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.

The Hyperuricosuric Subtype of Autism, Uridine and Antipurinergic Therapy

A subtype of people with classic autism have uric acid excretion which is elevated (>2 Standard Deviations above the normal mean). 

According to the research these hyperuricosuric autistic individuals may comprise approximately 20% of the autistic population.

There is nothing new in these findings and the research goes back 15 years.  At that time nobody looked too deeply as why uric acid was elevated and the role of the purine metabolism in behaviour.

Dr Naviaux at the University of California is the researcher who is developing antipurinergic therapy.  I suspect his research is really at the root of what is going on and that high uric acid is just a consequence of an upstream metabolic dysfunction.

In the meantime, is there any benefit of treating people with autism and hyperuricemia?

It does seem that in some people doing just that does produce tangible benefits and not just in autism; there was even a study in bipolar disorder.  In bipolar, verapamil can also sometimes be effective.

Uric acid

Uric acid is a chemical created when the body breaks down substances called purines. Purines are found in some foods and drinks. These include liver, anchovies, mackerel, dried beans and peas, and beer.

Most uric acid dissolves in blood and travels to the kidneys. From there, it passes out in urine.  A high level of uric acid in the blood is called hyperuricemia,  the standard test though is to measure uric acid in urine.

  

Purine metabolism and autism

To learn about the purine metabolism and autism, I suggest you read the research by Naviaux, like the study below:

Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy

Autism spectrum disorders (ASDs) now affect 1–2% of the children born in the United States. Hundreds of genetic, metabolic and environmental factors are known to increase the risk of ASD. Similar factors are known to influence the risk of schizophrenia and bipolar disorder; however, a unifying mechanistic explanation has remained elusive. Here we used the maternal immune activation (MIA) mouse model of neurodevelopmental and neuropsychiatric disorders to study the effects of a single dose of the antipurinergic drug suramin on the behavior and metabolism of adult animals. We found that disturbances in social behavior, novelty preference and metabolism are not permanent but are treatable with antipurinergic therapy (APT) in this model of ASD and schizophrenia. A single dose of suramin (20 mg kg⁻¹ intraperitoneally (i.p.)) given to 6-month-old adults restored normal social behavior, novelty preference and metabolism. Comprehensive metabolomic analysis identified purine metabolism as the key regulatory pathway. Correction of purine metabolism normalized 17 of 18 metabolic pathways that were disturbed in the MIA model. Two days after treatment, the suramin concentration in the plasma and brainstem was 7.64 μM pmol μl⁻¹ (±0.50) and 5.15 pmol mg⁻¹ (±0.49), respectively. These data show good uptake of suramin into the central nervous system at the level of the brainstem. Most of the improvements associated with APT were lost after 5 weeks of drug washout, consistent with the 1-week plasma half-life of suramin in mice. Our results show that purine metabolism is a master regulator of behavior and metabolism in the MIA model, and that single-dose APT with suramin acutely reverses these abnormalities, even in adults.

Hyperuricemia

  

Purine synthesis is increased approximately 4-fold in hyperuricosuric autistic patients, so they have elevated levels in their blood and also excrete high levels.

Be aware that there is both Hyperuricemia and Hypouricemia.

It looks like things can easily get mixed up.

Some people have low levels of uric acid in their blood, because the excrete too much in their urine.

Causes of hyperuricemia can be classified into three functional types: increased production of uric acid, decreased excretion of uric acid, and mixed type. Causes of increased production include high levels of purine in the diet and increased purine metabolism.

In the case study below where hyperuricosuric autism was successfully treated, they actually used a therapy which is claimed for Hypouricemia

You will see reference below to this:-

Antiuricosuric drugs are useful for treatment of hypouricemia and perhaps also hyperuricosuria

This is very odd and please let me know if you think of a logical explanation.

It seems that the therapies for hypouricemia may treat hyperuricemia in autism.

Here is a summary from Wikipedia:-

Hypouricemia

Treatment

Idiopathic hypouricemia usually requires no treatment. In some cases, hypouricemia is a medical sign of an underlying condition that does require treatment. For example, if hypouricemia reflects high excretion of uric acid into the urine (hyperuricosuria) with its risk of uric acid nephrolithiasis, the hyperuricosuria may require treatment.

Drugs and dietary supplements that may be helpful

·         Inositol

·         Antiuricosurics

                          

Antiuricosurics

Antiuricosuric drugs raise serum uric acid levels and lower urine uric acid levels. These drugs include all diuretics, pyrazinoate, pyrazinamide, ethambutol, and aspirin.

Antiuricosuric drugs are useful for treatment of hypouricemia and perhaps also hyperuricosuria, but are contraindicated in persons with conditions including hyperuricemia and gout.

Dietary sources of uridine

Some foods that contain uridine in the form of RNA are listed below. Although claimed that virtually none of the uridine in this form is bioavailable "since - as shown by Handschumacher's Laboratory at Yale Medical School in 1981 - it is destroyed in the liver and gastrointestinal tract, and no food, when consumed, has ever been reliably shown to elevate blood uridine levels', this is contradicted by Yamamoto et al, plasma uridine levels rose 3.5 fold 30 minutes after beer ingestion, suggesting, at the very least, conflicting data. On the other hand, ethanol on its own (which is present in beer) increases uridine levels, which may explain the raise of uridine levels in the study by Yamamoto et al. In infants consuming mother's milk or commercial infant formulas, uridine is present as its monophosphate, UMP, and this source of uridine is indeed bioavailable and enters the blood.

·         Sugarcane extract

·         Tomatoes (0.5 to 1.0 g uridine per kilogram dry weight)

·         Brewer’s yeast (1.7% uridine by dry weight)

·         Beer

·         Broccoli

·         Offal (liver, pancreas, etc.)

Consumption of RNA-rich foods may lead to high levels of purines (adenosine and guanosine) in blood. High levels of purines are known to increase uric acid production and may aggravate or lead to conditions such as gout. Moderate consumption of yeast, about 5 grams per day, should provide adequate uridine for improved health with minimal side effects.

Hyperuricemia

Medications most often used to treat hyperuricemia are of two kinds: xanthine oxidase inhibitors and uricosurics. Xanthine oxidase inhibitors decrease the production of uric acid, by interfering with xanthine oxidase. Uricosurics increase the excretion of uric acid, by reducing the reabsorption of uric acid once the kidneys have filtered it out of the blood. Some of these medications are used as indicated, others are used off-label. Several other kinds of medications have potential for use in treating hyperuricemia. In people receiving hemodialysis, sevelamer can significantly reduce serum uric acid, apparently by adsorbing urate in the gut

Non-medication treatments for hyperuricemia include a low purine diet (see Gout) and a variety of dietary supplements. Treatment with lithium salts has been used as lithium improves uric acid solubility.

Decreased excretion

The principal drugs that contribute to hyperuricemia by decreased excretion are the primary antiuricosurics. Other drugs and agents include diuretics, salicylates, pyrazinamide, ethambutol, nicotinic acid, ciclosporin, 2-ethylamino-1,3,4-thiadiazole, and cytotoxic agents.

A ketogenic diet impairs the ability of the kidney to excrete uric acid, due to competition for transport between uric acid and ketones

Hyperuricosuric Autism

Purine metabolism abnormalities in a hyperuricosuric subclass of autism.

 Abstract

A subclass of patients with classic infantile autism have uric acid excretion which is >2 S.D.s above the normal mean. These hyperuricosuric autistic individuals may comprise approx. 20% of the autistic population. In order to determine the metabolic basis for urate overexcretion in these patients, de novo purine synthesis was measured in the cultured skin fibroblasts of these patients by quantification of the radiolabeled purine compounds produced by incubation with radiolabeled sodium formate. For comparison, de novo purine synthesis in normal controls, in normouricosuric autistic patients, and cells from patients with other disorders in which excessive uric acid excretion is seen was also measured. These experiments showed that de novo purine synthesis is increased approx. 4-fold in the hyperuricosuric autistic patients. This increase was less than that found in other hyperuricosuric disorders. No unusual radiolabeled compounds (such as adenylosuccinate) were detected in these experiments, and no gross deficiencies of radiolabeled nucleotides were seen. However, the ratio of adenine to guanine nucleotides produced by de novo synthesis was found to be lower in the cells of the hyperuricosuric autistic patients than in the normal controls or the cells from patients with other disorders. These results indicate that the hyperuricosuric subclass of autistic patients have increased de novo purine synthesis, and that the increase is approximately that expected for the degree of urate overexcretion when compared to other hyperuricosuric disorders. No particular enzyme defect was suggested by either gross deficiency of a radiolabeled compound or the appearance of an unusual radiolabeled compound, and no potentially neurotoxic metabolites were seen. Although an enzyme defect responsible for the accelerated purine synthesis was not identified, the abnormal ratio of adenine to guanine nucleotides suggests a defect in purine nucleotide interconversion.

                                    

Here is a case study regarding the successful treatment of hyperuricosuric autism with uridine supplementation.

Metabolic treatment of hyperuricosuric autism.

Abstract

A single male subject with hyperuricosuric autism was treated for a period of 2 years with an oral dose of uridine, which increased from 50 to 500 mg/kg/day. This patient experienced dramatic social, cognitive, language, and motor improvements. These improvement decreased within 72 h of the discontinuation of uridine, but reappeared when uridine supplementation was resumed. Thus, it appears that patients with hyperuricosuric autism benefit from metabolic therapy with oral uridine therapy in a manner similar to that seen in other disorders of purine metabolism in which there is autistic symptomatology.

Uridine as a therapy in Bipolar Disorder

Here is a small trial using uridine to treat bipolar disorder in depressed adolescents:-

Open-Label Uridine for Treatment of Depressed Adolescents with BipolarDisorder

           Abstract

This report is an open-label case series of seven depressed adolescents with bipolar disorder treated with uridine for 6 weeks. Treatment response was measured with the Children's Depression Rating Scale-Revised and the Clinical Global Impressions scale. Uridine was associated with decreased depressive symptoms, and was well tolerated by study participants. Further systematic studies of uridine are warranted.

Conclusion

  

In people with autism and high levels of uric acid in urine and blood, there are some interesting avenues to pursue.  Very confusingly, they appear to be the therapies more commonly suggested for hypouricemia.

Uridine seems a good choice worth investigating for children with high levels of uric acid.

Beer is better reserved for adults with Asperger’s.

It may indeed turn out that high uric acid is a biomarker for people who will respond to Naviaux’s antipurinergic therapy.