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

https://gene.sfari.org/GeneDetail/MECP2

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 Farmaceutici’s 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.

  

Compounds for dementia from Hericium erinaceum

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

Improvement of refractory schizophrenia on using Amyloban_3399 extracted from Hericium erinaceum

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.

Case Report: Recovery from Schizophrenia Using AmylobanⓇ3399, Compounds Extracted from Hericium erinaceum

  

AmylobanⓇ3399---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 AmylobanⓇ3399 (Lotter, 2012). Results of the study showed that AmylobanⓇ3399 improved mood, memory and sense of wellbeing. Overall AmylobanⓇ3399 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 AmylobanⓇ3399. 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.

Autism, Schizophrenia, MR, 5 Overlapping Genes and Epigenetic Dysfunction

In a recent post I raised the issue of maybe we should be looking at the schizophrenia research, given that the condition appears very closely related to ASD.  Then I got rather side tracked by MR (Mental Retardation), now known as Intellectual Disability, in polite society.  Since schizophrenia is adult-onset, I thought it might attract some serious research; indeed it does.  

It turns out there may have been more sense than you thought, in my making “connections” between autism, schizophrenia and MR.

A striking study has just been published from Trinity College, Dublin.  It draws these three conditions together using genes and makes a remarkable conclusion regarding epigenetics.  Epigenetic change has already been highlighted as a key process behind the development of autism. 

The full paper is not openly available, but below is the abstract and here is a press release from the University. 

De novo mutations in schizophrenia implicate chromatin remodelling and support agenetic overlap with autism and intellectual disability

An excellent lay person’s summary is available in this article:-

A Single Genetic Variation Is Shared By People With Schizophrenia ,Autism, And Intellectual Disability

 

Scientists believe some cases of schizophrenia are caused by gene mutations passed from parents to children with environmental factors exacerbating the effects of such mutations. Yet researchers also believe some cases of the mental disorder may be caused by de novo genetic mutations (DNMs). DNMs are new defects in genes that occur only in offspring — in such cases, neither parent possesses the same defects as the child. These mutations are simple copying errors caused during mechanical DNA replication. They occur infrequently in every human being during sperm and egg development, but typically they have no overall impact on human health.

However, when de novo mutations occur in a gene or genes indispensable for normal development they have devastating consequences. For this reason, McCombie and his colleagues, in an ongoing collaboration with Dr. Aiden Corvin of Trinity College, Dublin, hypothesized there may some special link between schizophrenia and DNMs.

For the current study, then, the team enlisted the help of 42 “trio” families in which the child, but neither parent, was diagnosed with schizophrenia and/or psychosis. They also enrolled 15 trio families with a history of psychosis. Then they set to work, searching for de novo mutations. What did they discover?

Among the 42 affected children in the study, they discovered de novo mutations in three genes: AUTS2, CDH8, and MECP2. (In prior genetic studies, mutations on these very same genes have been identified in people with autism.) Two other mutated genes found in the participants — HUWE1 and TRAPPC9 — have been similarly linked to people with intellectual disability.  Of these five "overlapping" genes, three — CHD8, MECP2 and HUWE1 — play a role in what scientists call the epigenetic regulation of transcription. That is, these three genes are involved in a complex molecular process that determines when and which genes are switched on or switched off.

"There's a growing awareness of the importance of epigenetic regulation during brain development, as well as in cognition in the mature brain," said Dr. Shane McCarthy, a CSHL research investigator and lead author of the new study. This regulation is the reason why the team’s discovery is so important — normal brain development depends on these genes. With this study, then, de novo mutations of these genes have been linked to not just schizophrenia but autism and intellectual disability as well.

Conclusion

This is actually all very important.  Epigenetics is a mechanism whereby the environment can affect your genes (flipping a specific gene, from on to off, or off to on).  Epigenetic changes can be inherited and so pass through the generations.  In theory, it can potentially be reversed.  Epigenetic change is not a good thing; but it seems that in people with autism, key genes have mutated that make them more prone to such epigenetic change.  So this might explain why people with autism are prone to so many other things (comorbidities) as well.  It might also explain why they are autistic in the first place; they were already at risk, but in addition they were more vulnerable to any kind of environmental insult.  The number of environmental insults is increasing in modern society and we are slowly accumulating some of the epigenetic flaws of our ancestors.  This might explain the increase in autism, particularly in modern societies, where environmental insults are more likely.

The other interesting point is that the five overlapping genes related to autism, MR and schizophrenia in the study are all new mutations; they were not inherited from the parents.  Many parents, and indeed pseudo-experts with their therapy “protocols”, often suggest that autism is nothing to do with genetics and they look for other factors to "blame", like heavy metals.  Parents clearly do not want to feel autism was their “fault”.  As this study shows, these five critical genetic causes are not inherited, they are just the result of imperfections in the copying process.  So in the case of these five genes, parents can accept the scientific evidence without any feeling of guilt. 

People with autism, but no MR, should probably count themselves very lucky indeed.