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The genes of silence


Locked away in an impenetrable world, many autistic people are unable to communicate their feelings. European and US researchers are now trying to identify the genes which make a person susceptible to the development of this disorder. The first results of their work represent an important step forward in our understanding of the condition - and perhaps even its prevention and treatment.




Drawings by Lisa Perini shown at the international exhibition, 'Creation from Silence' (Burgos - E), organised by the Association of Parents of Autistic Children, where she won first prize.

Autism affects at least one child in every 2 500, mainly boys. Half of these never learn to speak and three-quarters have mental handicaps, though a small minority may show an exceptional talent for drawing, music or mental arithmetic. Although doctors now have a somewhat better understanding of how such individuals might perceive the outside world, they have yet to identify clearly the precise underlying brain dysfunction. "We are still only able to observe the development of the brain or study its functioning in a relatively unsophisticated way, particularly in young children, which is when autism first shows itself," explains Anthony Bailey of the Institute of Psychiatry in London.

Clues from twins
For several years now, researchers have adopted a genetic and molecular approach to try to improve their understanding of the origins of this disease. Studies carried out on families of autistic people have revealed certain predisposing factors. In monozygotic twins (genetically identical and coming from a single fertilised egg), if one child is affected, then in some 60% of cases the other one is too. In dizygotic twins (genetically non-identical, from two different eggs), this only occurs in about 4% of cases, indicating the importance of genetic influences. Studies of families with twins suggest that these influences might also extend to Asperger's syndrome and related disorders.

These studies led specialists to search for the few genes that they suspected must underlie the development of autism. The question was: how many and which ones? In 1995, in an attempt to identify the culprits, understand the origins of the disease and - ultimately - develop a treatment, an international consortium was set up to carry out a study of the molecular genetics of autism. Coordinated by researchers at the Institute of Psychiatry in London, it has received EU funding since 1997.(1) "About 200 families is generally considered to be the minimum sample for a study of this kind. This is far too many for any one country, " explains Dr Bailey. As virtually no individuals with autism have descendants, the genetic study has to focus on the relatively small number of families containing two individuals with autism or a related disorder. Hence the need for an international approach, and a consortium consisting of British, Dutch, German, French, Danish, Greek and American clinicians and researchers.

Enigmatic autism
First described by the American Leo Kanner in 1943, autism is a disorder which affects an individual's complete mental development. The symptoms (lack of social interaction, communication and imagination; limited interests and activities, etc.) vary greatly with age. The only treatment is early specialised education aimed at making the environment more accessible to the autistic child who may then possibly acquire language, social skills, learning ability and a knowledge of the world. Autistic adults, on the other hand, usually have to live in an adapted medico-social environment unless they can be cared for by their family. To find out more about autism: Uta Frith, Autism: Explaining the Enigma, Basil Blackwell, Oxford, 1989.

This computer image of a gel shows the markers from several families with autism, each marker being labelled with a different fluorescent dye. The gel shows where the markers shared between individuals vary; this data will help to pinpoint the genes responsible.

More precise diagnoses
Once the families had been identified and autism diagnosed, a blood sample was taken from each individual. Some of each sample was used to extract the DNA and to carry out the first molecular genetics studies in the laboratory of Professor Anthony Monaco at The Wellcome Trust Centre for Human Genetics in Oxford. The remainder was used to establish permanent cultures of cell lines. Kept in a cell bank, these cultures enable all the research teams to work on the same subjects. They also make it possible to carry out any additional analyses which may prove necessary.

The first stage, before the molecular biologists are brought in, is aimed at establishing a precise diagnosis and excluding subjects in whom autism is associated with a recognisable medical disorder that might distort the results. It is important to reliably quantify clinical heterogeneity in autism in order to be able to establish a link between the variability of the illness and the precise genes involved.

The project partners concentrated much of their efforts on this strategic aspect of selecting their subjects. They met regularly for working seminars on the use and reliability of their diagnostic tools and for in-depth discussions on problematic cases, based in particular on video recordings made during assessments of some patients.

Six suspect chromosomes
In 1998 - well ahead of schedule - this concerted effort to achieve precise diagnoses enabled the consortium to publish the first genetic study of autism ever carried out on a full genome.(2) This was based on 99 families, including 87 pairs of siblings and 12 families with more distant relationships (cousins, etc.).

The analysis of more than 300 genetic markers distributed at regular intervals across the full genome (and corresponding to regions which are in principle very variable from one individual to another), revealed six chromosomes (4, 7, 10, 16, 19 and 22) on which certain sites showed greater similarities among pairs of autistic individuals than would normally be expected. Two particularly significant regions were located on chromosomes 7 and 16. The region identified on chromosome 7 currently looks the most promising, as it shows the greatest similarities and also contains a number of genes involved in brain development and function.

Living in hope
To date, more than 130 families have been recruited for the purposes of this study. The researchers are concentrating their genetic analyses on the first regions identified as those being potentially linked to the development of autism. These links must be confirmed by other groups and the target areas refined to identify the gene(s) involved in each region. "The identification of these various susceptibility genes is just the first stage in understanding the development of the disease," concludes Dr Bailey. "This approach does, however, hold out the hope that we can begin to give a meaning to a whole set of biological data, with the prospect that this work will lead to the development of preventative approaches or specific treatments. This research also raises the possibility of identifying any non-genetic factors which, in the case of a subject prone to autism, may lead to either a moderate or severe form of the disease. Although we still have a long way to go before we achieve our goal, it does seem closer now than it has ever been."

(1) Through a concerted action (Molecular Genetic Study of Autism - BMH4-CT-97-2759 ) under the Biomed 2 programme.
(2) A full genome screen for autism with evidence for linkage to a region on chromosome 7q, International Molecular Genetic Study of Autism Consortium, Human Molecular Genetics, 1998, Vol 7, n3, 571-578


Anthony Bailey
MRC Child Psychiatry Unit,
Institute of Psychiatry - London
Fax: +44-171-252-5107

Philippe Jehenson - Research DG
Fax: +32-2-29 55365

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