperger syndrome, atypical autism, and
disintegrative disorder are often conceptualised as lying on a
spectrum with autism (hence the popularity of the term "autism
spectrum disorders"). Current estimates of the prevalence of autism
are 16 per 10 000, but this estimated prevalence increases to 63 per
10 000 when all forms of autism spectrum disorders are included1
much
higher than previously reported.
Along with these changes in taxonomy has been a greater understanding of the causes of autism, although, admittedly, the picture of the cascade of structural and biochemical events that culminate in the disorder is still not clear. Surely, however, we are much further ahead today than we were some years ago when blame was squarely placed on the shoulders of mothers who, it was claimed, were cold and indifferent to their infants. The distress caused by these claims is a painful reminder of the need for evidence based information on causation for all parents who have children with developmental or psychiatric disorders.
Developmental delay, epilepsy, dysmorphic features, obstetric complications, an unequal sex ratio, and extremes of head size 1 2 w1 represent non-specific signs that autism is a neuropsychiatric disorder. Perhaps the most important advance in changing our understanding of the cause of autism was the discovery that genetic factors have a key role. In 1977, Folstein and Rutter published the first twin study in autism and showed that the concordance rate in identical twins was very much higher than in non-identical twins.3 This finding has now been replicated several times and is well established.4 But the genetics of the disorder must be complex, as the mode of transmission does not follow any recognisable pattern. Modelling studies have shown that multiple genes in interaction probably account for the genetic complexity underlying the disorder.w2 5
These data do not exclude an environmental risk factor as well; as long as it is understood that "environmental" in this context can include any event after fertilisation. The only environmental factors for which we have preliminary evidence of such causation are thalidomide induced embryopathyw3 and anti-convulsants taken during pregnancy.w4 In spite of recent publicity, there is good epidemiological evidence that the measles, mumps, and rubella vaccine is not an environmental risk factor for autism.6
The strong genetic effects observed in family and twin studies have encouraged investigators to conduct linkage and association studies that attempt to identify actual susceptibility genes. Although several promising findings are based on candidate gene studies (particularly in the region 15q11-13w5 w6), these have yet to be replicated consistently. Several genome-wide linkage studies have found that regions on chromosomes 2, 7, and 13 may contain one or more susceptibility genes but actual susceptibility genes have not yet been identified.7 w7 Further progress may depend on collecting very large sample sizes. Another helpful approach is to identify more immediate biological effects of these putative susceptibility genes. Postmortem examinations and studies using magnetic resonance imaging have found larger volumes of white matter in general and subtle structural changes in cell density and alignment, particularly in the limbic system.w8 8 Functional imaging studies have also reported atypical activation of the amygdala and surrounding structures in response to social stimuli.w9 9
A minority of children with autism have a comorbid disorder of the central nervous system that presumably "causes" the disorder. In total, these comorbid conditions probably account for only 10-15% of cases,10 but they should be kept in mind as their diagnosis will have clinical implications.11 w10 In terms of comorbid medical disorders, good evidence now exists that disturbances of the gastrointestinal system are not more common in children with autism than in the general population of children.w11 No causative factors have been found to differentiate children with autism from children with other disorders on the spectrum such as Asperger syndrome. Good evidence exists that these related conditions arise from a common familial, presumably, genetic mechanism.12
It is gratifying to see that research into the causes of autism has helped to
temper the guilt so often experienced by parents when the disorder
was considered to be psychogenic in origin. However, the difficulty
of conducting sound studies of causation has now led some healthcare
practitioners to encourage parents to act on very poor quality data
and vigorously pursue hypothetical causes. It is generally
anticipated, however, that with newer technologies and study designs,
the risk factors initiating the causal chain that culminates in this
profoundly disabling disorder will soon be identified. The great hope
is that from this understanding, more definitive treatments can be
developed to improve long term outcomes for all children with autism
spectrum disorders.
Peter Szatmari
Department of Psychiatry and Behavioural Neurosciences, McMaster University,
Hamilton, ON, Canada L8N 3Z5 (szatmar@mcmaster.ca)
Footnotes
Competing interests: None declared.
| 1. | Chakrabarti S, Fombonne E. Pervasive developmental disorders in preschool children. JAMA, 2001; 285: 3141-3142[CrossRef][ISI][Medline]. |
| 2. | Zwaigenbaum L, Szatmari P, Bryson SE, MacLean JE, Tuff LP, Bartolucci G, et al. Pregnancy and birth complications in autism and liability to the broader autism phenotype. J Am Acad Child Adolesc Psychiatry 2002; 41: 572-579[ISI][Medline]. |
| 3. | Folstein S, Rutter M. Infantile autism: A study of 21 twin pairs. J Child Psychol Psychiatry 1977; 18: 297-321[ISI][Medline]. |
| 4. | Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995; 25: 63-77[ISI][Medline]. |
| 5. | Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J, et al. A genomic screen of autism: evidence for a multilocus etiology. Am J Hum Genet 1999; 65: 493-507[CrossRef][ISI][Medline]. |
| 6. | Taylor B, Miller E, Lingam R, Andrews N, Simmons A, Stowe
J. Measles, mumps, and rubella vaccination and bowel problems or
developmental regression in children with autism: population-based study.
BMJ 2002; 324: 393-396 |
| 7. | Folstein SE, Rosen-Sheidley B. Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet 2001; 2: 943-955[CrossRef][ISI][Medline]. |
| 8. | Casanova MF, Buxhoeveden DP, Switala AE, Roy E.
Minicolumnar pathology in autism. Neurology 2002; 58: 428-432 |
| 9. | Critchley HD, Daly EM, Bullmore ET, Williams SC, Van
Amelesvoort T, Robertson DM, et al. The functional neuroanatomy of social
behaviour: changes in cerebral blood flow in people with autistic disorder
process facial expressions. Brain 2000; 123: 2203-2212 |
| 10. | Fombonne E. The epidemiology of autism: a review. Psychol Med 1999; 29: 769-768[CrossRef][ISI][Medline]. |
| 11. | Filipek PA, Accardo PJ, Ashwal S, Baranek GT, Cook Jr EH,
Dawson G, et al. Practice parameter: screening and diagnosis of autism:
report of the quality standards subcommittee of the American Academy of
Neurology and the Child Neurology Society Neurology 2000; 55(4):
468-479 |
| 12. | MacLean JE, Szatmari P, Jones MB, Bryson SE, Mahoney WJ, Bartolucci G, et al. Familial factors influence level of functioning in pervasive developmental disorders. J Am Acad Child Adolesc Psychiatry 1999; 38: 746-753[ISI][Medline]. |
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