Lactoferrin - the "Liquid Gold" protein for babies, older people and some Autism

 

This post is rather long. You could summarise by "Trial lactoferrin, or camel milk."

For many families managing autism, the most challenging co-occurring issues are often chronic gastrointestinal (GI) problems and related behavioral challenges. The link between the gut, the immune system, and the brain—the Gut-Brain Axis—is a growing area of research, and one key protein is generating significant interest in Lactoferrin.

Lactoferrin is a multifunctional protein found naturally in milk, recognized for its anti-inflammatory, antimicrobial, and immune-modulating properties. But how exactly does this protein connect to the world of autism?

 

The "Good" Lactoferrin: Immune Support and Neuroprotection

When consumed as food or a supplement, lactoferrin acts as a protective agent. Its potential benefits for individuals with ASD are rooted in its ability to target two core issues: inflammation and microbial imbalance.

The Natural Power of First Milk

• Human Colostrum & Research Status: Lactoferrin is abundant in colostrum (the "liquid gold" first milk). It acts as the newborn's first immune shield, helping to "seal" the gut, prevent infections, and establish a healthy microbiome. In the context of ASD, bovine colostrum products (BCP), often combined with probiotics, have been the subject of small-scale pilot studies. These initial trials suggest BCP may be well-tolerated and can help reduce GI inflammation and improve gut function, leading to associated improvements in certain behavioral symptoms. However, large-scale clinical trials are still required to validate colostrum as an effective core therapy for ASD.

• Camel Milk's Unique Role: In regions like Saudi Arabia, camel milk has been traditionally used and studied as a complementary intervention for autism symptoms. Camel milk is naturally rich in lactoferrin—often higher than cow's milk—and possesses a unique protein profile.

• High Bioavailability: Crucially, the lactoferrin in camel milk is considered more resistant to stomach acid and digestive enzymes than bovine (cow) lactoferrin, suggesting higher bioavailability (more of the intact, active protein reaches the lower intestine) in humans.
• Immune Modulation & Allergy: Research suggests camel milk can modify the overall immune response. This is important because the benefits may not be limited to those with GI symptoms; its immune-rebalancing effect (immunomodulation) suggests it could benefit people with ASD who suffer from frequent allergies, eczema, or systemic immune dysregulation, even if they lack chronic GI distress.

 

How it Relates to Autism

Lactoferrin works by several different mechanisms:

Addressing Iron Dysregulation (The "Starvation" Mechanism)

• Harmful gut bacteria and pathogens (which contribute to gut dysbiosis in ASD) thrive on free iron. When there is excess, unregulated iron in the gut, these pathogens proliferate, worsening the microbial imbalance and gut-related inflammation.
• Lactoferrin is a powerful iron-binding protein that tightly sequesters two molecules of ferric iron (Fe3+) per molecule, even at the low pH often found in inflamed or infected tissues.
• This process effectively starves the harmful bacteria of the iron they need to grow, limiting their colonization and virulence. This helps rebalance the gut microbiome, which is the first step in calming the Gut-Brain Axis.

Limiting Oxidative Stress (The "Antioxidant" Mechanism)

• Free, unbound iron is highly reactive. It participates in the Fenton Reaction, leading to the creation of toxic Reactive Oxygen Species (ROS), which cause widespread oxidative stress. Oxidative stress is a well-documented biological abnormality in the brains and bodies of individuals with ASD, contributing to cellular damage and inflammation.
• By binding nearly all free iron in the gut and circulation, Lactoferrin acts as an iron scavenger, preventing this iron from participating in the damaging Fenton reaction.
• This significantly reduces overall oxidative stress and lipid peroxidation (damage to cell membranes), thus protecting brain cells from injury and supporting anti-neuroinflammatory mechanisms.

Optimizing Iron Delivery to the Brain (The "Transport" Mechanism)

• Iron is an essential nutrient, critical for key neurodevelopmental processes like myelination (insulation of nerve fibers) and the synthesis of neurotransmitters (like Dopamine and Serotonin). Both iron deficiency and improperly delivered iron are linked to cognitive and behavioral deficits in ASD.
• Lactoferrin is structurally related to transferrin (the main iron transporter in the blood) and has its own receptors that facilitate iron transport. LF can act as a more efficient, regulated iron supplier, particularly to cells that need it. Furthermore, it is believed to cross the Blood-Brain Barrier (BBB) and deliver iron to the central nervous system.
• Ensures that the brain receives a regulated supply of iron for proper neuronal function and neurotransmitter balance, which is vital for attention, mood, and socio-communicative skills.

In summary, Lactoferrin's primary role regarding iron is to sequester free iron to kill pathogens and stop oxidative stress, while simultaneously regulating the delivery of iron to the cells that need it for brain development.

Mechanisms Mediated by the Gut-Brain Axis

Reducing Gastrointestinal Inflammation (Anti-Inflammatory Action):

o reduces chronic, low-grade inflammation in the gut by downregulating pro-inflammatory signaling molecules (cytokines like IL-6 and TNF alpha and promoting anti-inflammatory ones like IL-10.

o    Alleviates gastrointestinal distress, which is a common comorbidity that can worsen behavioral symptoms in ASD.

Healing the Intestinal Barrier ("Leaky Gut")

o     supports the structure and function of the intestinal lining by promoting the repair and maturation of the epithelial layer and reinforcing the tight junctions between cells.

o    Prevents the abnormal passage of inflammatory molecules and neurotoxic compounds from the gut into the bloodstream, thereby reducing peripheral inflammation that can compromise the brain.

  Rebalancing the Gut Microbiome (Antimicrobial Action):

o    Reegulates the availability of iron, which is essential for certain pathogenic bacteria (like some Clostridium species) often found in higher levels in the gut of some people with ASD. By binding to iron, limits their proliferation.

o    Corrects microbial imbalance (dysbiosis), leading to a healthier gut environment and more beneficial microbial metabolites.

The "Bad" Lactoferrin - Fecal Lactoferrin (FLA)

It is crucial to understand that not all lactoferrin is beneficial in all contexts.

While the lactoferrin you consume is protective, the lactoferrin measured in stool tells a different story:

Fecal Lactoferrin (FLA) is a diagnostic marker, not a nutrient. A high FLA score is "bad" because it signals that large numbers of neutrophils (white blood cells) are migrating into the intestines to fight active, destructive inflammation (like IBD or severe infection). A high FLA indicates a serious problem, whereas a normal or low FLA suggests that symptoms are likely due to a non-inflammatory functional disorder (like IBS).

High Fecal Lactoferrin (FLA) is observed in a distinct subgroup of children with autism and indicates active inflammation within their gastrointestinal tract. While the average FLA level across the entire ASD population is usually normal, studies consistently identify a minority (often around 20-30%) whose FLA is significantly elevated. This finding is crucial because FLA acts as a biomarker, signaling a high level of neutrophil infiltration—white blood cells rushing to the site of damage—which means their chronic GI symptoms (like pain, constipation, or diarrhea) are likely caused by an inflammatory disease (like undiagnosed Colitis or IBD) rather than a non-inflammatory functional disorder (like IBS).

The presence of high FLA in this subgroup is vital to the Gut-Brain Axis hypothesis in autism research. It suggests that in these children, the underlying GI inflammation releases chemical signals (cytokines) that may travel to the brain, contributing to neuroinflammation and potentially exacerbating core autistic symptoms and co-occurring behavioral issues. Therefore, detecting high FLA helps clinicians distinguish this subgroup and target their treatment, focusing on anti-inflammatory interventions to address the root physical cause of their distress and associated behavioral challenges.

Fecal Lactoferrin (FLA) is a very common and increasingly standard laboratory test in gastroenterology, particularly for diagnosing and monitoring inflammatory bowel conditions.

For those with access to a very good lab and are going to test FLA, consider also TGF-β – one of the most reliable biomarkers of immune dysfunction in autism

One of the most consistently abnormal immune markers in autism is Transforming Growth Factor-β1 (TGF-β1), a cytokine that plays a central role in immune tolerance, gut barrier integrity, and neurodevelopment.

Over the past 15 years, multiple research groups—particularly the MIND Institute at UC Davis—have shown that children with autism frequently have reduced blood levels of TGF-β1. What makes this finding stand out is the strong correlation with clinical features. The lowest levels of TGF-β1 are typically found in children who also have:

• more severe social and communication impairments
• increased irritability and repetitive behaviours
• chronic gastrointestinal symptoms
• food sensitivities and allergic tendencies
• elevated pro-inflammatory cytokines (IL-6, TNF-α, IL-1β)
• impaired regulatory T-cell function (Tregs)

TGF-β1 is required to generate and maintain Tregs, the immune cells responsible for shutting down unnecessary inflammation and maintaining tolerance to foods and gut microbes. When TGF-β1 is low, the immune system becomes biased toward inflammation and over-reactivity. This immune profile is exactly what many clinicians observe in the “GI + immune activation” subtype of autism.

The abnormalities are not limited to the peripheral blood. Smaller studies examining cerebrospinal fluid (CSF) have found altered TGF-β1 levels in some autistic individuals, with links to developmental regression and stereotypy. This suggests that dysregulation of TGF-β signalling is occurring both in the immune system and centrally in the brain.

Because TGF-β1 plays a major role in strengthening the intestinal barrier, promoting mucosal repair, and dampening inflammatory responses, low levels can help explain why so many autistic children experience gastrointestinal disturbances, eosinophilic inflammation, and reactions to specific foods. Several interventions commonly used in autism—such as lactoferrin, sodium butyrate, Bifidobacterium infantis, Lactobacillus reuteri, and vitamin A/retinoic acid—are known from the scientific literature to increase mucosal or systemic TGF-β activity, which may partly account for their benefits in responsive individuals.

Among the many immune abnormalities reported in autism, low TGF-β1 is one of the most reproducible and clinically meaningful findings. It provides a biologically plausible link between gut dysfunction, immune activation, and behavioural symptoms, and it highlights a subgroup of children who may benefit from treatments aimed at restoring immune tolerance and improving epithelial barrier function.

Back to Lactoferrin

Direct Neurodevelopmental and Neuroprotective Mechanism

Supporting Neurodevelopment via IGF-1Signaling:

o    Insulin-like Growth Factor-1, which is often found alongside lactoferrin  in sources like camel milk, is crucial for neuronal growth, differentiation, survival, and synaptic plasticity (the brain's ability to form and strengthen connections).

o    May directly counteract potential IGF- dysregulation linked to ASD etiology, promoting optimal brain maturation, connectivity, and cognitive function.

o    The IGF- in camel milk is theorized to be highly stable against gastric acid, allowing it to cross the blood-brain barrier (BBB) effectively.

 Reducing Neuroinflammation and Oxidative Stress:

o    Both lactoferrin and IGF-1 possess potent antioxidant and anti-inflammatory properties that help protect the brain. Lactoferrin has been shown in preclinical models to reduce inflammation in brain support cells (astrocytes) and shield the developing brain from injury.

o    Dampens the chronic neuroinflammation and high oxidative stress levels observed in the CNS of individuals with ASD, preventing neuronal damage.

 Enhancing Brain Trophic Factors:

o    Preclinical studies suggest lactoferrin can enhance the production of neurotrophins, such as Brain-Derived Neurotrophic Factor (BDN).

o    BDNF is vital for learning, memory, and the survival of neurons. Increasing its levels supports overall neurological health and development.

 

Beyond the Gut: Systemic Anabolic and Anti-Aging Signals

The benefits of lactoferrin extend far beyond the digestive tract, touching on areas of foundational health that are important across the lifespan. Research highlights its systemic anabolic (tissue-building) and regenerative potential:

 

1. Anabolic Signal to Bone

Lactoferrin is a known factor that promotes osteogenesis (bone creation) and bone health while inhibiting bone loss. It provides a crucial anabolic signal, making it a focus for research on improving bone density and fighting age-related bone decline.

2. Supporting IGF-1 Signaling

Lactoferrin has been shown to work through the Insulin-like Growth Factor 1 (IGF-1) signaling pathway. IGF-1 is a key hormone that:

• Promotes cell growth and division (anabolism).
• Is essential for neuroprotection and cognitive function.
• Typically declines with age, with lower levels being linked to aging processes and poor metabolic health.

By supporting the IGF-1 pathway, lactoferrin may help maintain a critical regulatory signal for tissue regeneration, metabolism, and overall vitality, potentially counteracting some effects of aging and promoting optimal function.

  

Maximizing the Benefits: The Bioavailability Challenge

Lactoferrin is a protein, and like any protein, it is vulnerable to degradation by stomach acid and digestive enzymes. If the protein is broken down before it reaches the small intestine, its benefits are limited. This is the problem of bioavailability.

To maximize the therapeutic benefits of a lactoferrin supplement:

1.     Choose Liposomal Encapsulation: Look for liposomal lactoferrin. This technology encapsulates the lactoferrin molecule within a protective layer of fatty lipids (liposomes). This shield helps the protein survive the harsh acidic environment of the stomach intact, ensuring better delivery and absorption into the intestine.

2.     Timing is Key: For best absorption and targeted delivery, it is generally recommended to take lactoferrin on an empty stomach. Some suggest taking it before bed, as the digestive system is less active, allowing the protein longer contact time with the intestinal lining and minimizing competition with other food proteins for absorption.

 

Conclusion

Last year I did meet one of the Saudi authors of the research into camel milk, as an immunomodulatory treatment for autism.

If camel milk is impractical where you live, a little lyposomal lactoferrin might be an alternative. I do not think the benefits are limited to those with GI problems. It also looks interesting for older adults.

Camel milk not only contains ten times the level of lactoferrin than cow milk, but it appears to be more able to survive acid in the stomach. 

Camel milk also contains special protective proteins called immunoglobulins (which are essentially antibodies), but they are unique in the animal kingdom. Unlike the complex antibodies found in humans and cows, camel antibodies are missing half of their structure, making them incredibly small. These tiny, functional fragments are now known as nanobodies. Because they are so small, these nanobodies can reach tight spaces in the body that large antibodies cannot, helping them fight bacteria and viruses more effectively. Furthermore, they are very tough and stable, meaning they survive digestion even when consumed orally in the milk, which is why they are thought to help give camel milk its powerful health benefits. 

 

I think those people drinking camel milk in the Middle East are making a smart choice.

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

How good is Cincinnati Children’s Hospital at using Precision Medicine to treat kids with autism + ID ?

 

Cincinnati Children’s cares for patients and families from all 50 US states and dozens of other countries each year – including children with complex or rare disorders.

So, how good is Cincinnati Children’s Hospital at using precision medicine to treat kids with for autism + ID ?

Spoiler alert, I will leave you to answer the above question. It is up to you to decide!

I will give them 10 out 10 for at least trying to use genetic testing to improve the outcomes.

I was very surprised to find a paper with case studies showing how the clinicians tried to use mutations in autism/ID genes to develop a matching therapy.

If you are interested you can use your skills to see what kind of precision medicine you would have tried.

One of the children does have Glass syndrome (SATB2), which our reader Ling is interested in. I hoped they would do something clever, in fact what they did was find a fracture in his foot. Low bone density is a feature of this syndrome and an undiagnosed fracture in your foot is going to hurt and can trigger self-injurious behavior.

There is even a Pitt Hopkins kid, there is plenty in this blog about that syndrome.

The idea of the paper was to show that running WES/WGS on their residential kids with autism + ID resulted in better care and so reduced nights per year in the hospital.

The case studies are the interesting part. The logic of the paper is deeply flawed because the kids who did not get special insights after the WES/WGS also showed a dramatic reduction in their nights per year at the hospital. Also, in the diagnosed cohort / treatment group", many kids did not actually receive any treatment. (see table 4)

 DiCo = Diagnosed Cohort

Undico = Undiagnosed Cohort

You can look up all members of the DICo cohort that got a definitive genetic testing result.

There are plenty of familiar genes, I am really surprised these kids had not previously been diagnosed

You can see the therapy they tried. Judge for yourself. I would have done much more, but the authors are the doctors ! They did have some successes.

Click on this link to open the full table with 56 patients:

Table 4 | Conferring a Genetic Diagnosis for Children with Neurodevelopmental Disorders in the Inpatient Psychiatry Setting May Reduce Hospital Stays and Improve Behavior | Advances in Neurodevelopmental Disorders

I was amazed at how much time these kids with autism + ID spend in Cincinnati Children’s Hospital. They are in hospital for 2 to 4 weeks a year, year after year. This must cost someone a fortune.

Why are these kids in hospital so much? It looks like Intermittent Explosive Disorder (IED), the fancy name for self-injurious behavior. In the US, and some other countries, when your kid's behavior gets really bad you call the police and they get taken to the ER at the local hospital and some then make it to specialist units like Cincinnati Children's Hospital. Most parents across the world never have this option, and I actually think this is better. There is rarely any magic at the ER in these cases; better to find the solution at home, without spending $50,000.

  

Broader Landscape of Precision Medicine for Autism + ID in the U.S.

Cincinnati Children’s is one of roughly 15 specialized centers in the U.S. that manage children with severe autism and intellectual disability in residential or inpatient settings. Another well-known example is Kennedy Krieger Institute at Johns Hopkins, which has historically piloted innovative, often unpublished interventions for rare genetic syndromes. Across these centers, the use of whole exome or genome sequencing is slowly becoming more common, but actionable, gene-targeted therapies remain rare. Most “precision medicine” efforts focus on enhanced monitoring, early detection of medical complications, and tailored behavioral or supportive interventions rather than disease-modifying treatments. This context highlights both the promise and current limitations of precision medicine in neurodevelopmental disorders.

My blog is really all about disease-modifying treatments.

We did see that when Dr Kelley was at Kennedy Krieger/Johns Hopkins they did lots of clever things that are out of the mainstream, but were not published in the literature.

Today’s paper is definitely a step forward, because we can all see how much/little is being done.  

The paper is very readable, just click on the link and read it.

Conferring a Genetic Diagnosis for Children with Neurodevelopmental Disorders in the Inpatient Psychiatry Setting May Reduce Hospital Stays and Improve Behavior 

https://link.springer.com/article/10.1007/s41252-025-00466-w

These 56 diagnosed patients formed the Diagnosed Cohort—DiCo. Details of variant classification and interpretation are included in Table 4. A further 81 patients received nondiagnostic genetic testing results, including negative findings or VUS findings not felt to explain the phenotype or lacking functional evidence (forming the Undiagnosed Cohort—UndiCo). We then quantified the total inpatient psychiatric hospital days 12 months before and 12 months after genetic test result delivery. 

Individual 10 is a 17-year-old male with autism, intellectual disability, and intermittent explosive disorder admitted to inpatient psychiatry for aggressive behavior management. Additional medical history includes large habitus and obesity, non-alcoholic fatty liver disease, high-arched palate, dental crowding, foot pain, and back pain. Genetic testing (ASD/ID exome panel) initiated during inpatient psychiatry admission identified a likely pathogenic de novo variant in SATB2(NM_001172509.2):c.169G > A p.(Gly57Ser), diagnostic for SATB2-Neurodevelopmental disorder (glass syndrome). Intellectual disability, behavioral challenges, and craniofacial dysmorphology are well described in this condition. Furthermore, osteopenia and epilepsy have been reported in patients with this condition. After observing slightly elevated alkaline phosphatase levels on previously completed routine labs, 192 u/L (40–150 u/L normal range) bone density scans were ordered and were normal. With ongoing foot and back pain, x-rays and MRI studies were ordered and demonstrated a hairline toe fracture. The patient was placed in a walking boot to allow for recovery of the fracture. Being vigilant for fracture evaluation in a condition with known osteopenia was important to care for this patient. Bone pain is a likely contributor to behavior outbursts.

Individual 15 is a 13-year-old male with autism, mild intellectual disability, and intermittent explosive disorder admitted to inpatient psychiatry for aggressive behavior management. Medical history also includes obesity, large stature, and macrocephaly. Genetic testing (ASD/ID exome panel) initiated during inpatient psychiatry stay identified two variants in TBC1D7. One nonsense variant: TBC1D7 NM_001318809.1:c.6dup p.(Glu3Ter), and an in-trans variant consisting of a duplication of 335 bps in exon 6 arr[GRCh37]chr613,307,82,613,308,161 × 3 predicted to disrupt the reading frame of TBC1D7. Both variants were listed as VUS; however, on review of the literature, nonsense and loss-of-function biallelic variants have been reported in this gene with a phenotype of patients with intellectual disability and macrocephaly. Thus, with a consistent phenotype and two predicted loss-of-function variants, a clinical diagnosis of TBC1D7-NDD was conferred. As TBC1D7 is the third subunit of the TSC1-TSC2 complex, we initiated a trial of rapamycin, an mTOR inhibitor, to target autism comorbidities of aggression and irritability. Parental report after 6 months of medication trial was that aggressive symptoms had subjectively improved.

Individual 30 is an individual with autism and intellectual disability, admitted to inpatient psychiatry for self-injurious behavior management. The patient is nonverbal with behavioral stereotypies. Physical exam was notable for up-slanting palpebral fissures and multiple café-au-lait macules on the abdomen, back, and flank, along with axillary freckling. Genetic testing (exome) was initiated during inpatient psychiatry stay and identified a variant in NF1: (NM_001042492.3):c.7870-9 T > G p.? which, though listed as a VUS, was predicted to affect the splice site and alter protein function. As the patient qualified for a clinical diagnosis of NF1 with more than 6 café-au-lait macules and axillary freckling, the patient was conferred a diagnosis of NF1. Following this diagnosis, an MRI of the brain and orbits was ordered per NF1 tumor surveillance protocols, which identified a plexiform neurofibroma within the supra- and infrazygomatic left masticator space, superficial to the masseter and temporalis muscles, extending into the left temporomandibular joint, with mild anterior displacement of the mandibular condyle. Plexiform neurofibromas can be painful, and in a nonverbal patient it may be difficult to communicate this pain. A high-dose ibuprofen prescription was provided to the patient to treat any presumed pain, which also translated into less frequent behavioral outbursts.

In SATB2 there are not enough osteoblasts, the cells that build your bones. Activating Wnt can substitute for some missing SATB2 function (lithium, telmisartan, statins etc).

For NF1 you likely need a PAK1 inhibitor. They exist and the cheap one is now controversial because of its use to treat Covid-19. If I mention the name post-Covid my post gets deleted! Other options are bee propolis rich in Caffeic Acid Phenethyl Ester (CAPE), which is safe, or the experimental Fragile X drug FRAX486 still sitting on the shelf at Roche, who had bought Genentech, who had bought Afrexis, set up by a Japanese Nobel Laureate I once wrote about. I remember because Susumu Tonegawa was a faculty member at MIT when his son, an MIT freshman, killed himself. A sad story indeed. 

I recall being contacted a long while back by a Canadian whose adult child with severe autism had just received a genetic diagnosis that suggested a PAK1 inhibitor as a therapy. Of course, nothing was being done about it, and he ended up at my blog.  Did he persevere or give up?  One of our readers, long ago, was using FRAX486, so it is possible.

Conclusion

The interesting part of today’s paper for me was to see what therapy was considered for the 56 cases with a single genetic diagnosis. This is something I have done quite a lot of over the years. More people should be doing it.

Many parents tell me they are very disappointed when clinicians refuse to try and treat their child with a genetic diagnosis. It is as if the geneticist thinks “Okay there is the diagnosis, job done … next patient please”.

So, as I said at the start of this post, 10/10 to Dr Shillington for trying to help these kids, and 10/10 for sharing what she did. As to what she actually did, it was not as good. Maybe she should read this blog for ideas, Hah ! 😃