Thursday, 12 November 2015

More Support for the use of Statins in some Autism

Monty, aged 12 with ASD, has been taking Atorvastatin for two years, with a clear cognitive improvement from day one.  

This improvement is lost when this therapy is interrupted.

There are several posts in this blog giving the scientific basis why statins might be beneficial in some autism, these included the genes/proteins RAS, PTEN and BCL2.  In addition, statins possess potent anti-inflammatory properties.

Following a flood of visits to this blog to read about statins and autism, I did a quick check and in recent weeks at least three papers have been published suggesting the potential for statins to improve some autism.

I include the word “some” because with 800 currently identified autism genes, and I expect eventually it will be thousands, what works for one person’s “autism” may not help the next person’s “autism” and might even make it worse.

The first paper is the one getting the media coverage, it is from the University of Edinburgh, plus Mark Bear et al from MIT.  Mark Bear’s lab has featured in this blog several times, particularly relating to Fragile-X.  Lovastatin is being already trialed in humans with Fragile-X.

I use Atorvastatin (Lipitor) because it has best side effect profile.  Lovastatin and Simvastatin will have the same effect.  In some countries these drugs are available cheaply OTC.

Their therapeutic effect in autism, based on my sample of one, is from the first pill.

Over to the "experts":-

Intellectual disabilities and autism spectrum disorders could share similar defects although their genetic causes are different, according to Scottish scientists.

A study of two models of intellectual disability in mice by Edinburgh University has found that they share similar disease mechanisms.

Researchers also found that treatment with a statin drug called Lovastatin, which is often used to treat high cholesterol, can correct high levels of protein production in the brain linked to the conditions.

The findings suggest that different types of intellectual disabilities may benefit from common therapeutic approaches, the researchers say.

Professor Peter Kind, Director of the University of Edinburgh’s Patrick Wild Centre for Research into Autism, Fragile X Syndrome and Intellectual Disabilities, said: “Statins, such as lovastatin, are already used widely for treating people, including children, for high cholesterol with minimal side effects.

“Further studies are needed to determine whether these existing medications could also help people with intellectual disabilities.”

The study has been published in the Journal of Neuroscience

The full paper is here:-

Previous studies have hypothesized that diverse genetic causes of intellectual disability (ID) and autism spectrum disorders (ASDs) converge on common cellular pathways. Testing this hypothesis requires detailed phenotypic analyses of animal models with genetic mutations that accurately reflect those seen in the human condition (i.e., have structural validity) and which produce phenotypes that mirror ID/ASDs (i.e., have face validity). We show that SynGAP haploinsufficiency, which causes ID with co-occurring ASD in humans, mimics and occludes the synaptic pathophysiology associated with deletion of the Fmr1 gene. Syngap+/− and Fmr1−/y mice show increases in basal protein synthesis and metabotropic glutamate receptor (mGluR)-dependent long-term depression that, unlike in their wild-type controls, is independent of new protein synthesis. Basal levels of phosphorylated ERK1/2 are also elevated in Syngap+/− hippocampal slices. Super-resolution microscopy reveals that Syngap+/− and Fmr1−/y mice show nanoscale alterations in dendritic spine morphology that predict an increase in biochemical compartmentalization. Finally, increased basal protein synthesis is rescued by negative regulators of the mGlu subtype 5 receptor and the Ras–ERK1/2 pathway, indicating that therapeutic interventions for fragile X syndrome may benefit patients with SYNGAP1 haploinsufficiency.
SIGNIFICANCE STATEMENT As the genetics of intellectual disability (ID) and autism spectrum disorders (ASDs) are unraveled, a key issue is whether genetically divergent forms of these disorders converge on common biochemical/cellular pathways and hence may be amenable to common therapeutic interventions. This study compares the pathophysiology associated with the loss of fragile X mental retardation protein (FMRP) and haploinsufficiency of synaptic GTPase-activating protein (SynGAP), two prevalent monogenic forms of ID. We show that Syngap+/− mice phenocopy Fmr1−/y mice in the alterations in mGluR-dependent long-term depression, basal protein synthesis, and dendritic spine morphology. Deficits in basal protein synthesis can be rescued by pharmacological interventions that reduce the mGlu5 receptor–ERK1/2 signaling pathway, which also rescues the same deficit in Fmr1−/y mice. Our findings support the hypothesis that phenotypes associated with genetically diverse forms of ID/ASDs result from alterations in common cellular/biochemical pathways.

The other two papers are from 2015 Society for Neuroscience annual meeting in Chicago.


A drug that blocks a cancer-related pathway normalizes neuron number and prevents behavior problems in mice that lack a copy of the autism-linked chromosomal region 16p11.2. Researchers presented the unpublished results yesterday at the 2015 Society for Neuroscience annual meeting in Chicago.
Loss of 16p11.2 results in intellectual disability, enlarged head, obesity and, often, autism. This region spans 27 genes — including one called ERK1, part of a signaling cascade that regulates cell growth. The cascade, called the RAS pathway, is hyperactive in some types of cancer and in four rare autism-linked neurodevelopmental disorders, collectively dubbed ‘RASopathies.’ The proteins encoded by ERK1 and the related ERK2 gene carry out many of the molecular consequences of RAS pathway activation.

Paradoxically, the ERK proteins are hyperactive in mice lacking a copy of 16p11.21. This hyperactivation coincides with a period of intense neuron development in the mouse embryo. The animals also have too few neurons in some parts of the cerebral cortex, the brain’s outer layer, and too many neurons in others.

“Because of this aberrant ERK hyperactivity, we were thinking that we can potentially try to bring the levels down by using a specific ERK inhibitor,” says Joanna Pucilowska, a postdoctoral fellow in Gary Landreth’s lab at Case Western Reserve University in Cleveland, Ohio.

Sniffing clues:

Pucilowska and her colleagues used an experimental drug that blocks activation of the ERK proteins. They injected the drug into pregnant mice to investigate its effects on neuron development in mouse embryos.

Treating mice with the drug prenatally for five days stabilizes ERK activity, the researchers found. It also normalizes neuron numbers in the cerebral cortex.
The treatment has lasting effects on behavior, too. Unlike untreated mice that lack a copy of 16p11.2 — which are underweight, hyperactive and have memory problems — the treated mice resemble those that do not have the chromosomal deletion.
The researchers discovered for the first time that mice lacking 16p11.2 are quicker than those without the deletion to sniff out a hidden snack in their cage, suggesting they have a highly acute sense of smell, like some people missing 16p11.2. Female mice with the deletion are also faster to retrieve pups that stray from the safety of their nest, an innate maternal behavior. The drug treatment normalizes both behaviors.

Pucilowska says she and her colleagues would like to test the drug in cells derived from people missing a copy of 16p11.2. If it works in human cells the same way it does in mice, then it might be possible to treat people with the deletion using cholesterol-lowering drugs called statins, which are also known to block signaling in the RAS pathway. “This can potentially lead to the first treatment for children with 16p11.2 deletion,” Pucilowska says.

Structural changes in the connections between neurons may underlie the enhanced learning and motor skills seen in mice with an extra copy of the autism-linked gene MeCP2. Blocking these changes with a drug blunts the animals’ performance.
The findings, presented yesterday at the 2015 Society for Neuroscience annual meeting in Chicago, point to neural mechanisms underlying the restricted interests and, in some cases, exceptional learning abilities seen in people with autism.
“This could lead to enhanced learning and enhanced performance in constrained behaviors, like in autistic savants,” says Ryan Ash, a graduate student in Stelios Smirnakis’ lab at Baylor College of Medicine in Houston. “Maybe they can’t iteratively refine those kinds of behaviors over time, so they get stuck in a behavior, which can be exceptional in certain cases but then impaired in others.”
People carrying an extra copy of MeCP2 often have autism. Mice with the same duplication have autism-like symptoms, such as avoiding social interactions with other mice.
“But they also have a super-learner phenotype,” Ash says. They perform better than controls do on a test of motor skill learning that involves balancing on a rotating rod. Typical mice fall off the rod as its speed increases, but mice with the duplication learn to coordinate their feet so that they can stay on about 30 seconds longer.
When mice learn a motor task, new synapses, connections between neurons, form in the brain1. The researchers suspected that the superior learning abilities of the mice carrying the extra MeCP2 might stem from alterations in the formation and stability of these neuronal links.
To test this hypothesis, the researchers used microscopy to image neurons in the brain that connect to the spinal cord and control movement. They took pictures of the same neurons before and after the mice practiced the rotating rod test for four days, and again after the animals had four days of rest.
Spine support:
As expected, training spurred neurons in typical mice to form new signal-receiving projections, called dendritic spines. About half of these spines remained after four days of rest, suggesting the formation of stable memories. Mutant mice form more spines than controls do, and more of them stay put after the mice take a break.
The stable spines tend to cluster. Enhanced performance on the rod tracks with a greater number of clustered spines remaining after the rest period.
“We think this is important because spines that are near each other can drive the cell more strongly when they get activated at the same time,” Ash says.
Training stimulates greater activation of a signaling cascade called the RAS pathway in the mutant mice than it does in controls. Activation of this pathway is known to strengthen clustered spines2.
Blocking the activation of this pathway with an experimental drug called SL327 lowers the mutants’ performance on the rotating rod back to the normal range. And the spines in these animals also look more like those of typical mice.
The findings suggest that spine formation and stability underlie the enhanced learning abilities of the mutant mice. Both processes appear to depend on the activation of the RAS pathway.
The drug the researchers used lasts only for a few hours, so it is not likely to help people with autism, Ash says. But cholesterol-lowering drugs called statins block activation of the same pathway by a different mechanism. “Maybe you could do a more chronic treatment with a statin, but we haven’t tried that yet,” he says.
Other mouse models of autism show enhanced performance on the rotating rod test. These include mice with a duplication in chromosomal region 15q11-13 and with mutations in the CNTNAP2, NLGN3 and NRXN1 genes, Ash says.

Interestingly, mice that lack a copy of MeCP2 — the gene mutated in the autism-linked disorder Rett syndrome — have impaired performance on the same test, and show reduced spine stability. “I would hypothesize that all of these things are actually the opposite in the Rett mice,” Ash says.


  1. Hello Peter,
    It's really helpful to know that a subclass in autism shows elevated lipic profile and could be treated with statins or some other interventions you mention in earlier posts, like Biotin, Niacin and so on.
    Since lipic profile can "say something" what if it is the opposite? My son has a low lipic profile, cholesterol:118 (150-200), tryglicerides: 48 (50-200), HDL 65>35, LDL 43<160.
    Also his uric acid seems high, considering his general good results, 8 (3-7). Do you think uridine might be of some help? If so, should it be combined with choline?
    Thank you very much

  2. Sorry, it's Petroula again. Do you mean that the use of statins could be regardless of their lipic profile? Wouldn't that be risky in terms of side effects?

    1. The effect is not connected to high/low cholesterol. Statins were trialed in children with Neurofibromatosis, without side effects. It would nice if high cholesterol was a biomarker for those with autism who would respond behaviorally, but I doubt it.

      The main effect is cognitive, and I think your son is not challenged in that area. But it works from the first pill, so you can see if it works before worrying about long term side effects.

      I think trying uridine is a very good idea as suggested in that case study.

      Metabolic treatment of hyperuricosuric autism.

  3. Hi Peter, what do you think about the antidystonic effects of calcium channel antagonists like nifedipine? Could be effective and safe? Valentina

    1. Hi Valentina, other people have suggested the use of nifedipine in autism. I have no experience of it. People who respond well to Verapamil, but cannot tolerate it, certainly could consider other calcium channel blockers. They are all slightly different.

  4. My 4 year old with autism has a PTEN mutation. I just found your blog and I find your posts about Mtor and PTEN very interesting as I have been looking for potential treatments. In regards to statins, can this drug be given to kids with normal to low levels of cholesterol? Should we measures levels every couple of months?
    We have a very open minded doctor that might be ok prescribing if we show good research. Can you share a link that you find very useful? Thanks for the great information !

    1. Hi Laura,

      Statins effect on PTEN is not via the cholesterol lowering mechanism, but it will nonetheless lower cholesterol.

      In a trial on young children with Neurofibromatosis with normal cholesterol, the statin did not cause a cholesterol problem. (It did not help the Neurofibromatosis). I see that as an indication that statin use is possible in children with normal cholesterol. It is all about balancing risks. As you know, loss of PTEN is 100% certain to cause problems. So a 10% reduction in cholesterol may be a price very well worth paying.

      Here is a good study:-

      Regulation of the PTEN promoter by statins and SREBP

      That study also refers to PPARγ. It may well be that PPARγ agonists may also help your child. they are referred to in previous posts.

      Statins are FDA approved in obese children.

      If getting a blood sample is easy, I would measure cholesterol before trying the statin. After a few weeks of statin therapy there should be a new steady state, so I now only rarely check cholesterol level.

      In my son the effect of the statin as apparent from day one, but not in terms of thing that appear on any autism rating scale. He began to so things he was able to do before, but had somehow felt blocked from doing so. He would get "stuck" at the top of the stairs and be unable to walk down unless someone took his hand. Most notable was that he started to play the piano all by himself, without his teacher. Before he would only play when she was present. It suddenly changed after one statin pill. When I stop the statin, again he gets "stuck"/inhibited whatever you want to call it.

      So you have to be able to observe your child and notice these small changes, that are in fact really big changes. My son now plays the piano better than a neurotypical child of his age and genuinely follows mainstream education (with an assistant). Without Atorvastatin/Bumetanide/NAC it was a very different picture, falling further and further behind in all areas.

      Effect of Simvastatin on Cognitive Functioning in Children With Neurofibromatosis Type 1

    2. This guy has a good overview of mTOR and autophagy (which is decreased in PTEN mutant mouse models):

      Also, as far as supplements go I know that resveratrol inhibits mTOR as does spermidine (best source would be wheat germ in my opinion) and one study I read suggested they act synergistically, probably via the mTOR pathway.

      What I will do is mix some resveratrol powder from some capsules along with some trehalose (Swansons make it) which is a sugar that promotes autophagy and helps counter the bad taste from wheat germ, some wheat germ, and then mix it all up with peanut butter and then make a sandwich out of it for my son. Ideally you want as much wheat germ as you can in the sandwich but if it is not palatable then your child won't like it. Sometimes kids can be picky if they see anything on the edges of the bread so you might have to mask this peanut butter's appearance with a thin layer of peanut butter on the edges.

  5. hello Peter
    My son is Asd ,he has a 15q11.2 dup and 16p11.2 dup you mention on this post.
    Do you mean statins could help?

    1. Hello Olga, the above study refers to 16p11.2 deletion. Your son has the opposite, he has duplication.

      So that study itself does not indicate the statin.

      However, I have proceeded to successfully trial a statin, without any genetic evidence regarding my son.

      When effective, the statin improves cognitive function, so if your son has any challenges in this area, a short trial may be well worthwhile.

  6. Yes ,he has duplication in 16p11.2 .
    But you also mention 15q 11.2 dup and he has this dup too.
    He has very high level un cognitive function.
    His problem is on comunication and language

    1. Olga, the only way to know is to try. Atorvastatin is one of the most prescribed drugs in the world. If you try it for a few days, then you will know if it helps.

  7. Peter, when is your post on PANs/PANDAS/rheumatic fever coming?

    1. I have not forgoten it, just I came across some other rather simpler topics which have therapies. It should be ready in a couple of weeks.

  8. Hi Peter,
    I used 1mg Bumetenide everyday .My son is 5 years....37 lb.One thing I forgot to mention that on Bumedenide though it did not improve cognition,it helped my son get completely toilet trained.He got potty trained within 1 week of Miccil.He was almost toilet trained before that meaning that he did not have accidents but there was no initiation from his side.Now,he does everything on his own.
    Do you think atorvastation or clozo.....(the name that you mentioned ) ,which one would be better for cognition?Do you know of any online pharmacy that would be safe to order?I live in California.
    Warm Regards

    1. SB, I think if he has figured out the toilet he has gained cognitively. Lots of small steps can take you a long way. For my son both atorvastatin and clonazepam improved cognition. I know people in the US are ordering online from Mexico, but I have no experience of that.

  9. Case report of adult SYNGAP1 patient treated with lovastatin:



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