Autism was first described by psychiatrists Leo Kanner in 1943 and Hans Asperger in 1944. Since then, the definition and diagnostic criteria of autism have evolved, and knowledge is growing about the biological – primarily genetic – mechanisms involved. In the 1980s, British psychiatrist Lorna Wing rejected the idea that autism is a binary condition (either present or absent) and suggested that it is more akin to a series of symptoms whose intensity can be situated on a continuum. For example, if we consider social communication deficits, these may vary from difficulties establishing interactions with others to severe social withdrawal. By adopting this new approach, Lorna Wing suggested that autism occurs more frequently than initially thought.
The classification and diagnosis of ASD are constantly evolving. It is now included in the broad category of neurodevelopmental disorders (NDD), like attention deficit disorder (with or without hyperactivity – ADD/ADHD), intellectual disability, developmental coordination disorder or specific learning disorder. Neurodevelopment refers to all the mechanisms that guide the way in which the brain develops, orchestrating the brain's functions (motor, executive, sensory integration, language, emotional, reasoning, behavioral, etc.). It is a dynamic process influenced by biological, genetic, socio-cultural, affective and environmental factors. Neurodevelopment begins very early on, before birth, and continues until adulthood. This process of maturation changes the child's capacities on a daily basis. The pace at which it occurs depends on the individual, but it includes various essential stages. These developmental processes can show a degree of diversity and in some cases lead to NDD.
Symptoms and associated disorders
An individual with an ASD may exhibit some or all of these symptoms at any age (non-exhaustive list of common symptoms):
- restricted areas of activity / interest
- difficulty integrating socially, preference for solitude
- avoidance of eye contact
- difficulty in understanding/detecting the feelings of others
- language absent or presence of language delay/language impairment
- tendency to repeat syllables, words or stereotyped expressions (echolalia)
- repetitive behaviours (e.g. rocking, twisting of limbs)
- difficulty adapting to changes in routine/environment
- hyper- or hypo-sensoriality (to sounds, light, smells, tastes etc.)
ASDs are also frequently associated with other neurodevelopmental disorders (NDDs) such as Attention Deficit Disorder with or without Hyperactivity (ADD/ADHD), Developmental Coordination Disorder, Specific Learning Disability or Intellectual Disability, but also psychiatric disorders such as anxiety disorders (in particular social phobia or generalized anxiety disorder), bipolar or even schizophrenic disorders, or other illnesses such as epilepsy or functional colopathies (e.g. constipation). It is also common for individuals with autism to have sleep and/or eating disorders.
Unfortunately, it is only very recently that these associated disorders have been taken into account in research. They are indeed extremely important, both for understanding the origin of ASD and for improving the support of the individuals affected.
© Human Genetics and Cognitive Functions, Institut Pasteur
Studies estimate that 5 to 15% of children worldwide have a neurodevelopmental disorder (ranging considerably in terms of severity) and that more than one individual in every 100 could receive an ASD diagnosis. For a reason that remains unknown, boys are diagnosed with ASD around 4 to 8 times as often as girls. The probability of having a child with ASD is 10 to 20 times higher in families where the parents already have an autistic child. Monozygotic twins ("identical twins") are also more likely to share an autism diagnosis than dizygotic twins ("fraternal twins").
Diagnosis of ASD is clinical. It is based on a precise, detailed, tailored multidimensional assessment that considers various developmental and functional aspects and also the individual's environment in a variety of contexts.
This assessment is the result of a coordinated process between the individual, his or her family, and healthcare professionals. It is used to develop a tailored educational and therapeutic support program. It is based on:
- observations gathered using questionnaires completed by the individual's family, especially the parents but also professionals that the individual encounters regularly, for example at nursery or school, or in the workplace for older individuals.
- standardized tests (for language, motor skills, etc.) that are appropriate for the individual's age, development profile and behavior and for the context in which the test is being performed. Recognized tests and scales (e.g. those recommended by the French National Authority for Health or HAS) should be used if possible.
Various genetic and environmental factors are associated with ASD. Environmental factors that have been reported include the use of certain drugs (such as valproic acid) during pregnancy, and some viral infections. But the main contributing factor is genetic; in some cases a single de novo mutation (or DNM – a mutation that is absent in the parents and first appears in the child) is responsible for autism. In other cases, a combination of several genetic variations increases the probability of developing ASD. More than 200 genes are already known and new genes are regularly identified. Studies have also revealed that a significant proportion of the genetic variations associated with autism are shared by other conditions such as attention deficit disorder, with or without hyperactivity (ADD/ADHD), and intellectual disability.
Treatment and management
Currently no drug therapy has proven to be effective in ameliorating the major difficulties that some people with autism experience. Treatment of ASD is exclusively symptomatic (it treats the symptoms rather than the origins of the disorder) and involves tailored non-drug treatment strategies that may include speech therapy, psychoeducation and psychomotor therapy. These strategies are more effective when applied at an early stage of the individual's development. Several therapeutic trials for drug and non-drug treatments are under way to identify more effective therapeutic strategies.
Although there is currently no drug therapy for the patients with NDD, research suggests that the severity of some symptoms can be reduced, even in adults. Specific clinical trials in patients with mutations in the SHANK3 gene will soon be carried out. Using patient skin cells reprogrammed as neurons (induced pluripotent stem cells or iPSCs), scientists were able to perform high-throughput screening of pharmacological molecules and identify a chemical element, lithium, which may be able to restore the level of expression of the SHANK3 gene. A first clinical trial will be set up at Robert Debré Hospital. The main aim of this trial is to evaluate the effect of 12 weeks of lithium as a new treatment for social communication deficits in patients with Phelan-McDermid Syndrome (a form of autism in which the vast majority of patients have a mutation in the SHANK3 gene). If it has a positive impact on the symptoms of social deficits, this could represent a new avenue for other syndromic forms of autism. Therapeutic trials with other molecules are under way, especially as part of the European project AIMS-2-Trials (see below).
At the Institut Pasteur
At the Institut Pasteur, the Human Genetics and Cognitive Functions research unit, led by Thomas Bourgeron, a Professor at Université de Paris, is engaged in multidisciplinary research drawing on expertise in genetics and structural and functional brain imaging to elucidate the workings of the brain and neurodevelopmental disorders. The unit was the first to confirm the genetic basis of autism when it identified mutations affecting two genes on the X chromosome, NLGN3 and NLGN4X, in 2003. Since then, the team has revealed other genes.
The unit's current research is focused on:
- identifying new genes associated with vulnerability to ASD and characterisation of their specificities;
- stratification of autism by incorporating whole genome sequencing and brain imaging;
- understanding the biological mechanisms of autism, including those involved in brain connectivity and in melatonin deficits (linked to sleeping disorders, a symptom in more than half of those with autism);
- attempting to understand why some individuals are resilient to the severe consequences of certain genetic mutations – in other words they have few or no autistic symptoms despite carrying mutations known to be involved in NDD.
In collaboration with the InovAND Excellence Center at Robert Debré Hospital
Several projects are being carried out in close collaboration between the Institut Pasteur and the InovAND Excellence Center at Robert Debré Teaching Hospital (part of the Paris Public Hospital Network, or AP-HP), which is led by Professor Richard Delorme. The units in the Child Psychiatry Department hold consultations with families to assess children and develop tailored support programs. Whole genome sequencing is performed by the Genetics Department (Dr. Anne-Claude Tabet). A number of projects are under way to shed light on the recurrence and first signs of autism in young children and the links with identified neuroanatomical and genetic abnormalities. If they wish to do so, the child's parents and siblings can also be assessed in the same department (medical and psychiatric history, clinical interview and cognitive assessment), to improve our understanding of how genes associated with autism are passed on within families. A specific project on families with more than one person with ASD or neurodevelopmental disorders was recently launched (the "multiplex" families project).
European research projects: AIMS-2-Trials and CANDY
The AIMS-2-Trials project, funded by the European Union, involves 48 academic and industrial partners. The aim is to identify new biomarkers for autism that will help improve both diagnosis and the development of treatments. The consortium is conducting therapeutic trials involving various molecules (e.g. arbaclofen). The European project CANDY involves the same teams and is also investigating conditions such as ADD/ADHD and epilepsy, which occur more often in people with autism than in the general population. These projects include thousands of participants – newborn infants, children and adults – and monitor their development over several years. The projects involve collecting clinical, genetic and brain imaging data, which will help provide a comprehensive understanding of autism at different levels. This unprecedented volume of research data on ASD in Europe should lead to the identification of subgroups of individuals and facilitate the discovery of treatments tailored to these different subgroups. The Institut Pasteur team is responsible for genetic analyses and for hosting the database for these two projects (the data are centralized and shared by the consortium).
Other useful links
- Autisme Info Service : https://www.autismeinfoservice.fr
- Deux minutes pour mieux vivre l’autisme : https://deux-minutes-pour.org
- Autisme France : http://www.autisme-france.fr
- Association française du Syndrome de Phelan-McDermid : https://asso22q13.fr
- CléPsy : https://www.clepsy.fr
- Spectrum : https://www.spectrumnews.org/features/special-reports/autism-101/
- AIMS-2-Trials project : https://www.aims-2-trials.eu
- CANDY Project: https://www.candy-project.eu/