New insights into myelination reviewed through the What, When and Where autism framework

 

A new paper was recently published by researchers at the City University of New York (CUNY) may have implications far beyond myelin disorders such as multiple sclerosis. The study demonstrated that glucose is not merely a fuel source for the developing brain, but also acts as a developmental signal controlling myelin formation.

We know that myelination can be delayed, or just impaired, in many types of autism.

Modern imaging increasingly suggests that some neurodevelopmental disorders involve altered developmental timing of white matter maturation, rather than structural defects.

That fits very well with:

• delayed milestones
• asynchronous development
• regression windows
• partial catch-up trajectories

 

The technology available includes:

Conventional MRI — shows gross white matter and myelination patterns; useful for detecting delayed myelination, hypomyelination, or structural white matter abnormalities.

Diffusion Tensor Imaging (DTI) — advanced MRI technique measuring white matter connectivity and tract integrity indirectly through water diffusion.

Advanced myelin imaging (MTI, Myelin Water Imaging, MRS) — more specialized scans that estimate myelin content or metabolic function related to myelin and brain energy use.

 

Researchers Discover a New Link Between Brain Sugar Levels and Myelin Development

https://www.gc.cuny.edu/news/researchers-discover-new-link-between-brain-sugar-levels-and-myelin-development

 

Oligodendrocytes make myelin, and you need a lot of them.

An oligodendrocyte progenitor cell (OPC) is an immature brain cell that can divide and later mature into an oligodendrocyte, the cell responsible for producing myelin around nerve fibers.

The paper showed that high local glucose levels stimulated oligodendrocyte progenitor cells to divide and increase their numbers rather than mature immediately into myelin-producing cells.

While lower glucose states and alternative fuels such as ketone bodies supported maturation into myelin-producing oligodendrocytes. Importantly, when glucose-derived acetyl-CoA production was impaired, oligodendrocytes were still able to mature and eventually produce myelin by switching to ketone-derived metabolic pathways.

In essence:

·        Glucose was especially important for expanding the number of OPCs.

·        Ketones can support later oligodendrocyte maturation and myelin production when glucose pathways were impaired.

·        Ketones cannot replace glucose

·        Ketones can augment a glucose deficient brain

 

While the study focused on myelination, it may also provide a useful framework for thinking about autism and neurodevelopmental disorders.

One conceptual model I use to understand autism is what I call the “3W framework”, or the What When and Where of autism:

• What dysfunction?
• Where in the brain?
• When during development?

This new research fits remarkably well within this framework.

 

WHAT dysfunction?

Autism is unlikely to represent one single biological abnormality. Two autistic individuals may share behavioral features while having very different underlying neurobiology.

Potential dysfunctions may include:

• Synaptic dysfunction
• Mitochondrial abnormalities
• Redox dysregulation
• Neuroinflammation
• ER stress
• Myelination abnormalities
• Developmental timing abnormalities
• Excitation/inhibition imbalance

This new paper introduces another important candidate dysfunction -
metabolic regulation of oligodendrocyte development and myelination.

The important insight is that metabolism itself appears to regulate developmental state transitions.

The study showed that glucose-derived acetyl-CoA regulates histone acetylation and developmental gene expression in OPCs. In other words, metabolism is not simply supplying energy to the brain. It is helping instruct cells when to proliferate and when to mature.

This is a major conceptual shift.

In autism research, metabolism has traditionally been viewed mainly through the lens of energy deficiency or mitochondrial dysfunction. However, this paper supports a newer idea emerging across neuroscience:

Metabolism may act as a developmental signaling system.

This may help explain why some autistic individuals show:

• Delayed rather than absent development
• Uneven cognitive profiles
• Fluctuating developmental trajectories
• Temporary regressions
• Later partial catch-up

These patterns are difficult to explain using static “brain damage” models but fit more naturally with dysregulated developmental timing.

 

WHERE in the brain?

The same dysfunction can produce very different outcomes depending on where it occurs.

Abnormal myelination in:

• Frontal regions may affect executive function and social cognition
• Temporal regions may affect language processing
• Cerebellar circuits may affect sensory prediction and motor timing
• White matter tracts may affect long-range synchronization and processing speed
• Brainstem regions may affect autonomic regulation and arousal

This may explain why autism presents so heterogeneously.

Importantly, systemic treatments are too blunt. Most interventions affect the entire brain simultaneously. A therapy that improves one network may destabilize another.

This may partly explain why:

• Some individuals improve dramatically with metabolic interventions
• Others show little effect
• Some worsen paradoxically

The “Where” dimension is likely critically important but remains difficult to target clinically.

WHEN during development?

This may be the most important insight of all.

The developing brain is not static. Different developmental stages require different metabolic and signaling environments.

The paper demonstrated that:

• High glucose states supported OPC proliferation
• Alternative metabolic fuels supported oligodendrocyte maturation and myelin synthesis

This implies that metabolic requirements change across developmental stages.

That concept may have profound implications for autism.

Many developmental disorders show:

• Delayed milestones
• Asynchronous development
• Developmental plateaus
• Regression windows
• Later partial catch-up

The traditional assumption has often been that cells or circuits are permanently defective.

However, this paper suggests that some neurodevelopmental disorders may involve delayed or dysregulated developmental transitions rather than irreversible failure.

The study is particularly interesting because the mice initially showed reduced myelination but later partially compensated through alternative metabolic pathways involving ketone-derived acetyl-CoA.

This resembles the developmental trajectories seen in many neurodevelopmental disorders, where:

• Development is delayed rather than absent
• Skills may emerge late
• Periods of apparent stagnation may later resolve
• Regression may sometimes reflect failure of compensation during periods of rising developmental demand

This may help explain why some therapies only appear effective during certain developmental windows.

A treatment beneficial during one phase of development may be ineffective or even counterproductive during another.

 

Implications for autism therapies

This paper does not prove that autism is a myelination disorder, nor does it prove that ketogenic therapies are effective for autism.

However, it strengthens several emerging ideas:

• Metabolism may regulate developmental timing
• Myelination may be metabolically sensitive
• Alternative fuels such as ketones may support some developmental processes
• Neurodevelopmental disorders may involve impaired metabolic flexibility
• Therapeutic timing may matter enormously

The future of autism therapy may eventually require understanding:

• What dysfunction is present
• Where it is occurring in the brain
• When during development intervention is most effective

The era of searching for a single universal autism treatment may eventually give way to developmentally timed, biologically targeted interventions tailored to specific neurobiological profiles.

This new myelination research may represent an important step toward that future.

Note that this paper from CUNY does not mention autism, it is just about the myelination process.

 

The use of ketones in autism

A small number of people with autism appear to respond very well to ketone ester supplements. These products are still relatively niche, expensive, and can be difficult to obtain outside the United States. One of the best known examples is KetoneAid KE4.

Ketone esters can produce a substantial and measurable increase in blood levels of the ketone beta-hydroxybutyrate (BHB), often sustained for several hours. This differs significantly from many cheaper “ketone” products, particularly ketone salts, which typically produce much smaller and shorter-lived increases in BHB.

Why some autistic individuals respond positively to ketones remains unclear, but several mechanisms are plausible:

• Alternative brain energy supply
• Improved mitochondrial efficiency
• Reduced glucose dependence
• Changes in redox balance
• Effects on neuronal excitability
• Altered inflammation and signaling pathways
• Possible support for myelination and oligodendrocyte function

The new study showed that oligodendrocyte lineage cells can switch from glucose-derived acetyl-CoA to ketone-derived acetyl-CoA during later stages of myelin formation. This suggests ketones may play a more important developmental and signaling role in the brain than previously appreciated.

Importantly, ketones do not replace glucose entirely. The study demonstrated that glucose signaling remained necessary for oligodendrocyte progenitor cell (OPC) proliferation during early developmental stages, while ketones could support later maturation and myelin synthesis under some conditions.

This may help explain why ketones appear beneficial in some neurological and developmental conditions involving:

• impaired glucose utilization
• mitochondrial dysfunction
• epilepsy
• white matter abnormalities
• metabolic inflexibility

However, responses in autism are highly variable. Some individuals show improvements in:

• alertness
• cognition
• endurance
• behavior
• seizures
• language attempts

while others show little benefit or even worsening.

This variability likely reflects the biological heterogeneity of autism itself. Different individuals may have different underlying dysfunctions involving metabolism, redox balance, mitochondrial function, neuroinflammation, myelination, or neuronal signaling.

At present there is still very little formal clinical research on ketone esters in autism, and most evidence remains anecdotal or exploratory. Nevertheless, the growing understanding of brain metabolism and developmental myelination suggests this may become an increasingly important research area in the future.

Mutations in CACNA2D1 plus KDM6B -- Gabapentin and Calcium Folinate? Perhaps PQQ? Perhaps BHB?

 

A little research can sometimes be eye opening

I was recently sent genetic results from several parents and surprisingly some have multiple potentially highly causal genes. Some are mutations that are extremely rare and one was unique.

Today I am looking at one case with two genes highlighted in whole exome sequencing (WES), one is a calcium ion channel and the other is a gene extremely close to the one causing Kabuki syndrome.  Interestingly, two possible interventions did very quickly appear.

The report states:

UNCLEAR RESULT

Variants of uncertain significance (VUS) identified

Based on current evidence, the clinical relevance of the detected variants remains unclear.

Kabuki syndrome is caused by mutations in KMT2D or KDM6A.

KDM6A and today’s gene KDM6B both target trimethylation on lysine 27 of histone H3 (H3K27me3), a mark associated with gene silencing. By removing this mark, they activate gene expression. So, mutations in either gene will cause a cascade of effects on numerous other genes.

The old post below suggested the use of HDAC inhibitors to correct the mis expressed genes. In particular, BHB from the ketogenic diet was discussed.

Notably, histone deacetylase inhibition rescued structural and functional brain deficits in a mouse model of Kabuki syndrome.

 

Ketones and Autism Part 5 - BHB, Histone Acetylation Modification, BDNF Expression, PKA, PKB/Akt, Microglial Ramification, Depression and Kabuki Syndrome

           

The calcium channel involved today is not one we have previously looked at, but it is the target of the very well-known drug Gabapentin. This drug is used to treat epilepsy and neuropathic pain. The child does have abnormal EEG and seizures, plus autism, ADHD and absent speech.

Mutations of the KDM6B causing autism were first described only in 2019. In 2022 mutations in this gene were found in several patients with cerebral folate deficiency (CFD), one of the authors is our old friend Dr Ramaekers.

We know a lot about CFD, thanks to our reader Roger, Dr Frye, Dr Ramaekers, and now Agnieszka and Stephen. Over in the US one of the founders of an autism organisation told me her son was diagnosed in adulthood with CFD, when he finally had a spinal tap.

Interestingly, Agnieszka has pointed out a novel way to potentially increase folate in the brain using an OTC supplement called PQQ.

 

Protective effects of pyrroloquinoline quinone in brain folate deficiency

Results

Folate deficiency resulted in increased expression of inflammatory and oxidative stress markers in vitro and in vivo, with increased cellular ROS levels observed in mixed glial cells as well as a reduction of mitochondrial DNA (mtDNA) content observed in FD mixed glial cells. PQQ treatment was able to reverse these changes, while increasing RFC expression through activation of the PGC-1α/NRF-1 signaling pathway.

Conclusion

These results demonstrate the effects of brain folate deficiency, which may contribute to the neurological deficits commonly seen in disorders of CFD. PQQ may represent a novel treatment strategy for disorders associated with CFD, as it can increase folate uptake, while in parallel reversing many abnormalities that arise with brain folate deficiency.

 

PQQ is a relatively common OTC supplement that looks helpful in older people and those with mitochondrial dysfunctions (most older people, plus many with autism).  It can also improve sleep.  The common 20mg dose seems to be based on what was used in a clinical trial in Japanese adults. Japanese drugs are dosed to reflect the size of Japanese people. American women on average weigh 40% more than Japanese women.

PQQ is present in mother’s milk, so it is not some scary artificial compound.

CFD looks like another nexus point where may different genetic variants produce a downstream meeting point.  This means numerous different underlying autisms will share a common beneficial therapy. It will not be a cure, but it should improve the outcome.

The only way to access I/V calcium folinate looks to be via confirmation of very low levels in spinal fluid, so a spinal tap would be necessary.  This is not easy, as Agnieszka has found out.  For some people oral calcium folinate is not sufficiently potent to reverse CFD.

KDM6B

Mutations of the KDM6B gene causing autism were first described only in 2019. In 2022 mutations in this gene were found in several patients with cerebral folate deficiency (CFD).

 

Genetic variants in the KDM6B gene are associated with neurodevelopmental delays and dysmorphic features

Lysine-specific demethylase 6B KDM6B demethylates trimethylated lysine-27 on histone H3. The methylation and demethylation of histone proteins affects gene expression during development. Pathogenic alterations in histone lysine methylation and demethylation genes have been associated with multiple neurodevelopmental disorders. We have identified a number of de novo alterations in the KDM6B gene via whole exome sequencing (WES) in a cohort of 12 unrelated patients with developmental delay, intellectual disability, dysmorphic facial features, and other clinical findings. Our findings will allow for further investigation in to the role of the KDM6B gene in human neurodevelopmental disorders.

 

Layman’s guide to the KDM6B gene

https://www.simonssearchlight.org/research/what-we-study/kdm6b/

 

12% of people with CFD studied in the paper below had mutations in KDM6B. So clearly all people with a mutation in this gene should be tested for CFD vis a spinal tap.

 

KDM6B Variants May Contribute to the Pathophysiology of Human Cerebral Folate Deficiency

Cerebral folate deficiency syndrome (CFD) was defined as any neurological condition that was associated with low concentrations of 5-methyltetrahydrofolate in the cerebrospinal fluid. Previous clinical studies have suggested that mutations in the folate receptor alpha FOLR1 gene contribute to CFD. In this study, we identified six genetic variants in histone lysine demethylase 6B (KDM6B) in 48 CFD cases. We demonstrated that these KDM6B variants decreased FOLR1 protein expression by manipulating epigenetic markers regulating chromatin organization and gene expression. In addition, FOLR1 autoantibodies were identified in CFD patients’ serum. To the best of our knowledge, this is the first study to report that KDM6B may be a novel CFD candidate gene in humans.

The way to confirm CFD, with certainty, is via a spinal tap.  This can then open the door to intravenous therapy with calcium folinate.

There is a blood test which then would lead to oral calcium folinate therapy.  This is now very common in children with autism in the US. It improves speech.

www.fratnow.com

The problem is that some people need the more potent intravenous therapy and without a spinal tap there is not enough proof to get the therapy.

 

CACNA2D1

The CACNA2D1 gene encodes voltage-dependent calcium channel subunit alpha-2/delta-1. 

Different types of mutation will have different effects and varying degrees of severity.

Some mutations in this gene are associated with a condition called “Developmental and Epileptic Encephalopathy 110”.

Developmental and epileptic encephalopathy-110 (DEE110) is an autosomal recessive disorder characterized by profound global developmental delay and hypotonia apparent in infancy followed by onset of seizures in the first months or years of life. Affected individuals achieve almost no developmental milestones and show impaired intellectual development, poor or absent speech, inability to walk or grasp objects, peripheral spasticity, and poor eye contact. Brain imaging shows hypoplastic corpus callosum and cortical atrophy.

CACNA2D1 is also a novel Brugada Syndrome susceptibility gene.

Brugada syndrome may be a major cause of sudden cardiac death in men under 40. People with Brugada syndrome on average die between the ages of 26 to 56 years, with an average age of 40 years. If treated appropriately, patients can have a normal lifespan.

A pediatric cardiologist should be consulted.

Fortunately the Alpha-2/delta proteins are believed to be the molecular target of the gabapentinoids gabapentin and pregabalin, which are used to treat epilepsy and neuropathic pain.

This means that an obvious path to investigate is whether the drug gabapentin has a positive effect. Mutations could produce either gain of function of loss of function.

Gabapentin binds to a the α2δ subunit. This binding does not directly block or open the channel, but it influences its overall activity.

The exact mechanism of action is still not fully understood, but it is believed that gabapentin:

·       Reduces the release of certain neurotransmitters involved in pain signaling, such as glutamate and substance P.

·       Alters the trafficking and function of the calcium channels themselves.

·       Therefore, gabapentin's action is more complex than simply "blocking" or "opening" channels. 

Gabapentin is not guaranteed to help in this case, but certainly might do.

Conclusion

The take home is really that if you invest thousands of dollars/euros/pounds in genetic testing, it is well worth your time spending some time on the internet looking up any flagged genes.

People expect too much from the geneticist writing the report.

Double check these things yourself.  Take your findings to an open-minded neurologist, who reads the research literature.

Be aware that the same mutation can be present in one or even both parents, with no noticeable negative effect, but be disease causing in their child. Genetics is often about the probability of something happening, rather the certainty. 

Look at partially-effective or sometimes-effective interventions in the research. For example, one reader is looking at mutations in NF1 plus a gene affecting epigenetics. He might want to try Lovastatin.  NF1 causes an increase in RAS, which is a pro-growth signal, this leads to RASopathies which can cause intellectual disability (ID). Lovastatin reduces RAS and it was trialled to reduce ID in NF1 - the results were mixed. It probably matters at what age you start trying to reduce RAS.

Takeaways from Thinking Autism 2023

I did present at the Thinking Autism 2023 conference in London recently.  I was last there in 2019 and there were many familiar faces.

Emotions were very much on show - joy, desperation, bewilderment, hope, fear, frustration and more.

The United Kingdom is amongst the worst countries in the world if you want to treat autism.  Even the idea of treating autism can get you into trouble. For severe autism it is much better to say treating ID (intellectual disability) – what sane person could object to that?

My takeaways are very specific to me, but here they are anyway.

 

So many doctors!

This year I was approached by many doctors who have children with ASD.  Among them were GPs, pediatricians, a neurologist, and a psychiatrist.

When you understand the basis of autism it is not surprising that so many doctors have kids with autism, particularly doctors married to a doctor.

 

Fertility treatment increasing the risk of autism

I did mention in my book the link between difficulty conceiving and having children with autism. Mothers who have had miscarriages are at risk of having a child with autism and children produced via IVF therapy have an elevated chance of autism.

One of the speakers at the conference, who uses diet as a therapy, told us that 30-40% of her patients where conceived by IVF therapy.  Wow – I thought. They are mainly children with milder autism, only 10% of her patients have severe autism.

 

From struggling to get on IVIG to how to come off it

Many parents struggle to get onto IVIG therapy for their child.  It is very expensive and, being an intravenous therapy, it is not so easy to administer to a child with severe autism.

Having finally got on IVIG therapy and responded well to it, how do ever wean the child off it, without losing all those gains?

This was a side issue arising from the conference and is an issue to some other readers of this blog.

What is very interesting is the potential to give IVIG therapy just once to very young children who developed normally but then suffer a regression into “autism.”  It seems to work for some. You might get it in Russia, but don’t bother asking in the UK.

 

My son is 14, I have tried everything else now I am ready for pills

Some people do respond well enough to dietary modification and OTC supplements, but more severe autism likely needs pharmaceuticals. For one mother at the conference she had come to this conclusion.  It is never too late to start to treat severe autism. Good luck to her!

 

Never give up

Never give up was the last point on my talk.

One mother at the conference was a very good example. She had finally had her twins examined at the UK’s top children’s hospital, Great Ormond Street Hospital (GOSH).  They have had MRIs, lumbar punctures to get spinal fluid samples and they have had genetic testing.  That is a triumph in the UK health system.

As she told us, she had to play the cancer card. She told her doctors “why do you go to such great lengths to save my life from cancer and yet do nothing for my twin boys with severe autism?”

Now one has a diagnosis of cerebral folate deficiency and one has a mutation is DISC1, a schizophrenia gene already covered, with therapy ideas, in my blog.  High dopamine in spinal fluid was only to be expected - it is a feature of schizophrenia. Light is at the end of the tunnel.  This mother was also very helpful to other mothers present.

 

School reporting on parent treating autism

I was disappointed to hear that a school had reported one mother for treating her child’s autism.

 

Ketones really do benefit some!

I did write a lot about the multiple possible benefits of ketones/BHB in autism.

The week before the conference one mother wrote to tell me that both she and her child with autism respond well to HVMN Ketone-IQ.

I knew our doctor reader Agnieska was a big fan of the BHB ester product Ketoforce, which seems to have disappeared during Covid.

At the conference a Spanish psychiatrist was listing the therapies in my blog that have helped his son and they included NAC, Bumetanide and BHB.

There are several new ketone products based on diol ketone esters, like HVMN Ketone-IQ.

Our reader Daniel mentioned very recently that he is using a product called DeltaG, a proprietary blend of diol ketone esters. HVMN Ketone-IQ is a pure diol ketone ester, while DeltaG is a proprietary blend of diol ketone esters.

The active ingredient in Ketone-IQ is R-1,3 Butanediol, also referred to as R-1,3-Butylene glycol, which maintains FDA GRAS status as a flavor molecule.

 

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=173.220

 

1,3-Butylene glycol (1,3-butanediol) may be safely used in food in accordance with the following prescribed conditions:

(a) The substance meets the following specifications:

(1) 1,3-Butylene glycol content: Not less than 99 percent.

(2) Specific gravity at 20/20 deg.C: 1.004 to 1.006.

(3) Distillation range: 200deg.-215 deg.C.

(b) It is used in the minimum amount required to perform its intended effect.

(c) It is used as a solvent for natural and synthetic flavoring substances except where standards of identity issued under section 401 of the act preclude such use.

 

This raw ingredient is very cheap.

Once it is packaged up as a supplement, it becomes very expensive.

As Agnieszka mentioned on the conference sidelines, you do have to look at the ingredients. In HVMN Ketone-IQ there is potassium benzoate as the preservative.  Potassium benzoate is a DAO inhibitor. DAO, or diamine oxidase, is an enzyme that breaks down histamine, a compound that can cause a variety of symptoms in histamine-sensitive people, such as headache, flushing, hives, and diarrhea.

 

“If my son can take the bus aged 20, I’d be happy”

One doctor mother showed me a video of her untreated young son with severe autism.  I told her how I have treated my son since 2012 and what the result has been. He passed his high school exams (GCSEs) in maths, science, geography, and English.  Now he has learnt how to travel independently from home by bus.  Time for those pills.