Showing posts with label Autism phenotypes. Show all posts
Showing posts with label Autism phenotypes. Show all posts

Friday, 6 December 2013

Future Science - Accurate Diagnosis of Autism Phenotype using Brain Biopsies grown from Skin Cells

This is a post for the scientists among you, that like to separate science from pseudoscience.

You may not be aware that in recent years some revolutionary science has been developed allowing you to create a brain biopsy from a sample of skin.  I was rather taken aback when I first read about it, but it is true.  Researchers are now creating their own artificial biopsies, on which to experiment.
I first read about this in work being done at Stanford, looking at Timothy Syndrome.  I did not really focus on the importance of what they had done.  Without physical samples, it almost impossible to develop medical therapies and you cannot take brain biopsies from living people.  Rats and other lab animals are never going to be an adequate substitute.   

Here is a link to Johns Hopkins, where there used the same technology to make a brain sample with Huntington’s disease.

The true potential of this technology is amazing.  Today, it is being used to create samples, with which researchers can carry out experiments.  In future, it could be used as a diagnostic tool, just like when somebody goes to the gastroenterologist and has an endoscopy.  The doctor takes a sample from your intestines and sends it to the lab for analysis; hopefully a few days later you get a call saying the sample had no cancerous biomarkers, or other nasties.

In the case of autism, the skin sample would be turned into stem cells and then neurons from specific parts of the brain could be made.  These samples would then be tested to reveal specific dysfunctions.  This is exactly what was done at Stanford to make samples of Timothy Syndrome, a rare condition nearly always comorbid with autism.

Stanford Research
“We developed a way of taking skin cells from humans with Timothy syndrome and converting them into stem cells, then converting those stem cells into neurons,” says Ricardo Dolmetsch.

He then identified an experimental drug that could reverse the effects.  This phenotype can be reversed by treatment with roscovitine, a cyclin-dependent kinase inhibitor and atypical L-type-channel blocker.
Roscovitine, also known as Seliciclib or CYC202, is an experimental cancer drug produced by a Scottish/American company called Cyclacel. Don’t expect it to be a cheap drug; Goldman Sachs is one of the main shareholders.
Ricardo is from Cali in Colombia and so I had better shift him to my Dean’s List post-haste.

At some, not so distant point in time, people with a lot of money will be able to identify the precise phenotype of their child’s ASD and then they will know exactly what the optimal treatment is.

Once this technology becomes established, maybe in 50 years, I think Psychiatrists will become an endangered species.  We will need a lot of neurologists and for many people with mental health problems, there will at last be the chance of a very precise diagnosis and a matching drug therapy, created and tested on “human” brain samples made from stem cells.
Hopefully by then, the American Psychiatric Association’s DSM nonsense will be relegated to the trash can (or dustbin, for British readers).  Patients with brain disorders will be diagnosed and treated by neurologists and supported by psychotherapists, psychologists, behavioural analysts and other professionals.





Thursday, 5 December 2013

Autism Phenotypes

Hardly a week goes by without somebody mentioning to me a wonder treatment or even “cure” for autism; the latest one being the GAPS diet.

I think all such reports are worthy of investigation, but many lead to nowhere.

Why is this?

·       Medical science has failed to adequately define autism, so we are not all talking about the same autism

·        Many people putting forward theories have not read even the most basic (and not contested) autism research.  Some are even, apparently, qualified “doctors”.
Autism Phenotypes

What is not disputed is that autism has many sub-types (phenotypes). Researchers tell us 10-20% of cases referred to as autism have a known genetic defect (Fragile X, SLOS, Timothy syndrome etc.).  80% do not have a known genetic marker/cause.

Autism can be subdivided into regressive (when a child loses speech and other learnt skills) and non-regressive (early onset).  Even this can be a subjective judgment, since it effectively relies on parents to determine it, after the event.
Then you have cases of autism which clearly have nothing to do with Kanner’s classic version.  In this blog I showed how even cerebral malaria in a child can lead to the onset of autism.  This clearly is a case of brain damage caused by malaria; but to the observer, months later, it would probably be classed as regressive autism or childhood disintegrative disorder.
Testing for Autism
Researchers and doctors keep repeating that there is no test for autism.  This is not strictly true, but it does explain why so many different conditions are all lumped together as “autism”.

In fact, if you read the research closely, you will see that there are many tests for autism; although they may not be perfect.
The only way to know for sure that it is genuine autism is to examine the brain itself.  The only way to do this 100% accurately is via post-mortem analysis of the brain.  Recently, non-invasive methods have been developed to confirm the same findings of brain malformation that occurred prior to birth.

So the kind of autism that relates to tissue held in brain banks is best understood.  But what kind of autism would that be?  Well, it refers mainly to children and young adults who died prematurely.  They died from things like seizures or drowning.  What does that tell us?  This tells us that these people were most likely severely affected by autism.  The mild, social difficulties, type of autism is, fortunately, hardly likely to make it to the brain tissue bank.
If the person interpreting the MRI of a child’s brain knows what to look for, they may very well be able to identify this type of autism.  The expert here is Eric Courchesne.
A similar approach can followed using Electroencephalography (EEG) to identify autism; but it would be smart to cross check this with Eric.

Regressive vs. Early-Onset
Then you have the difference between regressive and non-regressive autism.  Here again, from my Dean’s List of researchers, we look at Paul Ashwood’s research to see that kids with regressive autism have HIGHER levels of inflammatory markers in their blood.  These include cytokines like interleukin 6, which can be inexpensively measured in most laboratories.  This tells us that perhaps regressive autism is an entirely different condition from non-regressive/early onset autism.  As I would expect, increasing cytokine levels were associated with more impaired communication and aberrant behaviors. 
Lab Testing
We have seen earlier in this blog that some very expensive lab tests exist for autism, but their usefulness and integrity is highly disputed.  There are, of course, many hundreds of other tests that are entirely validated by medical science.  Many of these tests are cheap and available all over the world.

Hormonal Screening
We know from the research that about 30% of people with autism have high blood serotonin. A standard lab test is required.
We know that many have high levels of insulin-like growth factor (IGF-1).  A standard lab test is required.
Thyroid hormone levels and in particular a blunted response of TSH to TRH (i.e. central hypothyroidism) can help define further phenotypes.

The TRH test is now not widely used, but TSH, FT3 and FT4 are cheap tests.
Growth Hormone (GH) is also implicated in autism, along with IGF-1; there is a lab test to measure pituitaryfunction to see how well GH is being produced.

By screening for hormonal dysfunction, it would be possible to identify phenotypes that would most likely benefit from therapies targeting those defects, like NNZ-25266.

Pancreatic Dysfunction
It is reported by Joan Fallon, of Curemark, that 50+% of kids diagnosed with “US autism” seem to have a pancreatic dysfunction.  This can be tested for by measuring fecal chymotrypsin level.  The test measures how well your pancreas is working, and is a standard test for people with cystic fibrosis.  Since the US diagnoses far more kids with autism than other countries, it seems highly plausible that “US autism” includes many more phenotypes than, say, “French autism”.

I was quoted about $8 for a chymotrypsin test.

Ion-Channel Diseases (Channelopathies)
Many diseases like Parkinson’s disease, Spinocerebellar Ataxia and Timothy Syndrome are caused by faulty calcium ion-channels.

The Bumetanide autism therapy, undergoing trials in Europe, is based on another channelopathy, this time a faulty chloride transporter NKCC1.
It is clear from reports I have received, that Bumetanide therapy is totally ineffective in some children with ASD, but in other children, like my son, it is effective.
So some types of autism have certain channelopathies and other types have different ones or, quite possibly, none at all.  

My conclusion today is pure conjecture.  I imagine that possibly as few as a quarter of cases of “US autism” are actually “real” autism, that is with all the brain damage/malformation that is identified in those post mortem brain studies and which forms the basis of 90% of autism research.

The other three quarters may be something entirely different, just like the case of the mosquito that bit the child, produced cerebral malaria and then later the full symptoms of autism.  Within the three quarters may be food allergies, digestive enzyme deficiencies, gut disorders, mastocytosis, blood brain barrier defects, undefined calcium ion-channel diseases etc.
This would account for those occasional amazing “recoveries” and the apparent success, in some cases, of diets like GAPS.  Sadly, diet is unlikely to 100% fix brain damage.  If you are lucky enough to totally “recover”, you cannot have had brain damage in the first place.  It is evident that in some phenotypes of autism, diet can reduce autistic behaviours.  This can only be proved in trials, if biomarkers are established for that specific phenotype.
Most likely the only biological thing all these “autisms” have in common is oxidative stress and neuroinflammation; but only a non-medical scientist, like me, can say such a thing.