By Mary Coleman
Finally, in 2014, we are beginning to resolve some of the long-standing controversies in autism and move research is a more fruitful direction.
Controversy: Autism is one gigantic disease entity, with variations in the intensity of clinical expression, so it should be called ‘The Autism Spectrum’.
Resolution: As established both by clinical observation, metabolic testing and genetic protocols, autism is in fact more than one single disease — as first shown by a very large double-blind study as early as 1976. Autism symptoms are seen in many, many separate diseases — the same pattern as seen in the multiple forms of intellectual disability (ID). Just as in intellectual disability, each disease entity so far defined in autism is separate and distinct, each disease has its own separate mechanisms of action. The word ‘spectrum’ used in autism should only refer to the different degrees of clinical expression within one of the defined disease entities.
Controversy: Autism is a genetic disease and a gene causing autism will be found.
Resolution: After more than a decade of genetic testing on large groups of individuals with autistic symptoms, it is now known that autism is not a single genetic disease. In fact, it is not a disease at all, but rather a syndrome of many different diseases. That many of these diseases will be found to be associated with a genetic mutation is highly likely, but even this is not fully established at this time. We already know that there is no unique ‘autism gene’. In fact many of the genetic mutations found in children with autism overlap with other brain diseases, such as intellectual disability, epilepsy, ADHD, schizophrenia, etc. Besides genetic mutations, autistic symptoms also can be associated with in utero infections, drug exposure, toxic chemical exposure, and endocrine syndromes, as well as postnatal infections.
Controversy: How much work-up is indicated in evaluating a patient with autistic symptoms prior to being admitted to a genetic study?
Resolution: Each child needs a full work-up of history (including family history), physical and neurological examination, and a laboratory ruling-out of known etiologies of autism. There are now a number of disease entities separated out of the huge pool of patients with autistic symptoms, most of them encompassing a genetic mutation. Each individual with autistic symptoms needs to have the benefit of a ruling in of such disease entities, so they can have the long-term benefit of any research (knockout/knockin rodent studies, experimental therapeutic trials, etc.) currently ongoing for patients with that particular genetic error plus contact with established parent support groups for that single disease.
Controversy: Is autism inherited?
Resolution: Although the disease appears to be highly heritable in some families and may span generations with different patterns of Mendelian inheritance, a slight majority of genetic mutations documented to date have been de novo.
Controversy: Why do the majority of patients with autism remain undiagnosed in 2014?
Resolution: This issue is not resolved and is the main problem to confronting us in 2014. This failure likely has several main sources.
- More than a decade of focus, money and resources were partly wasted trying to study autism as if it were one gigantic disease.
- A search for the mutations of DNA itself leading to errors in its protein may, in the end, account for only a small percentage of genetic errors found in individuals with autism. There are already indications of an important, perhaps quite a major, role for epigenetics in autism. One of the problems is that copy number variation is so diverse in humans that separating the normal determinants from the disease determinants is extremely time-consuming and challenging. Besides the problem of finding specific genetic/genomic etiologies, there is also the problem of risk factors. For example, already there is a finding that small deletions impacting only one or two genes possibly may add to the risk of autism.
- Laboratory procedures are constantly improving, including the cost of whole exome and whole genome sequencing that thankfully are steadily decreasing with time. Nevertheless there remain constant, new, unexpected discoveries about gene behavior, a number of unresolved technical questions and any sequencing studies involve very experienced sophisticated interpreters.
- There is now good reason to believe that there may be many hundreds or even thousands of different genetic errors to be found in individuals with autism; this makes for an challenging overwhelming task for researchers. Unlike intellectual disability, where there are large numbers of patients with the same genetic (chromosomal) error such as Down syndrome, no such large number of individuals with the same genetic error have yet been located in the autism population; the largest identified diseases to date are in the 1% range.
We have been learning how to teach children with autism leading to an improvement in the quality of their adult life. Now we must enter a new paradigm and learn how to accurately medically diagnose them, which possibly could someday lead to medical amelioration of their condition.
Mary Coleman is a pediatric neurologist specializing in neurodevelopmental disorders. She has published over 100 papers and nine medical books, five of which are on autism. She was educated at the University of Chicago, Johns Hopkins University and George Washington University with neurology training at Columbia-Presbyterian Medical Center and Children’s Hospital in D.C. She is the co-author of The Autisms, Fourth Edition with Christopher Gillberg.
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Image credit: A hand writing the word Autism on a chalkboard under colorful puzzle piece drawings. Image by sdominick, iStockphoto.