Showing posts with label Tuberous sclerosis. Show all posts
Showing posts with label Tuberous sclerosis. Show all posts

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.

Tuesday 7 May 2013

Pep up those Purkinje cells

In the previous post we established that both oxidative stress and neuroinflammation can be measured.  We learned from the clever people at Johns Hopkins that the site of the greatest inflammation is in the  cerebelleum; as they put it:-

Based on our observations, selective processes of neuronal degeneration and neuroglial activation appear to occur predominantly in the Purkinje cell layer (PCL) and granular cell layer (GCL) areas of the cerebellum in autistic subjects.

Now, you may recall that I recommended an excellent book called "Autism: Oxidative Stress, Inflammation and Immune Abnormalities".  The book is from 2010, and since then the authors have been busy.  In 2012 they published a study called:   Brain Region-Specific Glutathione Redox Imbalance in Autism
This study tells us which parts of the brain are most affected by oxidative stress.  The abnormal level of GSH redox (the marker for oxidative stress) was highest in the cerebellum and in the temporal cortex.
This is good to hear, since I have assumed that oxidative stress and neuroinflammation are essentially part of the same process and that what halts one, will likely halt the other.

Purkinje Cells
Purkinje cells are a class of GABAergic (controlled by the neurotransmitter GABA) located in the cerebellum.
Purkinje cells are some of the largest neurons in the human brain, perhaps this makes them target of stress and inflammation.
Purkinje cells send inhibitory projections to the deep cerebellar nuclei, and constitute the sole output of all motor coordination (and maybe more?) from the cerebellum.

In humans, Purkinje cells are affected in a variety of diseases ranging from toxic exposure (alcohol, lithium), to autoimmune diseases and to genetic mutations (spinocerebellar ataxias, Unverricht-Lundborg disease and autism) and neurodegenerative diseases that are not thought to have a known genetic basis (cerebellar type of multiple system atrophy, sporadic ataxias).

Purkinje Damage in Autism
It has been shown that there is a 35 to 50% reduction in the number of Purkinje cells in the autistic cerebellum when compared with a normal cerebellum.  (this comes from a paper on glutamate neuro-transmitter abnormalities)

Here is an excellent and  very readable study all about Purkinje damage in autism, from 10 years ago:-
 Purkinje cell vulnerability and autism: a possible etiological connection

It is proposed that the cell death in the Purkinje cell layer produces the autistic-like behaviours.

Functions of the and temporal lobe and cerebellum
(where the oxidative stress was measured to be highest)

The temporal lobe seem very much related to the problematic areas of autistim, namely:-
·         Processing sensory input

·         Language comprehension
It also contains the hippocampus.  The hippocampus has made an earlier appearance on this blog since one of its main functions is the realease of hormones including TRH (thyrotropin releasing hormone) CRH (Corticotropin releasing hormone) GHRH (growth hormone releasing hormone).  Disfunction of the hippocampus is known to occur in epilepsy (often comorbid with autism).
If you want to read all about the temporal lobe, try this : Anatomy of the temporal lobe.

The cerebellum is commonly associated with motor control function, but it may have a role in cognitive function, such as language.  Damage to the cerebellum is known to causes disorders in fine movement (sloppy handwriting in autism?)
So it would appear at first glance that inflammation in the temporal lobe and cerebellum could indeed account for many autistic-like behaviors.  

Pep up those Purkinje cells  -  Indirect or direct action?
As is often the case, there is the direct approach and the indirect approach.  I usually favour the subtle indirect approach; this would be to work on reducing the oxidation and inflammation. 

There may also a direct approach, using a drug developed as an anti-fungal agent, that turned out to be a potent immunosuppressant.    It prevents activation of T cells and B cells by inhibiting their response to interleukin (IL-2). 

Since nothing in neuroscience is clear cut, there is of course a far more complicated alternative explanation of what is going on.  It could be a genetic disorder that is causing the failure in the Purkinje cells.  Take a look:-

Tuberous sclerosis complex (TSC) is a dominant tumour suppressor disorder caused by mutations in either TSC1 or TSC2. TSC causes substantial neuropathology, often leading to autism spectrum disorders (ASDs) in up to 60% of patients. The anatomic and neurophysiologic links between these two disorders are not well understood…. These studies provide compelling evidence that Purkinje cell loss and/or dysfunction may be an important link between TSC and ASD as well as a general anatomic phenomenon that contributes to the ASD phenotype.

The good news is that TSC already has a viable therapy (in mice at least, and in clinical trials), with a drug called rapamycin/sirolimus.  If you look on the web, you will find people experimenting with it.
There have been several studies using mutant mice. 

Autism in mice

In a study of sirolimus as a treatment for TSC, researchers observed a major improvement regarding effects related to autism. The researchers discovered sirolimus regulates one of the same proteins the TSC gene does, but in different parts of the body. They decided to treat mice three to six months old (adulthood in mice lifespans); this increased the autistic mice's intellect to about that of normal mice in as little as three days.

Here are two studies:- 

Before heading down to the pharmacy to ask about Rapamycin, click on this to see a warning or two.  Also TSC is a genetic condition that usually leads to autism.  This does not mean that if you have autism you also have TSC.  It does mean that better understanding TSC may help to better undertand autism.

It looks like the indirect approach is best again.  Just keep taking the NAC !!