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Tuesday, 24 November 2015

A Possible Therapy for Rett-like Autism Variants, as well as MCI and even Schizophrenia?

Today’s post was triggered by an intriguing comment left on this blog.

As we have seen in previous posts, the single gene causes of “autism” like fragile X and Rett syndrome are themselves on a spectrum, with some people worse affected than others.  Boys almost always being more severely affected than girls.

It also appears possible that a partial dysfunction of this same gene/protein may lead to a much milder version of these same syndromes.

Rett syndrome is well studied and as we saw in the earlier post about growth factors in autism, one key feature is an almost complete lack of Nerve Growth Factor (NGF).  Reduced levels of NGF are associated with several diseases and also the aging process.  In many cases of Mild Cognitive Impairment (MCI), as seen in dementia in older people, reduced NGF can be the root problem.


Rett Syndrome

Rett syndrome usually gets grouped as part of autism.

Almost all people with Rett syndrome are female; here is why.  

Rett syndrome is caused by mutations in the gene MECP2 located on the X chromosome. Because the disease-causing gene is located on the X chromosome, a female born with an MECP2 mutation on her X chromosome has another X chromosome with an ostensibly normal copy of the same gene, while a male with the mutation on his X chromosome has no other X chromosome, only a Y chromosome; thus, he has no normal gene. Without a normal gene to provide normal proteins, the male fetus is unable to slow the development of the disease, hence the failure of male fetuses with a MECP2 mutation to survive.

MECP2 is known to play a wider role in some autism, epilepsy and MR/ID




We saw that the Italian Nobel Laureate, Rita Levi-Montalcini, who discovered Nerve Growth factor (NGF), maintained her mental sharpness into her 90s by taking her homemade NGF eye drops in her old age.

Human Growth Factors, Autism and the Centenarian Nobel Laureate


The problem with NGF is that it does not cross the blood brain barrier (BBB), so there are no NGF tablets.  Rita’s solution was eye drops; I expect the nasal route might also be possible.

Dompe Farmaceutici are developing NGF eye drops as an orphan drug to treat Retinitis pigmentosa

Bypassing the BBB is of great interest to medical science as we have seen in earlier posts.



Stimulating NGF with Hericium Erinaceus (Lion’s Mane Mushroom)

There is a surprising amount of literature about the use of a mushroom called Hericium Erinaceus, or Lion’s Mane, to treat various neurological conditions.  The made mode of action is stimulating production of NGF.

It was Lion’s Mane that the reader of this blog is giving to his daughter.  This is not typical autism, but in this era of diagnosing almost any childhood developmental dysfunction as autism, I expect autism is label many would apply to it.  


“Our 14 year old daughters previous diagnoses of PDD has recently been dropped, re-evaluated, and named Mild Cognitive Disability with Anxiety and Dementia. This turned out to be a great turn of phrase for us because we began to see and approach her condition differently. To begin with we started look at the similarities between her poor working memory and irritability as more similar to the dementia you would see in early stages of Alzheimer’s than something that could be treated with ABA as we had previously tried


Is this a mild version of Rett Syndrome, like the Zappella variant is?


Anyway, it responds to a therapy that increases NGF, a key deficit in Rett Syndrome.



Studies supporting the use of Hericium Erinaceus / Lion’s Mane/ Yamabushitake and also Amyloban 3399


Lion’s mane is also called Yamabushitake and a rather expensive concentrated product derived from it is called Amyloban 3399.

As always, the problem with supplements is quality control, lack of standardization and even contamination.

There would seem to be the potential to make an effective drug based on Lion’s Mane.

It would also seem logical to trial  Dompe Farmaceuticis NGF eye drops in children with Rett Syndrome and in older people with early dementia, not to mention adults with schizophrenia (see study on  Amyloban 3399 below).




Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: a double-blind placebo-controlled clinical trial.

 

Abstract

 

A double-blind, parallel-group, placebo-controlled trial was performed on 50- to 80-year-old Japanese men and women diagnosed with mild cognitive impairment in order to examine the efficacy of oral administration of Yamabushitake (Hericium erinaceus), an edible mushroom, for improving cognitive impairment, using a cognitive function scale based on the Revised Hasegawa Dementia Scale (HDS-R). After 2 weeks of preliminary examination, 30 subjects were randomized into two 15-person groups, one of which was given Yamabushitake and the other given a placebo. The subjects of the Yamabushitake group took four 250 mg tablets containing 96% of Yamabushitake dry powder three times a day for 16 weeks. After termination of the intake, the subjects were observed for the next 4 weeks. At weeks 8, 12 and 16 of the trial, the Yamabushitake group showed significantly increased scores on the cognitive function scale compared with the placebo group. The Yamabushitake group's scores increased with the duration of intake, but at week 4 after the termination of the 16 weeks intake, the scores decreased significantly. Laboratory tests showed no adverse effect of Yamabushitake. The results obtained in this study suggest that Yamabushitake is effective in improving mild cognitive impairment.
  



Our group has been conducting a search for compounds for dementia derived from medicinal mushrooms since 1991. A series of benzyl alcohol derivatives (named hericenones C to H), as well as a series of diterpenoid derivatives (named erinacines A to I) were isolated from the mushroom Hericium erinaceum. These compounds significantly induced the synthesis of nerve growth factor (NGF) in vitro and in vivo. In a recent study, dilinoleoyl-phosphatidylethanolamine (DLPE) was isolated from the mushroom and was found to protect against neuronal cell death caused by b-amyloid peptide (Ab) toxicity, endoplasmic reticulum (ER) stress and oxidative stress. Furthermore, the results of preliminary clinical trials showed that the mushroom was effective in patients with dementia in improving the Functional Independence Measure (FIM) score or retarding disease progression.



Reduction of depression andanxiety by 4 weeks Hericium erinaceus intake.

 

Abstract


Hericium erinaceus, a well known edible mushroom, has numerous biological activities. Especially hericenones and erinacines isolated from its fruiting body stimulate nerve growth factor (NGF) synthesis, which expects H. erinaceus to have some effects on brain functions and autonomic nervous system. Herein, we investigated the clinical effects of H. erinaceus on menopause, depression, sleep quality and indefinite complaints, using the Kupperman Menopausal Index (KMI), the Center for Epidemiologic Studies Depression Scale (CES-D), the Pittsburgh Sleep Quality Index (PSQI), and the Indefinite Complaints Index (ICI). Thirty females were randomly assigned to either the H. erinaceus (HE) group or the placebo group and took HE cookies or placebo cookies for 4 weeks. Each of the CES-D and the ICI score after the HE intake was significantly lower than that before. In two terms of the ICI, "insentive" and "palpitatio", each of the mean score of the HE group was significantly lower than the placebo group. "Concentration", "irritating" and "anxious" tended to be lower than the placebo group. Our results show that HE intake has the possibility to reduce depression and anxiety and these results suggest a different mechanism from NGF-enhancing action of H. erinaceus.



Peripheral Nerve Regeneration Following Crush Injury to RatPeroneal Nerve by Aqueous Extract of Medicinal Mushroom Hericium erinaceus (Bull.:Fr) Pers. (Aphyllophoromycetidea







We treated 10 patients with schizophrenia in this study, randomly selected by each doctor, working at six different institutions. Patients ranged across age, duration of illness, sex, or psychotropic drugs used.
All patients were refractory to currently available antipsychotic agents, but improved without exception and with no adverse reactions.
Average scores on the positive and negative syndrome scale (PANSS) improved significantly for all items, including positive, negative, and general psychopathology.



  
Amyloban3399---contains Amycenon, a standardized extract of HE containing hericenones and amyloban – and is currently being tested for safety as a health food supplement (Mori, Inatomi, Ouchi et al., 2009). A clinical trial with 8 volunteers was conducted to demonstrate the cognition-enhancing properties of Amyloban3399 (Lotter, 2012). Results of the study showed that Amyloban3399 improved mood, memory and sense of wellbeing. Overall Amyloban3399 was generally well tolerated.

Schizophrenia is the most devastating disease of the major psychoses. It has been repeatedly observed in clinical practice that although positive symptoms may be reduced within a few week treatment period, while it takes months or years to see improvements in cognitive symptoms. Atypical neuroleptic clozapine is associated with reduced liability for extrapyramidal symptoms and is effective in treatment-resistant schizophrenia. However, adverse effects limit the widespread use of clozapine.

Amyloban3399 was originally thought to be a drug for dementia.

However, based on my clinical observation, I asked a schizophrenia patient presented in this report to take Amyloban3399. He had been treatment-resistant and suffered from severe side effects for more than 30 years. He agreed to take Amyloban3399 and he has experienced dramatic life improvements and has been doing quite well for these three years.




Conclusion


Most autism variants appear to have high NGF, so the therapies discussed here relate to Rett Syndrome and other low NGF variants of autism, not to mention dementia.

Signs of Rett syndrome that are not similar to autism:

  • affects almost exclusively girls


Signs of Rett syndrome that are similar to autism:

·         incontinence
·         screaming fits
·         inconsolable crying
·         breath holding, hyperventilation & air swallowing
·         avoidance of eye contact
·         lack of social/emotional reciprocity
·         markedly impaired use of nonverbal behaviors to regulate social interaction
·         loss of speech
·         sensory problems
Signs of Rett syndrome that are also present in cerebral palsy (regression of the type seen in Rett syndrome would be unusual in cerebral palsy; this confusion could rarely be made):

·         possible short stature, sometimes with unusual body proportions because of difficulty walking or malnutrition caused by difficulty swallowing
·         hypotonia
·         delayed or absent ability to walk
·         gait/movement difficulties
·         ataxia
·         microcephaly in some - abnormally small head, poor head growth
·         gastrointestinal problems
·         some forms of spasticity
·         chorea - spasmodic movements of hand or facial muscles
·         dystonia
·         bruxism – grinding of teeth




In people with low NGF, therapies known to increase it, look well worth investigating.






6 comments:

  1. Is NGF somehow related to Insulin Growth Factor,which now has Orphan Drug Designation by the US Food and Drug Administration for Rett Syndrome?

    http://www.kgi.edu/news-and-events/rett-syndrome-designation

    Features similar to Alzheimer' or dementia were a big part of my clinical picture until my cerebral folate deficiency was treated.For me,this is due to Severe MTHFR Deficiency and Homocystinuria.This is also the cause of my autism and other brain issues.I wonder if features that resemble Alzheimer's or dementia are common to all more serious,genetic causes of autism.I have many of the other features you list here as well,but I know from my WES,I have an additional genetic diagnosis beyond Severe MTHFR Deficiency,that is much rarer than Rett's.

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    Replies
    1. Roger, all the growth factors are related. So if you are low in NGF, you will likely be in IGF-1 and GH (growth hormone). You will likely be small, with a small head. There are various IGF-1 related drugs in development, including NNZ-2566.

      The growth factors are related but perform different functions. It seems that most people with autism have he opposite, ie too much growth factors, at least in the first couple of years. This is why many people with autism had accelerated brain growth in the first 3 years and in some people this also results in a big head.

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  2. This is off topic so feel free to delete this post after reading it but I am sure you would be interested in this paper that was released just today:

    https://pure.royalholloway.ac.uk/portal/files/25728469/Chang_et_al_Brain_2015.pdf

    The paper identifies decanoic acid (aka capric acid c10:0 ) which is a medium chain triglyceride as a broad spectrum AMPA receptor inhibitor for controlling epileptic seizures and is the primary component in why the MCT diet for those with drug-resistant epilepsy is one of the most if not the most potent interventions for treating the condition. Decanoic acid both prevented seizures in two separate seizure models; one via blocking GABAergic inhibition and the other by potentiating NMDA receptors via blocking/lowering magnesium.

    MCT oil's main components are decanoic acid and octanoic acid (found not to have any significant effect except when they chemically mutated its structure slightly). My child does not have seizures (age 6_, but they usually develop when autistic children hit puberty so it is thought high risk populations for seizures should take preventative measures. Valproate (a close analog of decanoic acid) of course is one drug used for controlling seizures and has many known long-term side effects, but as best I know there are no known downsides to ingesting massive quantities of MCT oil (as some people do already when following a ketogenic diet as a typ 2 diabetes intervention).

    Just some food for thought (no pun intended).

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    Replies
    1. Thanks Tyler, it is interesting. Nobody seemed to know why the ketogenic diet helped with seizures.

      Wikipedia have already updated "Decanoic Acid" with your paper, it highlights:-

      "It should however be noted that orally ingested medium chain fatty acids would be very rapidly degraded by first-pass metabolism by being taken up in the liver via the portal vein, and are quickly metabolized via coenzyme A intermediates through β-oxidation and the citric acid cycle to produce carbon dioxide, acetate and ketone bodies"

      So are they suggesting eating decanoic acid will not help ???

      I agree with you that the risk of developing seizures can and should be lowered. I think that bumetanide and verapamil can contribute to this.

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    2. Well, who really knows for sure. The 2013 paper now cited by Wikipedia

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3625124/

      actually cites another paper from 2002 that as far as I can tell does not discuss anything at all about decanoic acid specifically in terms of its metabolism other than this paragraph:

      http://jn.nutrition.org/content/132/3/329.long

      "Fats varying in fatty acid chain lengths are metabolized differently (1–8). Medium-chain triglycerides (MCT),3 containing 6–12 carbon fatty acids, differ from long-chain triglycerides (LCT), which have fatty acids of > 12 carbons, in that they are absorbed directly into the portal circulation and transported to the liver for rapid oxidation (1). LCT, however, are transported via chylomicrons into the lymphatic system, allowing for extensive uptake into adipose tissue. Therefore, it has been hypothesized that the rapid metabolism of MCT may increase energy expenditure (EE), decrease their deposition into adipose tissue and result in faster satiety. The objective of the present article is to review literature concerning the effects of MCT on EE, fat deposition and food intake as a means to establish the potential efficacy of MCT in the prevention of obesity in humans."

      Also, the 2013 paper specifically talks about other MCFAs in goat milk that are not in MCT oil and them not being very abundant and therefore not likely to do much because of being quickly metabolized by the liver (that is my reading). Of course, this "review" was done in 2002 and cites research that is even older, so I have no idea how relevant all of this is, especially considering there is some debate as to a lot of substances getting into the brain these days as the BBB is not as much of a barrier as some have thought. For example, it is thought GABA supplementation is a waste of money because of the BBB, but some of it does make it through and even more so apparently when combined with L-Arginine which raises the nitric oxide levels in the blood (and also thought to make the BBB more permeable).

      Nevertheless, The MCT diet has been shown to reduce seizures and it was always thought ketones were the reason, but now that does not seem to be the case, so perhaps the liver does not metabolize all of the dietary decanoic acid before it reaches the brain, or perhaps the guy editing the Wikipedia entry made an error in reading the 2013 paper (which sounds ambigous to me and which cites a paper that is only a review that doesn't actually have an experiment to back it up).

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  3. Hello, Thank you for the information. Our son struggles with language and we give him Lion's Mane.
    You said there was problems with getting good quality LM. We started a small mushroom farm last year and sell dehydrated LM on ebay at a great price. My husband studied mycology for a decade and grows excellent quality mushrooms. https://www.facebook.com/Mycovations

    ReplyDelete

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