Friday, 29 August 2014

Just How Rare are the Known Genetic Causes of Autism?

"Gene" by Courtesy: National Human Genome Research

As we have seen so far in this blog, a great deal is already known about various causes of autism.  It is claimed that only 5-8% of cases are caused by the mutation of a single gene, as in Fragile-X and Retts syndrome.

When I was researching the new drug Arbaclofen, that was being trialed as a therapy for Fragile-X, and autism in general, I was surprised to learn that within Fragile-X there is a wide spectrum.  Some people are very severely affected, both mentally and physically and others are quite mildly affected.

It turns out the same spectrum effect applies to other known genetic causes of autism, including NeurofibromatosisTuberous Sclerosis Complex (TSC) and Timothy Syndrome.

We also have the case of Anderson-Tawil syndrome, which was drawn to my attention by a reader of this blog.  This, supposedly extremely rare, syndrome appears to run in families with a high incidence of autism.  Some of the symptoms do overlap with autism.  As with Fragile X, there can be visible physical differences.  The reader informed us that sufferers are often initially misdiagnosed with Fibromyalgia.  This blog did already look at Fibromyalgia, which also seems to run in families where autism is present and particularly affects females.  Doctors tend to diagnose Fibromyalgia when they cannot identify any other cause of the patient’s reported aches and pains, and they want to put an end to the matter.

Further Observations

There is a general perception that people with autism “look different” and I do not mean just act differently, or walk funny.
Indeed, one of the things those rare doctors specialized in autism look for, is a big head (Macrocephaly) as an indicator of possible autism and possible MR.

When Monty, aged 11 with ASD, went to visit the parents of his afternoon assistant, who is a special educator in training, there was an unexpected, but interesting comment:-  “he looks normal”.

I was recently discussing my blog with a relative who works for the UK National Health Service (NHS).  I was asking why children diagnosed with autism were not routinely screened for known genetic causes, like Retts, Fragile-X etc.  I suggested that perhaps if more people were screened, we would find that these “rare” conditions might be more common that we think.

What the Science Tells Us

Since this blog is supposed to be based on science, let’s go see what those clever scientists can tell us.

It pretty much fits in with what I am saying.  They have a new term, “Mendelian diseases” – diseases caused by a single gene.

The Broad Institute (Ivy League types) has found that milder forms of otherwise severe “Mendelian” diseases can be found in autism.  Only a partially-disabling mutation has occurred in those genes.

One study, led by Mark Daly, a senior associate member of the Broad and co-director of its Medical and Population Genetics program, found that approximately 5% of autism cases could be linked to inherited, recessive mutations that completely disrupt gene function. A second study, led by Broad associate member Christopher A. Walsh, found that autism risk could also be attributed to inherited mutations that resulted in only a partial loss of gene function. Moreover, Walsh’s team found that many of these partially-disabling mutations occurred in genes in which a complete disruption of the gene has been known to cause more severe or even fatal inherited diseases. This suggests that milder forms of some severe, Mendelian diseases – diseases caused by a single gene – may present as autism spectrum disorders.

Tuberous Sclerosis Complex (TSC), as an example

An example of a known genetic mutation leading to autism is Tuberous Sclerosis Complex (TSC).

TSC is caused by a mutation of either of two genes, TSC1 and TSC2, which code for the proteins hamartin and tuberin respectively. These proteins act as tumor growth suppressors, agents that regulate cell proliferation and differentiation.
The graphic below shows the symptoms of TSC and the age at which they tend to present themselves.

Source: Wikipedia

The symptom that caught my attention was “Facial angiofibromas”, since these little marks on the face can be easily noticed, if you look at people when you talk to them.

These marks tend to make a butterfly shaped pattern on the face and vary from highly noticeable to nearly invisible,

Here is an example from Wikipedia:-

In the case of Fragile X, prominent characteristics of the syndrome may include an elongated face, large or protruding ears, and low muscle tone.

Why does this matter?

If you are a parent, don’t go worrying about a new syndrome to deal with.

As time goes by, certain types of autism will eventually be matched to effective drug therapies.  So it makes sense to know who is mildly affected by these single-gene disorders, as well as those with the full-blown version, only some of whom have already been diagnosed.

So, if you are mildly TSC, you would follow the TSC research and if you have low muscle tone and a long face, then the forthcoming Fragile X therapies could be relevant.

Since genetic testing is extremely uncommon, the logical way to go is to look at the outward symptoms of these conditions, starting with the very obvious ones.

I do not know many people with autism, but even I can notice some tell-tale physical features, once you know what to look for. As these features are inherited, the physical manifestation may be more visible in siblings, even though the behavioural symptoms are absent.

So those single gene disorders may not be as rare as we thought.


  1. My autistic son was recently diagnosed with 22q13 - Phelan-McDermid Syndrome. A Chromosonal deletion. Thank-you for your blog, I have found it most interesting.


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