GENETICS STUDY

The Causes of Autism Spectrum Disorders*

Peter Szatmari

Autism is a developmental disability with onset in infancy. Its clinical presentation is characterized 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 conceptualized 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 included ¹ -- much higher than previously reported.

Along with these changes in classification of the disorders has been a greater understanding of the causes of autism, although, admittedly, just how the biochemical and other features frequently seen in affected children lead to 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, minor facial and bodily abnormalities, increased rate of obstetrical complications, an unequal sex ratio, and extremes of head size ^1-3 represent subtle, but still not clearly defined, 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.⁴ This finding has now been replicated several times and is well established.⁵ But the genetics of the disorder must be complex, as the mode of transmission does not follow any recognizable pattern. Modelling studies have shown that multiple genes in interaction probably account for the genetic complexity underlying the disorder.^6,7 It is important to point out that 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 fertilization. The only environmental factors for which we have preliminary evidence of such causation are thalidomide-induced abnormalities produced during the embryonic period⁸ and anti-convulsants taken during pregnancy.⁹ 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.¹⁰

The strong genetic effects observed in family and twin studies have encouraged investigators to conduct studies that attempt to identify actual susceptibility genes. Although several promising findings are based on candidate gene studies (particularly in a region on the long arm of chromosome 15^{11, 12}), these have yet to be replicated consistently. Several studies have found that regions on chromosomes 2, 7, and 13 may contain one or more genes that are associated with the development of autism. ^{13, 14} But actual susceptibilty genes have not yet been identified. Further progress may depend on collecting very large sample sizes. Another helpful approach is to identify more immediate biological effects of these presumed susceptibility genes. Autopsy examinations and MRI studies have found larger volumes of white matter in general and subtle structural changes in cell density and alignment, particularly in the limbic system.^15,16 Imaging studies have also reported unusual activation of the amygdala (a brain structure that deals with emotion and such things as facial recognition) and surrounding structures in response to social stimuli.^17,18

A minority of children with autism have a co-existing disorder of the central nervous system that presumably "causes" the disorder. In total, these conditions probably account for only 10-15% of cases, ⁹ but they should be kept in mind as their diagnosis will have clinical implications.^20,21 In terms of co-morbid 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.²² 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.²³

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 due to parenting practices. 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 to vigorously pursue supposed causes. It is generally anticipated, however, that with newer technologies and study designs, the risk factors that start the causal chain that ends with 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.

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*Adapted from:
The Causes of Autism Spectrum Disorders
BMJ 2003.