What does Cancer Risk and Autism tell us?

Today’s post is a short one.

As you look deeper into how the body functions you come across many, only recently understood, pathways.  In reality these are still “works in progress”, but some will eventually lead to a better understanding of diseases like cancer, diabetes, Parkinson’s, Alzheimer’s and, eventually, many types of autism.

Within this blog we have seen how many common diseases share some underpinnings with autism.  As a result these diseases appear more commonly in people with autism, and so they get called comorbidities.

Some comorbidities get talked about quite a lot, things like epilepsy and MR/intellectual impairment.

For me the really interesting ones and the ones that might actual lead you to some therapeutic implication.  In this respect, allergies (food and airborne) have proved to be the most useful.

Not far behind are heart disease, diabetes and cancer.

In Paul Whiteley’s blog he recently highlighted a study showing how heart disease was increased in autism.  This has been noted before and I believe leads back to calcium channels, known to be dysfunctional in autism.  One particular channel is called Cav1.2 and it is widely expressed in the brain and the heart.  In earlier posts I have covered this channelopathy from the point of view of autism.  Not surprisingly, if you have Cav1.2 dysfunction in the brain, it might very well occur elsewhere.

There are little genetic errors called Single Nucleotide Polymorphisms, or SNPs.  In the CACNA1C gene there are 12,932 known SNPs.  Some of the most common ones are associated with autism, bipolar and schizophrenia.

You can look up this gene, or any other one, and see for yourself.

Genecards database

If you read the gene description above, the idea that heart disease is comorbid with autism is no surprise. 

The lower red arrow points at hypokalemic periodic paralysis.  This has appeared many times on this blog, along with Hypokalemic Sensory Overload.  I discovered long ago that there is a potassium ion channel dysfunction in autism; it appears to be behind the odd sensory overload experienced by many with autism and also in some people with ADHD.  What is interesting is that this dysfunction co-occurs with CACNA1C dysfunctions.

Cancer and Autism

The science behind cancer is complex and so as not to research it in vain, it is useful to know that there is solid evidence linking autism and cancer.

The following study of 8,438 people with autism, compared their incidence of cancer with the incidence in the general population

To understand the jargon first read this excerpt from a fact sheet on cancer statistics:

Fact Sheet: Explanation of Standardized Incidence Ratios

How an SIR Is Calculated

The expected number is calculated by multiplying each age-specific cancer incidence rate of the reference population by each age-specific population of the community in question and then adding up the results. If the observed number of cancer cases equals the expected number, the SIR is 1. If more cases are observed than expected, the SIR is greater than 1. If fewer cases are observed than expected, the SIR is less than 1.

Examples:

60 observed cases / 30 expected cases: the SIR is 60/30 = 2.0

Since 2.0 is 100% greater than 1.0, the SIR indicates an excess of 100%.

45 observed cases / 30 expected cases: the SIR is 45/30 = 1.5

Since 1.5 is 50% greater than 1.0, the SIR indicates an excess of 50%.

30 observed cases / 30 expected cases: the SIR is 30/30 = 1.0

A SIR of 1 would indicate no increase or decrease.

Here is the autism study:-

Risk of Cancer in Children, Adolescents, and Young Adults with Autistic Disorder

Objectives

To investigate whether individuals with autism have an increased risk for cancer relative to the general population.

Study design

We enrolled patients with autistic disorder from the Taiwan National Health Insurance database in years 1997-2011. A total of 8438 patients diagnosed with autism were retrieved from the Registry for Catastrophic Illness Patients database. The diagnosis of cancers was also based on the certificate of catastrophic illness, which requires histological confirmation. The risk of cancer among the autism cohort was determined with a standardized incidence ratio (SIR).

Results

During the observation period, cancer occurred in 20 individuals with autism, which was significantly higher than a total number of expected cancers with a SIR estimate of 1.94 (95% CI 1.18-2.99). The number of cancer in males was greater than the expected number with a SIR of 1.95 (1.11-3.16), but no excess risk was found for females with a SIR of 1.91 (0.52-4.88). Cancer developed more than expected in individuals age 15-19 years with the SIR of 3.58 (1.44-7.38), but did not differ in other age range groups. The number of cancers of genitourinary system was significantly in excess of the expected number (SIR 4.15; 95% CI 1.13-10.65), and increased risk was found in ovarian cancer with SIR of 9.21 (1.12-33.29).

Conclusions

Our study demonstrated that patients with autistic disorder have an increased risk of cancer.

So, overall, the risk of all cancers is about twice as high if you have autism.  

Certain cancers are particularly high risk and understanding why this is the case might lead to a better understanding of the “pathways” leading to some types of autism. Due to the rarity of some cancers, like ovarian, one might need to validate the result; note the (1.12-33.29) range for ovarian cancer.

Rather than worry about this risk, we should use these observations to understand and treat autism.

Just as we can counter the elevated risk of heart disease we can do the same for cancer.

Clearly the cancer pathways that will soon be appearing in this blog are relevant to autism.  But in the meantime anyone can reduce their cancer risk by ensuring a high level of antioxidants in their body.  People at higher risk are those with low levels of antioxidants, which include almost all older people and people of all ages with autism.

A vast wealth of information already exists showing the chemo-protective effect of antioxidants.  Cancer clearly generally results from multiple hits, and you may be unlucky to have a single gene that “ups” your risk.  By upping your antioxidant intake you can slash one risk, in this multiple step process.

It does not seem to matter which potent antioxidant you take, but you do need enough of it.  They are all slightly different and most likely a mix of several will yield the best result.

My current favourites are:-

·        NAC (N-acetyl cysteine)

·        ALA (Alpha lipoic acid) - Nrf2 activator

·        Sulforaphane – Nrf2 activator

·        Cocoa Flavanols

·        Lycopene (cooked tomato)

These should reduce both the risk of cancer risk and heart disease.

Other antioxidants mentioned in this blog include:-

·        L-Carnosine

·        Silibinin – Nrf2 activator

·        Selenium

One should be aware that avoiding cancer and treating an existing cancer are different tasks.  Once a cancer has developed, some antioxidants can interfere with the body’s own response mechanism.

My focus is preventative “medicine”.

We saw in an earlier post how children at risk of developing asthma could be identified by their atopic dermatitis.  By treating these children with a cheap mast cell stabilizer called Ketotifen, a trial showed how it was possible to avoid the onset of asthma.

I suspect that the same thing might be possible with epilepsy.  We saw in an earlier post that the first epileptic attack make a (epigenetic?) change, and thereafter there is a greatly increased risk of future seizures.

Other interesting preventative interventions, include statins to avoid Parkinson’s disease and Verapamil to avoid the onset of Type II diabetes.

I did explain all this to the European Medicines Agency some months ago, the idea of treating the comorbidities of autism BEFORE they occur.  Perhaps an idea before its time?

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 Neurofibromatosis, Tuberous 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.

  

New research investigates inherited causes of autism

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.

Using Whole-Exome Sequencing to Identify Inherited Causes of Autism

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.

The Singing Statin, the BCL-2 Gene and Epigenetics

This post has something for both the casual reader and the scientists among you.  Today I will start with the science.

Epigenetics

Epigenetics are chemical markers that can appear on your DNA as the result of some environmental exposure, like diet or stress.  Methylation is a type of epigenetic change in which methyl groups are added to DNA and switch on or off the underlying gene.  This can have severe consequences depending on which gene is affected.

Identical Twins

It seems that if one identical twin has autism, there is a 70% chance that the other twin will be autistic.  In 30% of the cases the twin is neurotypical.  Researchers have very cleverly started to analyse pairs of twins from this 30% group and look for epigenetic marks.  This would highlight genetic causes of autism.

Apoptosis

Apoptosis is a tricky word to spell, for somebody like me, but is actually something quite simple; it is programmed cell death.  Apoptosis happens in all of us, all day long.  If it gets out of control, it becomes bad and something called atrophy will occur.  Too little apoptosis can result in irregular cell growth and cancer.

 

Candidate Genes

Using the epigenetics approach, in 2010 a study was published that identified two “candidate” genes linked to autism.  They were BCL-2 and RORA.

According to that study, BCL-2 is an anti-apoptotic protein located in the outer mitochondrial membrane that is important for cell survival under a variety of stressful conditions.  In other words BCL-2 inhibits cell death.

According to another source, BCL-2 is “one of the foremost anti-apoptotic molecules”.

A very recent study has identified more such genes, using the same approach.

 

If you are really interested in the genetics of autism, there is actually a database of all the indicated genes, maintained by the Simons Foundation.

  

BCL-2 and autism

Going back to 2001, researchers had already noted that the autistic brain was deficient in BCL-2 and they suggested that:-

“These results indicate for the first time that autistic cerebellum may be vulnerable to pro-apoptotic stimuli and to neuronal atrophy as a consequence of decreased BCL-2 levels.”

The study is called :- Reduction in anti-apoptotic protein Bcl-2 in autistic cerebellum

As we have already learned, in the autistic brain the important Purkinje Cells are reduced in number by half due to atrophy.  If BCL-2 can indeed reduce this excessive apoptosis, it should be a friend indeed.

 

Stimulating production of Bcl-2

Fortunately the clever people working with Professor Wood, at the University of Minnesota, have been studying cholesterol regulation in the brain for some time.  Here is what they have been up to:-

“The lab has recently made the novel discovery that statins both in vivo and in vitro stimulate gene expression and protein levels of one of the foremost anti-apoptotic molecules, Bcl-2. Currently, studies are focused on mechanisms of statin-induction of Bcl-2”

Or in plainer English, statin drugs increase your level of BCL-2 and so reduce cell death.
 

If you want to read more here is an open access paper:-  Simvastatin Stimulates Production of the Antiapoptotic Protein Bcl-2 via Endothelin-1 and NFATc3 in SH-SY5Y Cells

 

The Singing Statin

Now we have finished with the pure science and we move back to the practical world of applied science.

Monty, aged 9, has been taking atorvastatin for a few weeks.  After day one, he developed the urge to play the piano outside of lesson time.  Every day since, he has played more and more.  Now his piano teacher says she thinks he has absolute pitch.  It turns out that this is far more common in the autistic population and there is a great deal of research that has been done on this and music/autism in general.  Here is a short article on the subject.

Now in an earlier post we established the importance of the stress hormone cortisol and also the interesting finding that you can reduce it by singing.  Then I got people asking about, “what about just listening to music” or “what about playing an instrument”.  I did not do the research, but I think nothing works like a good sing.

So yesterday I was delighted to hear that Monty has started to sing spontaneously in his room.  He put on his Mozart CD and started to sing, with his own lyrics and not just in English, but also in his second language.

I have to thank Mr Pfizer and in fact Mr Bruce Roth for bringing us Atorvastatin (called Lipitor or Sortis, depending on where you live).  Mr Roth invented it in 1985.

Perhaps BCL-2 could be better named the Singing Gene?

 

 

 

Disorders leading to Autistic-like Symptoms

When you read the research it eventually becomes clear that "autism" is just a bunch of symptoms, rather than a single disease. So autism, as such, has no cure. A specific cause of autistic symptoms in a particular person, may indeed have a remedy, but most sadly do not.

Many causes of autistic symptoms though will have therapies that can reduce and help manage the symptoms. Combine this with the neuroplasticity of the brain and behavioural therapies and a clear way forward emerges.

You will see below that oxidative damage is the main culprit. In the more rare disorders, a genetic mutation is invariably the cause, but even a mosquito can be guilty.

This blog is focused at finding effective therapies for Classic Autism.  In spite of what could be reasonably expected, this is proving very fruitful and genuinely effective therapies actually do exist.

Notes

Oxidative Brain Injury					Comments
	Classic Autism				In utero malformation of cerebellum following oxidative shock.
					Ongoing neuroinflammation. Mixed outcome.
	Regressive Autism				As for classic autism, but with a shock event that triggers inceased inflammation and prompts regression.  Mixed outcome.
	Asperger's				Mild case of classic autism. Prognosis if usually good.
	ADHD				Mild case of classic autism. Prognosis is good.
Neurological Complication of Parasitic Disease
	Cerebral Malaria				Shock inflammation of the cerebellum causes massive damage.
					Treatable if detected early
Unknown
	Childhood disintegrative disorder				Cause unknown, causes complete loss of all skills
					onset between 2 and 10 years old
Genetic mutations/malfunctions
	tuberous sclerosis complex (TSC)				Multi organ genetic disorder
					Rapamycin is used to shrink the tumors.
	Rett Syndrome				Subjects are mainly girls, male fetuses rarely survive.
					Prognosis is often poor.
	Fragile X				Neurodegeneration increases in middle age.
	Phenylketonuria				Treatable if detected early
	Adenylosuccinate lyase deficiency				Viewed as untreatable
	Guanidinoacetate Methyltransferase Deficiency (GAMT)
					Creatine deficiency syndromes
	Arginine: Glycine Amidinotransferase Deficiency (AGAT)				Treatment of oral creatine supplementation can improve
					symptoms, if initiated early, in GAMT and AGAT patients.
					Treatment for CRTR patients, oral creatine supplementation’s
	Creatine Transporter Deficiency (CRTR)				therapeutic effects are limited.
	Smith–Lemli–Opitz Syndrome				inability to produce or synthesize cholesterol due to
					mutation of the DHCR7 gene. Treatable with cholesterol
	Biotinidase deficiency				treatable with biotin
	Infantile Neuronal Ceroid Lipofuscinoses				very rare and fatal
	Sanfilippo syndrome				possible treatment with flavonoid GENISTEIN
	Histidinemia				Rare generally, except in Japan
	Succinic semialdehyde dehydrogenase deficiency (SSADHD)				Defect in ALDH5A1 gene, causes defect in GABA pathway
	Dihydropyrimidine dehydrogenase deficiency (DPD deficiency)				Genetic mutation of DPYD gene