High dose L-Serine to treat children under 7 with severe autism + ID ? It works in Korea

 

Source: Joon Kyu Park, CC BY-SA 3.0 <https://creativecommons.org/licenses/by-sa/3.0>, via Wikimedia Commons

 

Today’s post is a follow up to the recent one that showed Memantine was beneficial to people with level 1 autism, normal IQ, with ADHD and anxiety/depression.

Our reader Hoang, highlighted a recent trial in Korea that used the OTC supplement L-serine, which has a biological effect that is the opposite of Memantine. The trial is part of series looking at treating those with severe autism with ID (intellectual disability). 

High-dose L-serine has been tested in children with severe autism and intellectual disability, and the main benefits were seen in those under 7 years old. While it may work by boosting NMDA receptor activity through conversion to D-serine, other brain-supporting roles of L-serine—like helping neuron membranes and reducing stress on brain cells—could also contribute. Older children may not respond as well, possibly because their brains are less plastic or they convert less L-serine to D-serine. Researchers should now explore whether direct D-serine dosing might help older kids, but safety must be considered.

 

The Trials and Target Group

The trials of AST-001, a syrup formulation of L-serine, focused on children with severe autism and intellectual disability (ID). The phase 2 study included children aged 2–11, but the most pronounced improvements were in those under 7 years old. The benefit did not entirely disappear after age 7, but it was smaller and harder to measure.

Dosing was weight-tiered:

Weight (kg)	Dose (g, twice a day)
10–13	2
14–20	4
21–34	6
35–49	10
>50	14

The outcomes measured were adaptive behavior (Vineland Adaptive Behavior Scales II) and clinical global impressions, with high-dose L-serine showing a statistically significant improvement over placebo.

 

How L-Serine Might Work

1. NMDA Receptor Modulation

L-serine can be converted in the brain to D-serine, a co-agonist of NMDA receptors, which are critical for learning, memory, and social behavior. This mechanism aligns with the idea that boosting NMDA signaling could help in some autism. This is the exact opposite of what Memantine does.

2. Other Neuroprotective Roles

However, L-serine also supports:

• Phospholipid and myelin synthesis, crucial for neuron structure
• One-carbon metabolism and methylation, which help maintain healthy brain chemistry
• Reducing cellular stress, oxidative damage, and excitotoxicity
• L-serine is the precursor to glycine. This matters because glycine is also an NMDA co-agonist (alongside D-serine). In some brain regions glycine—not D-serine—is the primary co-agonist.

So, the clinical effect might not be solely through NMDA receptor modulation.

 

Why Benefits Are Seen Mainly in Children Under 7

Several factors may explain the age effect:

1.     Brain Plasticity – Younger brains are more adaptable, so interventions may show stronger effects.

2.     Conversion to D-serine – L-serine is converted to D-serine by serine racemase, and this may be less efficient in older children.

3.     Ceiling Effects – In older children with long-standing autism and ID, neural circuits may have already stabilized in ways that make observable behavioral improvements harder.

It is unclear whether older children truly cannot benefit, or if the benefit is harder to measure with standard adaptive behavior scales.

 

Could D-Serine Directly Help Older Children?

A hypothesis is that older children might need higher levels of D-serine than their bodies can produce from L-serine. In theory:

• Direct D-serine supplementation might overcome this bottleneck.
• Safety is the main concern, as excessive D-serine can stress kidneys or neurotransmitter systems.

No large trials have tested this yet in older children with autism.

About the Researcher

Dr Yoo-Sook Joung led the AST-001 trials. She is a psychiatrist with an interest in autism interventions and has explored approaches like animal-assisted therapy. While not a basic science researcher, her clinical insights have helped design practical trials in children with severe autism and ID.

Takeaways

• High-dose L-serine shows promising results in children under 7 with severe autism and ID. The low dose was not effective.
• Benefits may involve NMDA receptor modulation, but other neuroprotective effects are likely relevant.
• Older children may require alternative approaches (e.g., D-serine), but evidence is lacking.
• Safety and careful dosing are essential; trials so far show good tolerability, with diarrhea being the most common side effect.

 

Here is the associated research leading up the recent trial

Population Pharmacokinetic Model of AST-001, L-Isomer of Serine, Combining Endogenous Production and Exogenous Administration in Healthy Subjects

AST-001 is an L-isomer of serine that has protective effects on neurological disorders. This study aimed to establish a population pharmacokinetic (PK) model of AST-001 in healthy Korean to further propose a fixed-dose regimen in pediatrics. The model was constructed using 648 plasma concentrations from 24 healthy subjects, including baseline endogenous levels during 24 h and concentrations after a single dose of 10, 20, and 30 g of AST-001. For the simulation, an empirical allometric power model was applied to the apparent clearance and volume of distribution with body weight. The PK characteristics of AST-001 after oral administration were well described by a two-compartment model with zero-order absorption and linear elimination. The endogenous production of AST-001 was well explained by continuous zero-order production at a rate of 0.287 g/h. The simulation results suggested that 2 g, 4 g, 7 g, 10 g, and 14 g twice-daily regimens for the respective groups of 10–14 kg, 15–24 kg, 25–37 kg, 38–51 kg, 52–60 kg were adequate to achieve sufficient exposure to AST-001. The current population PK model well described both observed endogenous production and exogenous administration of AST-001 in healthy subjects. Using the allometric scaling approach, we suggested an optimal fixed-dose regimen with five weight ranges in pediatrics for the upcoming phase 2 trial.

  

Population pharmacokinetic and pharmacodynamic model guided weight-tiered dose of AST-001 in pediatric patients with autism spectrum disorder

AST-001, a novel syrup formulation of L-serine, was developed for the treatment of autism spectrum disorders (ASD) in pediatric patients. This study aimed to establish a pharmacokinetic (PK)-pharmacodynamic (PD) model to elucidate the effect of AST-001 on adaptive behavior in children with ASD. Due to the absence of PK samples in pediatric patients, a previously published population PK model was used to link the PD model by applying an allometric scale to body weight. The time courses of Korean-Vineland Adaptive Behavior Scale-II Adaptive Behavior Composite (K-VABS-II-ABC) scores were best described by an effect compartment model with linear drug effects (Deff, 0.0022 L/μg) and linear progression, where an equilibration half-life to the effect compartment was approximately 15 weeks. Our findings indicated a positive correlation between the baseline K-VABS-II-ABC score (E0, 48.51) and the rate of natural progression (Kprog, 0.015 day⁻¹), suggesting enhanced natural behavioral improvements in patients with better baseline adaptive behavior. Moreover, age was identified as a significant covariate for E0 and was incorporated into the model using a power function. Based on our model, the recommended dosing regimens for phase III trials are 2, 4, 6, 10, and 14 g, administered twice daily for weight ranges of 10–13, 14–20, 21–34, 35–49, and >50 kg, respectively. These doses are expected to significantly improve ASD symptoms. This study not only proposes an optimized dosing strategy for AST-001 but also provides valuable insights into the PK-PD relationship in pediatric ASD treatment.

 

AST‐001 versus placebo for social communication in children with autism spectrum disorder: A randomized clinical trial

Aim

This study examined the efficacy of AST‐001 for the core symptoms of autism spectrum disorder (ASD) in children.

Methods

This phase 2 clinical trial consisted of a 12‐week placebo‐controlled main study, a 12‐week extension, and a 12‐week follow‐up in children aged 2 to 11 years with ASD. The participants were randomized in a 1:1:1 ratio to a high‐dose, low‐dose, or placebo‐to‐high‐dose control group during the main study. The placebo‐to‐high‐dose control group received placebo during the main study and high‐dose AST‐001 during the extension. The a priori primary outcome was the mean change in the Adaptive Behavior Composite (ABC) score of the Korean Vineland Adaptive Behavior Scales II (K‐VABS‐II) from baseline to week 12.

Results

Among 151 enrolled participants, 144 completed the main study, 140 completed the extension, and 135 completed the follow‐up. The mean K‐VABS‐II ABC score at the 12th week compared with baseline was significantly increased in the high‐dose group (P = 0.042) compared with the placebo‐to‐high‐dose control group. The mean CGI‐S scores were significantly decreased at the 12th week in the high‐dose (P = 0.046) and low‐dose (P = 0.017) groups compared with the placebo‐to‐high‐dose control group. During the extension, the K‐VABS‐II ABC and CGI‐S scores of the placebo‐to‐high‐dose control group changed rapidly after administration of high‐dose AST‐001 and caught up with those of the high‐dose group at the 24th week. AST‐001 was well tolerated with no safety concern. The most common adverse drug reaction was diarrhea.

Conclusions

Our results provide preliminary evidence for the efficacy of AST‐001 for the core symptoms of ASD.

 

The what, when and where of treating autism

The human brain is a work in progress up until your mid 20s.

It is near adult-sized at the age of 5, but many key developmental processes remain.

As brain development goes through it various steps, it requires certain genes to be activated to produce specific proteins. This is why in some single gene autisms babies are born appearing entirely typical, because at that point they are typical. Shortly thereafter when the gene cannot produce enough of its protein (haploinsufficiency) things start developing off-track. The human body is highly adaptable and the brain keeps on changing, but now on a different track.

Many dysfunctions in autism are localized to just one part of the brain and indeed you can have the opposite dysfunction in different parts of the brain at the same time. Some dysfunctions can be just transitory, or indeed just extreme in one particular developmental window.     

When it comes to NMDA activity we know that very often in autism and schizophrenia it is disturbed. But, it can be too much or too little (hyper/hypo) and very likely this changes over time and varies in different parts of the brain.

Viewed in this broader context, it is not odd to see an intervention that is most effective up to the age of seven.

  

Conclusion

If you know a child with severe autism and intellectual disability, who is under 7 years old, maybe suggest to the parents to investigate following our proactive reader Hoang and make a trial of the OTC supplement L-Serine. You can buy it inexpensively on-line, just search “L serine bulk powder.” In the US 1kg costs about $50. Just follow the dosage in the trials.

L-serine is very safe.

Using D-serine is more problematic. In clinical studies for schizophrenia and cognitive disorders, doses ranged from 30 mg/kg/day to 120 mg/kg/day in divided doses. D-serine is mostly safe at moderate doses, but very high doses carry risks of kidney stress and excitotoxicity.

Modest amounts of L-serine can be found in eggs, chicken, milk etc. The body then converts this to D-serine using an enzyme called serine racemase and vitamin B6. Once these are used up, no more D-serine can be produced “naturally.” This is why schizophrenia researchers use D-serine itself. D-serine is also sold as a bulk OTC supplement.

If the child was actually an undiagnosed Memantine-responder, you would expect to see the following if they took high dose L-serine:

·        ↑ irritability

·        ↑ sensory overload

·        ↑ hyperactivity

·        ↑ emotional volatility

·        ↑ stereotypy

·        ↑ anxiety

Because a memantine responder is a child whose biology is defined by NMDA receptor overactivity, where excessive glutamate signalling drives irritability, sensory overload, anxiety, and cognitive stress and memantine works precisely because it reduces this hyper-NMDA state.

L-serine does the opposite, it increases D-serine and so enhances NMDA activity and so in an L-serine responder it improves:

·        learning and cognitive processing

·        social attention and engagement

·        adaptive behaviour

·        overall developmental trajectory

 

In this group, the core bottleneck is not excessive glutamatergic activity but insufficient NMDA co-agonism, especially in early development when social circuits and sensory-integration networks are still forming.

 

What does “insufficient NMDA co-agonism” mean?

NMDA receptors do not work like simple on/off switches.

They need two keys to open:

·        Glutamate – the main excitatory neurotransmitter

·        A co-agonist – either D-serine or glycine

If glutamate is present but the co-agonist is missing or too low, the NMDA receptor cannot fully activate, even though the neuron is trying to fire normally.

This situation is called NMDA hypofunction caused by insufficient co-agonism

In plain terms, the glutamate system is not actually weak. The receptor is not working properly because the “second key” is missing.

 

Neural circuits needed for learning, plasticity, and social behaviour do not work properly, because the key is missing. Go find it!

   

Why does this matter in autism with ID?

Several studies (postmortem, CSF, MR spectroscopy) show that in many children with severe autism + language delay + ID, D-serine levels are reduced in key brain areas (prefrontal cortex, temporal cortex, hippocampus).

Possible reasons:

·        Low activity of serine racemase (the enzyme converting L-serine → D-serine)

·        Higher breakdown of D-serine by DAO (D-amino acid oxidase)

·        Developmentally immature astrocytes (which supply D-serine early in life)

·        Genetic factors affecting NMDA co-agonist pathways

When D-serine is low, NMDA receptors cannot activate normally even if glutamate levels are normal or high.

 

The result:

Cognitive delay, poor adaptive behaviour, weak learning reinforcement, sensory disturbances, and poor social reciprocity.

How does L-serine help?

·        L-serine is the precursor to D-serine.

 

By giving large doses of L-serine

·        The brain produces more D-serine

 

D-serine binds the NMDA co-agonist site

·        NMDA receptors can finally reach normal activation

·        Neural circuits can strengthen and rewire more effectively

·        Behaviour improves, especially in younger children where plasticity is high

 

This is why L-serine produces the opposite clinical effect of memantine:

 

• Memantine helps when NMDA activity is too high

• L-serine helps when NMDA activity is too low because of a missing co-agonist

Wandering, Water, Sense of Danger and Accidents

We were recently at the seaside in Greece, where Monty was enjoying swimming in the sea. He is now a very competent swimmer and behaves in the water just like any other confident swimmer. Together with Mum he actually rescued a Russian swimmer in distress.  Monty does not get crazy ideas to swim to islands in the distance, or anything like that. Not so far, at least. 

Water is behind a shocking number of wanderings and deaths.

In the North American media, you can see that on a very regular basis children with autism and/or ID/MR (Intellectual Disability/Mental Retardation) wander off and get lost. Very often they are found in or beside water.

In Europe you hear much less frequently about children wandering. A high-profile case recently was an Irish teenage girl with MR/ID who disappeared while on holiday at a tiny jungle resort in Malaysia.  She left behind an open ground floor window and was found 10 days later beside a stream in a ravine a mile away. 

She had holoprosencephaly, which is an umbrella term for conditions relating to when the forebrain of the embryo fails to develop into two separate hemispheres, it includes Agenesis of the Corpus Callosum (ACC) when the part of the brain that is supposed to connect the two hemispheres fails to develop. Partial ACC and the exact opposite are features appearing in some severe autism.

People with MR/ID have no sense of danger and are usually enchanted by water. Wandering is far more likely than abduction.

Another case recently was an American teenager on a cruise arranged by his residential care home, it appears that he jumped over the deck railing at night to go for a swim in the ocean.

Even a bath tub can be dangerous, a young man with autism and epilepsy was left unattended in a bath at a UK care facility. He had a seizure and drowned.

I do think much more could be done to prevent wandering and water-related accidents. Firstly, people (parents) should be made more aware of who is at risk; anyone with a low IQ and unable to travel independently is at risk.

People with ID/MR often live in a world of cartoons, where all kinds of crazy things are possible, like jumping off a cruise ship and nobody ever gets hurt.  Going to a jungle retreat, like you are living in the Jungle Book cartoon, why wouldn’t you sneak downstairs in the night and enter your private jungle world?

Just because you have never been able to wander before does not mean you never will. 

The shortened life expectancy of people with severe autism is in large part down to preventable accidents, seizures and poor basic healthcare.

I do think that treating MR/ID would be much more socially acceptable than treating autism. Understanding the danger of crossing a road, or falling into a lake is more important than being able to tie your shoe laces.  If you can improve cognition with a pill, who could possibly object to that? 

It is no surprise that we have www.Treatable-ID.org but no www.Treatable-ASD.org 

In reality you will struggle to have treating ID taken seriously, although for many people it is possible.

Wnt, TCF4 and Pre-myelinating Oligodendrocytes

Cartoons in art class - Monty is getting ready for Easter break, but not in the Maldives

Today’s post may sound very complicated and narrow, but it is very relevant to people with the following: - 

·        Pitt Hopkins Syndrome (insufficient expression of the Transcription Factor #4  TCF4 gene)

·        Multiple Sclerosis

·        Some Mental Retardation/Intellectual Disability (MR/ID)

·        Schizophrenia

·        Impaired Wnt signalling

·        Perhaps PAK1 inhibitor responders

I do feel that Multiple Sclerosis could be treated very much better if some effort was made to translate the existing science, freely available to all, into therapy. You could greatly improve many people’s lives just by repurposing cheap existing drugs.

In simple terms, to produce myelin that you need to coat axons in your brain, you need a type of cell called an oligodendrocyte (OL).  You need a lot of these cells and you need them to get busy. They place tiny pieces of white insulation along axons of your brain cells, this produces the so called “white matter”.  These pieces of insulation are needed to make electrical signals flow correctly in your brain.

It has been shown that in some people the oligodendrocyte precursors (OLPs) do not “mature” and instead get stuck as premyelinated oligodendrocytes (pre-OL). That means reduced myelination and loss of white matter.

It is clearly shown in the graphic below: -

Tcf4 is expressed in oligodendrocyte lineage in human developmental white matter and in active areas of MS lesions. (A) Tcf4 is expressed in white matter tracts during myelination of human developmental brain at postnatal age 1 mo, 3.5 mo, and 16 mo, but is not expressed by 7 yr. Tcf4 colocalizes with Olig2 when expressed in the developing human corpus callosum. (B) Tcf4 protein expression is evident in active MS lesions, but it is not seen in normal-appearing white matter (NAWM) or in the core of chronic MS lesions. An illustrative MS case is shown with several lesion types present. NAWM stains with Luxol Fast Blue (LFB) and contains sparse LN3(HLA-DR)-positive inflammatory cells, organized SMI-31 axon fibers, and no Tcf4-positive cells. Chronic plaques have sparse LFB staining and LN3-positive cells, intact axons, but no Tcf4-positive cells. In contrast, Tcf4-positive cells are present in active areas of plaques with abundant LN3-positive cells and intact demyelinated axons. Tcf4 expression in active lesions colocalizes (open arrowheads) with a subset of Olig2 cells.


Don’t worry if you don't follow everything. There is nothing wrong with your white matter.

We come back to Wnt signalling that we covered in depth in older posts. This is a complex signalling pathway implicated in autism, some cancers and other conditions. You can both increase and reduce Wnt signalling, which will affect the transcription of numerous genes.

TCF4 is the Pitt Hopkins gene. We have across this syndrome several times, while it is rare, a milder miss-expression of the gene is actually quite common.  Reduced expression of TCF4 is a common feature of MR/ID very broadly. TCF4 has been found to be over-expressed in schizophrenia.

People with Multiple Sclerosis (MS) have been found to have oligodendrocytes “stuck” as non-myelinating (premyelinated oligodendrocytes, pre-OL). Inhibiting the Wnt pathway might play a role in treatment during periods of acute demyelination, when there is a lack of newly minted myelin-producing oligodendrocytes. The study below does refer to Wnt inhibitors in the pipeline as potential cancer therapies.  It looks to me that safe Wnt inhibitors like the cheap drugs widely used to treat children with parasites (Mebendazole/ Niclosamide) could be repurposed to treat the acute phase of multiple sclerosis.

Mebendazole/ Niclosamide are safe and dirt cheap, whereas the (slightly) disease changing MS drugs currently cost $50,000+ a year.

TCF4 links everything together

Wnt signalling needs to be active to block premyelinated oligodendrocytes into transforming into oligodendrocytes (OL). So by inhibiting Wnt signalling you may remove one of the problems in MS; you probably only need to do this during relapses of MS.  

There actually is a finally stage to getting the oligodendrocytes (OL) to myelinate many axons and not be lazy.

In the jargon “dysregulation of Wnt–β-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination”.

A miss-expression of TCF4 is clearly also going to affect myelination and its does in both Pitt Hopkins and MS.

One feature of Pitt Hopkins (caused by haploinsufficiency of the transcription factor 4) is indeed delayed myelination measured via MRI at the age of 1. By the age of 9 white matter (the myelin-coated part of your brain) appears normal. This fits with what I highlighted in red under figure 6 above.

Nothing is simple. Activating Wnt signalling is known to increase expression of TCF4.  

Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS

The progressive loss of CNS myelin in patients with multiple sclerosis (MS) has been proposed to result from the combined effects of damage to oligodendrocytes and failure of remyelination. A common feature of demyelinated lesions is the presence of oligodendrocyte precursors (OLPs) blocked at a premyelinating stage. However, the mechanistic basis for inhibition of myelin repair is incompletely understood. To identify novel regulators of OLP differentiation, potentially dysregulated during repair, we performed a genome-wide screen of 1040 transcription factor-encoding genes expressed in remyelinating rodent lesions. We report that ∼50 transcription factor-encoding genes show dynamic expression during repair and that expression of the Wnt pathway mediator Tcf4 (aka Tcf7l2) within OLPs is specific to lesioned—but not normal—adult white matter. We report that β-catenin signaling is active during oligodendrocyte development and remyelination in vivo. Moreover, we observed similar regulation of Tcf4 in the developing human CNS and lesions of MS. Data mining revealed elevated levels of Wnt pathway mRNA transcripts and proteins within MS lesions, indicating activation of the pathway in this pathological context. We show that dysregulation of Wnt–β-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination, based on (1) conditional activation of β-catenin in the oligodendrocyte lineage in vivo and (2) findings from APC^Min mice, which lack one functional copy of the endogenous Wnt pathway inhibitor APC. Together, our findings indicate that dysregulated Wnt–β-catenin signaling inhibits myelination/remyelination in the mammalian CNS. Evidence of Wnt pathway activity in human MS lesions suggests that its dysregulation might contribute to inefficient myelin repair in human neurological disorders 

Potential Tcf4-catenin activities in oligodendrocyte development

The pattern of Tcf4 protein expression, from P1 to P30 and during remyelination after injury, defines the window of potential canonical Wnt pathway functions. Within this context, we observed that Tcf4 expression marked ∼15%–20% of OLPs at any given stage assessed. These findings were consistent with two possibilities. First, Tcf4 expression could demarcate a subset of OLPs. Second, it was possible that Tcf4 expression transiently marks all (or the vast majority) of OLPs during development. Our functional evidence strongly supports the latter conclusion, based on the fact that activity of activated β-catenin is Tcf-dependent (van de Wetering et al. 2002), coupled with the robust phenotype in DA-Cat and APC^Min animals, in which we observe pervasive effects of Wnt pathway dysregulation on myelin production throughout the CNS. Interestingly, although Tcf4 proteins are coexpressed with nuclear Olig1 proteins, Tcf4 segregated from cells expressing Olig1 mRNA transcripts, consistent with the possibility that Tcf4 is expressed at a transition stage when nuclear Olig1 proteins become down-regulated during remyelination.

Previous work has suggested inhibitory functions of Tcf4 on myelin basic protein gene expression in vitro (He et al. 2007), and our studies indicate that Tcf4 interactions with β-catenin inhibit myelination in vivo. Additional studies are warranted to rule out possible β-catenin-independent roles for Tcf4 in oligodendrocyte development. Although Wnt pathway activation has conventionally been thought of as activating gene targets, recent work has identified novel Tcf–β-catenin DNA regulatory binding sites that repress targets (Blauwwkamp et al. 2008). In this regard, one intriguing candidate target is HYCCIN (DRCTNNB1A), a Wnt-repressed target (Kawasoe et al. 2000) with essential roles in human myelination (Zara et al. 2006), which is expressed in rodent oligodendrocytes and down-regulated in Olig2cre/DA-Cat mice (Supplemental Fig. 8). Further studies are needed to better understand Tcf4–catenin function and its direct gene targets during oligodendrocyte lineage progression.

Wnt pathway dysregulation in OLPs as a mechanism leading to chronic demyelination in human white matter diseases

Therapeutic opportunities might arise from an enhanced understanding of the process regulating normal kinetics of remyelination. How might the negative regulatory role of the canonical Wnt pathway help to explain the pathology of demyelinating disease? Delayed remyelination due to Wnt pathway dysregulation in OLPs could lead to chronic demyelination by OLPs then missing a “critical window” for differentiation (Miller and Mi 2007; Franklin and Ffrench-Constant 2008). This “dysregulation model” of remyelination failure requires the Wnt pathway to be active during acute demyelination, as suggested by data from our animal systems and human MS tissue.

Canonical WNT signaling has been implicated in a variety of human diseases (Nelson and Nusse 2004), and gain-of-function mutations in β-catenin are etiologic in several cancers including the majority of colon adenocarcinomas. Approaches for treating Wnt-dependent cancers by promoting differentiation (and hence cell cycle arrest or apoptosis) using pharmacological inhibitors of the pathway are under development (Barker and Clevers 2005). It is possible that such antagonists might play a role in the therapeutic enhancement of remyelination by normalizing the kinetics of myelin repair. If so, the animal models described here (e.g., APC^+/−) should be useful in preclinical testing. However, it is important to note that while dysregulation of a pathway might delay remyelination, it is overly simplistic to expect that inhibition of the same pathway would accelerate repair in the complex milieu of an MS lesion in which several inhibitory pathways might be active, compounded by the presence of myelin debris (Kotter et al. 2006). Indeed, because of the need to synergize with other processes (e.g., those associated with inflammation), accelerated differentiation might negatively affect repair (Franklin and Ffrench-Constant 2008). Further work is needed to comprehensively understand interactions of regulatory networks required for optimal remyelination and how these may be dysregulated in human demyelinating diseases.

Neurologic and ocular phenotype in Pitt-Hopkins syndrome and a zebrafish model.

Abstract

In this study, we performed an in-depth analysis of the neurologic and ophthalmologic phenotype in a patient with Pitt-Hopkins syndrome (PTHS), a disorder characterized by severe mental and motor retardation, carrying a uniallelic TCF4 deletion, and studied a zebrafish model. The PTHS-patient was characterized by high-resolution magnetic resonance imaging (MRI) with diffusion tensor imaging to analyze the brain structurally, spectral-domain optical coherence tomography to visualize the retinal layers, and electroretinography to evaluate retinal function. A zebrafish model was generated by knockdown of tcf4-function by injection of morpholino antisense oligos into zebrafish embryos and the morphant phenotype was characterized for expression of neural differentiation genes neurog1, ascl1b, pax6a, zic1, atoh1a, atoh2b. Data from PTHS-patient and zebrafish morphants were compared. While a cerebral MRI-scan showed markedly delayed myelination and ventriculomegaly in the 1-year-old PTHS-patient, no structural cerebral anomalies including no white matter tract alterations were detected at 9 years of age. Structural ocular examinations showed highly myopic eyes and an increase in ocular length, while retinal layers were normal. Knockdown of tcf4-function in zebrafish embryos resulted in a developmental delay or defects in terminal differentiation of brain and eyes, small eyes with a relative increase in ocular length and an enlargement of the hindbrain ventricle. In summary, tcf4-knockdown in zebrafish embryos does not seem to affect early neural patterning and regionalization of the forebrain, but may be involved in later aspects of neurogenesis and differentiation. We provide evidence for a role of TCF4/E2-2 in ocular growth control in PTHS-patients and the zebrafish model. 


Conclusion  

If you have a myelinating disease, you might want to read up on TCF4 and Wnt signalling. Probably not what the Minions take to read on the beach in the Maldives.

We also should recall the importance of what I am calling the "what, when and where" in neurological disorders. This is important for late onset disorders like schizophrenia, since the symptoms often develops in late teenage years and so it is potentially preventable, if identified early enough.

Today we see that TCF4 is expressed in white matter only in early childhood. If you knew what changes take place in the brains of children who go on to develop schizophrenia, you might well be able to prevent its onset.

Preventing some autism is already possible, as has been shown in mouse models, but in humans it is more complicated because of the "when" and quite literally the "where". There will be a post showing how the brain overgrowth typical of autism can be prevented using bumetanide, before it occurs, at least in mice.


  

Accept Autism or Treat It?

Back in the old days autism was a hidden condition and those affected were usually tucked away in institutions. A trend then slowly developed towards inclusion, with the Individuals with Disabilities Education Act (IDEA) being passed in 1975 in the US.  Other countries have slowly moved in this direction, with France only this year finally following suit.

Having moved on from hiding autism, we then had the new diagnosis of Asperger’s appearing in the 1990s and so autism became a much broader diagnosis. Then followed the idea of awareness and diagnosing adults.

Now we have an ever-growing number of people diagnosed with this “autism” thing, that other people are supposed to be aware of. Is it a disease, a dysfunction, a disability or just a difference?

Most importantly are you supposed to treat it, or just accept it?

I recently watched a BBC documentary where a doctor was the presenter and she was talking about schizophrenia. She said that at medical school she was taught that there are medical problems and there are mental health problems, for some reason she was taught that mental health problems are not just medical problems of the brain. Somehow mental health problems are supposed to be different and not based in biology, where did that idea come from?

The program went on to show that about 8% of schizophrenia appears to be caused by NMDAR antibodies. This is a condition where antibodies attack NMDA receptors in the brain, this causes hallucinations and other symptoms that a psychiatrist would diagnose as schizophrenia.  Rather than treating lifelong with anti-psychotics, the patient needs immunotherapy and can then resume a normal life.

It looks like 30% of modern autism is associated with cognitive impairment leading to a measured IQ of less than 70. This is intellectual disability (ID) to autism parents and mental retardation (MR) to the rest of the world.

The interesting finding in this blog is that some MR/ID is actually treatable. I did suggest to the Bumetanide researchers that they should include measuring IQ in their clinical trials.

I do not see how anyone could object to treating MR/ID, even those parents with Asperger’s who find the idea of treating their child’s severe autism to be repulsive.

Maths, Autism and Hans Asperger

Some people with Asperger’s are brilliant at maths, and I think these are the ones that Hans Asperger was mostly studying in Vienna in the 1940s. Lorna Wing came along in 1981 and then Uta Frith in 1991 and translated into English one of Asperger’s 300 papers, the 1943/4 “Die Autistischen Psychopathen im Kindesalter” and then named autism with no speech delay as Asperger’s Syndrome.

In 1994 the Americans adopted Asperger’s as a diagnosis and then rejected it two decades later in 2013 (DSM5).

In Asperger’s 1943 paper he described Fritz, Harro, Ernst and Hellmuth, who he termed "autistic psychopaths”; all four had high IQs and Asperger called them "little professors" because they could talk about the area of ​​their special interest in detail and often accumulated amazing knowledge.

I think Asperger’s should have been left as the "Little Professor’s Syndrome" (high IQ only).

In 2018 some people have realized that from the mid 1930’s almost all people in high positions in Austria and Germany were implicated in some pretty evil Nazi programs, including killing mentally disabled children. Asperger, being a senior psychiatrist at the University of Vienna, obviously played a role, not wanting to pay a visit to the local Gestapo basement.  He was living in a police state, where people tend to do what they are told.  Unlike most of the University medical faculty he was not a member of the Nazi party.

The particularly evil Austrian psychiatrist was Dr Emil Gelny, who modified an ECT (Electro Convulsive Therapy) device to give his subjects lethal shocks. Having personally killed hundreds of mental patients, after the end of the war he escaped to Baghdad, continued practising as a doctor and lived till he was 71. He was never brought to account and Mossad clearly never paid a visit, so I guess there were no Jewish victims.  His highly publicized use of ECT is one reason why it is little used today, even though it does seem to help certain otherwise untreatable conditions.

What surprised me was that in 1930 (before the rise of Hitler) half of the doctors in Vienna were Jewish and indeed half of the Vienna medical faculty were Jewish. So not so anti-Semitic in 1930.  All these doctors had to leave and so the young Hans Asperger made rapid career progress.

Things were not all rosy elsewhere.

I recently read that in London in the 1950s Jewish doctors struggled to progress within the faculty of medical schools and so some emigrated to the US.

We should also note that the Nazis took their inspiration for eugenics from America, where it backed by well-known names such as the Carnegie Institution and the Rockefeller Foundation. California, which we now might consider very liberal, was the centre for forced sterilization.  Between 1907 and 1963 over 64,000 individuals were forcibly sterilized under eugenic legislation in the United States.

So, I think Asperger deserves a break, he was likely no better or worse than other Austrians, unlike most he did not join the Nazi Party. Wing and Frith (a German) were naïve to name a psychiatric syndrome based on the work of an Austrian written during the Nazi period. I think you would not name a reservation for native Americans after General George Custer. 

Back to Maths

One group of kids with severe autism do have near/distant relatives who have remarkable maths skills but were never diagnosed with anything other than being a bit odd.

Monty, now aged 14 with ASD, had great difficulty with even the most basic maths until the age of 9, so much so that we did not bother to teach it, we focused on literacy.

Five and a half years of drug treatment has produced a boy who is now great at maths, at least in his class of 12 years olds.

Coordinates, no problem; negative numbers, no problem. It still now shocks those who knew him from before.

Today I received a message from Monty’s assistant at school and a photo of his classwork, where he is solving simple equations like
7x - 6 = 15

That is not a complex problem for a typical boy, but at the age of 9, after 5 years of intensive ABA therapy, we were still challenged by the most basic single digit addition.  

Nice neat handwriting

Should you treat autism? 

Pretty obviously I think autism should be treated. I would favour treating all types of genuine disease.

If you can treat it, I’d definitely call it a disease.

I would treat people with Down Syndrome to raise their IQs to improve their quality of life and I would also treat them preventatively to avoid early onset Alzheimer’s, which they are highly likely to develop. By the age of just 40 years old, studies have shown significant levels of amyloid plaques and tau tangles, which will lead to Alzheimer’s type dementia.

If you cannot treat it, then you’re just going to have to accept it.

But how would you know you cannot treat it, if you do not at least try?

Since there are hundreds of types of autism, there is no one-stop treatment shop for autism. For medical advice you should go to see a doctor, but mainstream medicine believes autism is untreatable. Today it is really up to the parents themselves to figure out what, if anything, to do.  Dr Frye might suggest you try Leucovorin, B12 and NAC; some DAN doctor will tell you it is all about candida; another will treat everyone with cod liver oil; another will blame parasites; most will blame vaccines.  One lady will charge you large amounts of money for her genetic tests, baffle you with complicated looking charts and then sell you her supplements by the bucket-load. This blog suggests numerous therapies may be partially effective in specific people, a case for personalized medicine.  My Polypill is what works for my son's autism; it is nice to know it works for some others, but it does not work for all autism, that would never be possible.  

With schizophrenia, you could start by treating that 8% with NMDAR antibodies via a science-based medical therapy; this has got to be a big step forward over psychiatric drugs.

We have gone from aged 9, struggling with: -

5 + 2 =  ?

To aged 14, solving worded maths questions, where you have to create the formula and to neatly solving simple equations like:

7x – 6  =  15                  

In algebra there is no doubt effective treatment wins over acceptance.

There is more to life than algebra, but it looks pretty clear that going through life with an IQ 30+ points less than your potential is a missed opportunity. 

Trivial autism

Many people with mild autism and an IQ much greater than 70 are happy the way they are and do not want treatment. For them autism is not a disability, it is just a difference, so we might call it trivial autism.  Unless years later they commit suicide or hurt other people, then it was not so trivial after all.

Unfortunately, some people with trivial autism will go on to produce children with not so trivial autism.

Then you end up with situation that the adult can block what is in the child’s interest, just like deaf parents who refuse their deaf child to have cochlear implants to gain some sense of hearing. Cochlear implants are only effective when implanted in very young children, so by the time you are old enough to have you own say in the decision, it is too late.  Some deaf parents do not want hearing children – odd but true.

So, I come back to my earlier point better to treat ID/MR, don’t even call it treating autism.

How can the Asperger’s mother then refuse treatment to her son with autism plus MR/ID? She can still be able to celebrate her difference, while he gets a chance to learn to tie his own shoe laces, put his shirt on the right way around and do all kinds of other useful things.

So, focus on the 31% of autism? 

CDC - Community Report on Autism 2018

What was the intellectual ability of the children identified with ASD?

                     
Unfortunately, in the research trials they often exclude severe autism, so they exclude people with epilepsy, people with MR/ID and people will self-injurious behaviour (SIB). The very people who clearly need treatment are excluded from the trials to determine what are effective autism treatments. Rather odd.