Genetic methylation testing: Leucovorin trial

Understanding My Autistic Son’s Genetic Methylation Results

We decided to do genetic methylation testing to better understand whether there were any underlying biological factors where our son might need extra support as he grows and learns. The report came back full of gene names — MTHFR, MTR, MTRR, COMT, CBS. At first it was overwhelming, but once I found a way to visualise what was actually happening, it started to make sense.

Skip to: Two Roads • Messaging System • Exhaust (Glutathione) • CBS Gate • Traffic Jam in Real Life • Support Team • Leucovorin Trial • Preparation • Quick Visual Summary • References

The Busy Little Town

Every day, this town is building things: new roads, new houses, new phone lines. Those are things like learning, attention, emotional regulation and communication. To keep building, the town needs supplies and instead of throwing old materials away, it’s very clever and recycles them.

Meet the Recycling Factory (Methylation)

Inside the town is a recycling factory. Its job is to take used materials and turn them back into fresh supplies the builders can use again.

To run properly, the factory needs:

• Folate (vitamin B9)
• Vitamin B12
• Helpers like magnesium, zinc, and vitamin B2

Most of the time, the factory runs quietly in the background and goes unnoticed. In fast growing, fast working brains, it becomes especially important. The name for this recycling process is methylation. ¹

Two Roads Into the Factory

Because this recycling job is so important, the town has two roads leading into the factory.

Everyone has both roads.

What My Son’s Genetics Suggest

My son’s genetic results suggest that both roads might be a bit narrower than average. That means fewer trucks can get through at once. On a quiet day things tick along fine. On a busy day things back up.

Busy days include things like:

• Learning new skills
• Growth spurts
• Illness
• Big changes
• Lots of therapy
• New environments

Because the backup road also has genetic variants that may make it narrower, it can’t be assumed to automatically pick up the slack. Instead, it benefits from active support.

Choline-rich foods become more important:

• Eggs (especially the yolks!)
• Liver and organ meats
• Fish
• Beef and chicken

Think of it like this: if both roads are a bit narrow, we need to make sure both roads are well maintained and have enough trucks ready to go.

The Town’s Messaging System

The recycling factory isn’t the only thing running in the town. There’s also a messaging system, think of it like the town’s phone network and emergency sirens. Every time something happens (excitement, stress, joy, fear), the town sends out signal flares. These are chemicals called neurotransmitters:

• Dopamine = the “reward and focus” signal 🎯
• Adrenaline/Noradrenaline = the “alert! pay attention!” signal 🚨
• Serotonin = the “calm and steady” signal 🌊

After the message is received, the flares need to be cleared away so the town is ready for the next signal. This is where COMT and MAOA come in. Think of them as the clean-up crew that takes down the old flares. ^3a3b

My son’s results suggest his clean-up crew works a bit slowly. This isn’t necessarily bad:

• Signals last longer in his system
• He might feel things more intensely
• Good feelings can linger (yay!)
• But stress and overwhelm can linger too (not so yay)

What does a slow clean-up crew look like in real life?

• Taking longer to “come down” after excitement or upset
• Sensitivity to busy, loud, or chaotic environments
• Big emotional responses that seem out of proportion
• Difficulty switching gears
• Sometimes described as “intense” or “sensitive”
• May be more reactive to stimulants (like caffeine, or even certain supplements)

Here’s the connection to the recycling factory:

The clean-up crew needs supplies from the factory to do their job, particularly something called SAMe (which comes from the recycling process). When the recycling factory backs up, the clean-up crew can fall behind too. It’s all connected.

The Exhaust Problem

Like any factory, the recycling process creates some waste we can think of as exhaust fumes. The town has a cleaning system for this too — glutathione, the body’s master antioxidant. It mops up the mess so nothing builds up. ⁴ My son’s results suggest his glutathione production might be a bit slower than average (variants in genes called GSS).

This could mean:

• On busy days, the “exhaust” might build up faster than it can be cleared
• This can contribute to that foggy, overwhelmed, “running on empty” feeling
• Supporting antioxidant systems becomes more important

Things that support this clean-up:

• Antioxidant rich foods (berries, colourful vegetables)
• Reducing unnecessary toxic exposures where possible
• Sulphur-rich foods

One Gate That Might Be Too Open

Most of my son’s genetic variants suggest things moving a bit slowly. There’s one exception. There’s a gene called CBS that acts like a gate between the recycling factory and the pathway that makes glutathione and processes sulphur.

My son’s results suggest this gate might be more open than usual. What does this mean? Imagine the recycling factory is trying to process materials, but one of the side doors keeps letting trucks out before they’ve finished the main job. ⁵

This can:

• Drain resources away from the main recycling process
• Potentially create more ammonia and sulphites as by-products
• Make it even more important to support the main pathways

It also means we keep an eye on sulphur intake — things like garlic, onions, cruciferous vegetables, and certain supplements. Not necessarily avoiding them, but being aware that more isn’t always better.

What Does a Traffic Jam Look Like in Real Life?

When these systems can’t keep up, the town doesn’t fall apart. It gets a bit chaotic.

From the recycling factory backing up:

• Struggling to focus
• Progress coming in bursts instead of steadily
• Seeming to “stall” when learning ramps up

From the clean-up crew falling behind:

• Getting overwhelmed more easily
• Emotional ups and downs
• Poor sleep
• More stimming
• Taking ages to calm down after excitement or upset
• Sensory sensitivities seeming worse

From the exhaust building up:

• Foggy, tired, “running on empty” feeling
• Slower recovery from illness or stress

Nothing is broken. The system is just working harder than usual. Research linking metabolic stress, redox imbalance, and regulation difficulties in autistic children supports this kind of pattern. ⁴⁶

The Town’s Support Team

Now that we understand how the town works, let’s talk about what helps keep it running.

B12: The Key That Needs a Good Delivery Driver

B12 is the key that turns the machines on. It works closely with folate and is essential for neurological development in children. My son’s results suggest the delivery driver bringing that key might be a bit unreliable.

He has variants in genes that:

• Transport B12 into cells (TCN2)
• Reactivate B12 once it’s been used (MTRR)

This may mean even if there’s plenty of B12 in his blood, it may not be getting where it needs to go efficiently. ⁷ This is why the form of B12 matters. Methylcobalamin (methyl-B12) or adenosylcobalamin are active forms that may be easier for his system to use.

Magnesium, Zinc & B2: The Oil and Mechanics

These nutrients keep everything running smoothly. They’re cofactors, meaning the enzymes in the factory need them to do their jobs. Without enough of these helpers, even a perfectly good enzyme can’t work properly.

Choline: Fuel for the Backup Road

Choline feeds the backup road, reducing pressure on the main pathway. Because my son has variants affecting both roads, keeping this pathway well supplied becomes especially important. None of these supports make the factory go faster than it’s meant to — they simply help prevent breakdown under pressure.

Leucovorin trial (Refolinon in the UK)

Normally, folate has to go through several checkpoints before it can enter the factory. Some of my son’s genes are involved in those checkpoints (like MTHFR), which may be slowing things down. Leucovorin skips one of those checkpoints.

That means more usable folate can reach the factory without causing a bigger jam. ⁶

Why This Matters for a Slow Clean-up Crew

Kids with COMT / MAOA variants already clear neurotransmitters more slowly. Regular methylfolate floods the system with methyl groups. For many kids, that’s fine. But for kids whose clean-up crew struggles to keep up, it can tip things into overdrive:

• Irritability
• Hyperactivity
• Sleep problems
• Emotional meltdowns

Leucovorin supports the recycling factory without overwhelming the messaging system in the same way. It’s a gentler approach.

What Are We Hoping For?

We’ve just started our leucovorin trial with our son. Based on his genetic results, we have good reason to believe his recycling factory may benefit from that VIP side entrance.

Looking at his results as a whole:

• The main road has multiple narrow points (MTHFR, MTHFD1, FOLH1)
• The backup road is also narrower than average (BHMT, PEMT, CHDH)
• The B12 delivery system is unreliable (TCN2, MTRR)
• The clean-up crew is slow, so we need to be cautious with methyl donors (COMT, MAOA)
• The exhaust system works harder than average (GSS, SOD2)
• One gate drains resources (CBS)

Leucovorin gives us a way to support the recycling factory without overwhelming a slow clean-up crew.

What does the research say?

Folinic acid has been studied in autistic children, particularly those with:

• Language and communication difficulties
• Reduced folate availability to the brain
• Folate receptor autoantibodies (FRAAs)

A randomised, placebo-controlled trial showed improvements in verbal communication in some autistic children, especially in certain subgroups. ⁶ Other studies have shown benefits for children with cerebral folate deficiency. ⁹ This doesn’t mean it works for everyone. But given my son’s genetic picture, it gives us a solid, evidence-informed reason to try a carefully supervised trial.

What Might Improvement Look Like?

If the leucovorin helps, we might see:

• A calmer town (less overwhelm, quicker recovery)
• Fewer traffic jams (steadier progress)
• Builders showing up more reliably (readiness to learn and engage)
• The clean-up crew keeping pace (more manageable emotions)
• Less exhaust building up (more energy, less fogginess)

Speech and communication might improve, that’s where the research is strongest. Meltdowns may be shorter. Sleep may improve. Therapy gains may stick instead of slipping away. The good days may start to outnumber the hard ones.

We’re hoping for a town that runs a little more smoothly and a child with more capacity to grow, connect, and thrive.

Preparation for the Leucovorin trial

Because my son’s clean-up crew works slowly, we need to be careful about how much support we add and how fast. Methyl donors (like methylfolate, methyl-B12, SAMe, and even foods such as beetroot) are like adding fuel to the system.

For some kids, that’s exactly what they need. For kids with slow clean-up crews, adding too much too quickly can cause:

• Irritability
• Hyperactivity
• Sleep disruption
• Emotional meltdowns
• A “wired” feeling

This is sometimes called overmethylation. The lesson: start low, go slow, and watch carefully.

Our Approach

Before starting leucovorin:

• Priming with B12 for one week, so the machines are ready when folate arrives
• Removing dairy, as some research suggests dairy proteins may trigger folate receptor autoantibodies ¹⁰
• Avoiding folic acid, which competes with leucovorin for the same pathways

During the trial:

• Starting at a low dose (10 mg/day)
• Increasing very gradually (monthly)
• Watching closely for overstimulation
• Keeping a simple daily log
• Working closely with our practitioner

We’ll give it a proper trial, likely 12 weeks minimum before drawing conclusions. These things take time. ⁸

We’ll keep you posted.

A Quick Visual Summary

For parents who want a quick reference, here’s how my son’s genetic results fit together:

References

1. Food for the Brain — Methylation: why is it important for mental health?
2. NIH Office of Dietary Supplements — Choline (Consumer)
3. MedlinePlus Genetics — COMT gene
4. MedlinePlus Genetics — MAOA gene
5. MedlinePlus Genetics — GSS gene
6. MedlinePlus Genetics — CBS gene
7. Frye et al. (2016) — Folinic acid improves verbal communication in children with autism and language impairment (full text)
8. NIH Office of Dietary Supplements — Vitamin B12 (Consumer)
9. Parents.com — Leucovorin for autism (realistic framing + cautions)
10. Ramaekers et al. — Cerebral folate deficiency + folinic acid response (full text)
11. Ramaekers et al. — Milk-free diet downregulates folate receptor autoimmunity (full text)