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Emily Gutierrez, DNP, C-PNP, CCN, IFMCP, FMAPS explores the brain-folate connection and the role of cerebral folate deficiency in autism, PANS/PANDAS, and neurodevelopmental health. She explains how folate supports DNA synthesis, myelination, neurotransmitter production, and other critical functions in the brain, while highlighting how blood folate levels may appear normal even when folate availability in the central nervous system is inadequate.
The conversation examines folate receptor alpha autoantibodies and the mechanisms that can interfere with folate transport into the brain. Dr. Gutierrez discusses their significant overlap with autism and PANS/PANDAS, the potential contributions of mitochondrial dysfunction and genomic variants, and the use of the Folate Receptor Antibody Test (FRAT) to identify blocking and binding autoantibodies. She explores dietary, inflammatory, and immune factors that may influence folate receptor autoimmunity and cerebral folate availability.
Dr. Gutierrez discusses folinic acid and prescription leucovorin as strategies to increase folate availability in the brain, including dosing, titration, potential side effects, and factors that may influence treatment response. She explains how higher doses may utilize alternative folate transport mechanisms, why addressing inflammation, infections, and nutrient cofactors may be important, and how restoring adequate folate availability may support language, development, neurological function, and resilience.
In This Episode
- Cerebral folate deficiency and impaired folate availability in the brain
- Folate receptor alpha autoantibodies and their effect on folate transport
- Autism and PANS/PANDAS prevalence in cerebral folate deficiency
- Mitochondrial dysfunction and energy-dependent folate transport
- FRAT testing for folate receptor alpha autoantibodies
- Blocking, binding, and soluble folate receptor findings and clinical severity
- Folate receptor autoantibodies and fluctuations in folate transport
- Genomic variants and their relationship to folate metabolism and FRAT positivity
- Dietary folic acid and dairy considerations with folate receptor autoantibodies
- Inflammation, infections, nutrient cofactors, and preparation for high-dose folinic acid
- Leucovorin dosing and clinical response to folinic acid
- Folinic acid side effects and its relationship to tetrahydrobiopterin
- High-dose folinic acid and alternative folate transport mechanisms
- Immune dysregulation and folate receptor autoimmunity in autism
Transcript
[INTRODUCTION]
[0:00:01] ANNOUNCER: Welcome to the BetterHealthGuy Podcast, where we take a deep dive into complex chronic conditions and explore ways to build resilience, improve vitality, and achieve better health. To stay updated on Scott’s work, you can sign up for his newsletter in the show notes, where you’ll also find ways to support the show and help make more episodes like this one possible. If you find the podcast valuable, please subscribe, rate, or leave a review, as it helps the show reach additional listeners exploring similar questions.
The content of this show is for informational purposes only and is not intended to diagnose, treat, or cure any illness or medical condition. Nothing discussed on this podcast should be considered medical advice. As always, please discuss any health-related decisions with your own personal medical authority. And now, here’s Scott, your BetterHealthGuy.
[0:00:58] SCOTT: Welcome to episode 237 of the BetterHealthGuy podcast. If you are seeking new ways to find better health, I might just be your guy. Today we explore the Brain Folate Connection: Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies, and Leucovorin. My guest today is Dr. Emily Gutierrez, and she is a doctorally prepared nurse practitioner and nationally recognized expert in functional medicine.
With advanced clinical training in both pediatric and adult care, she brings a root cause evidence-based approach to optimizing neurological and mental health across the lifespan. As a doctor of nursing practice from Johns Hopkins University, she specializes in translational medicine, applying the latest scientific research to real world patient care. She has served as adjunct faculty at Johns Hopkins University for six years, teaching integrative and functional health.
She is a fellow of the Medical Academy of Pediatric Special Needs, an Institute for Functional Medicine Certified Practitioner, a Certified Clinical Nutritionist, and a Primary Care Mental Health Specialist. Her clinical background includes extensive training in neuronutrition, genomics, and integrative strategies to support complex mental health and neurodevelopmental conditions.
In her role as Chief Scientific Medical Liaison and formulator for Neuro Nutrients, she develops clinically informed, research-backed supplements that support brain function, mood balance, and overall neurological resilience designed for both pediatric and adult populations. And now my interview with Dr. Emily Gutierrez.
[INTERVIEW]
[0:02:46] SCOTT: Today we are diving deep into folate and the impact of folate deficiency in autism and other conditions. It’s an honor to have Dr. Emily Gutierrez with us to share her work in supporting children impacted by this important topic. Welcome to the show Dr. Emily.
[0:03:03] DR. GUTIERREZ: Thank you, Scott. I’m so excited to be here. I am a big fan of your podcast. It is in my rotation of podcast I always listen to, and I learned so much from you. You are a fabulous interviewer and you ask very smart questions.
[0:03:18] SCOTT: Hopefully I can ask some smart questions of you. And I’ve definitely been looking forward to the impact that I hope this conversation will have for children.
How did you become passionate about working with children with complex conditions like autism, like PANS and PANDAS? What really drives you to help this population? Was there a personal health journey that you experienced that was kind of the catalyst for the work that you do today?
[0:03:44] DR. GUTIERREZ: I think all of us in this space have our own personal journey around health and just being disenchanted with what mainstream or allopathy has to offer. And certainly, from a teenager to a young mom, I really struggled with my mental health and anxiety. I had a pretty serious postpartum year that really was radically transformative for me because I learned a lot of things on how to help my mental health that were not just medication.
And then in 2015, we opened up Neuronutrition Associates in Austin, Texas. And we were one of the first pediatric-focused functional medicine clinics in Texas. And so, who came to us were those that had chronic illness that the allopathic or mainstream paradigm really didn’t have a lot to offer or support to reverse what was going on.
For example, autism. So, in autism, we have behavioral therapies and antipsychotics, but nobody’s really trying to understand the why behind this disorder. So, opening up our practice, we had a lot of very chronically ill children coming and parents that had been to the mainstream, been to the specialist, and nothing was working and their children weren’t getting better.
And so, when you’ve helped one child with autism, you’ve helped one child with autism because they’re so unique. However, when you see somebody start to have language, start to be able to participate in school without special services, there’s nothing that can touch your heart and fuel your fire for wanting to help these kids. And that’s the basis of how we got started.
[0:05:28] SCOTT: And maybe just to kind of set the stage, I know there are people that maybe will take offense to the word disorder when we’re talking about autism spectrum disorders, but what you’re working with and what we’re really talking about here today are kids that are really significantly impacted, right? These are not kids generally that are functional, that are verbal, that are able to kind of manage their own lives. And so that’s just to set that context so that those people who feel that their autism is more neurodiversity that that’s fine, but that’s not really the audience of who we’re talking about today. Would you agree with that?
[0:06:05] DR. GUTIERREZ: Yes. And I’m really glad you brought it up because some people do get very offended. And let’s just be honest, we need to blow the word autism up because it’s too broad. You can have what we used to call Asperger’s that no longer is an official diagnosis of somebody who has some social nuance. They’re pretty intelligent in certain areas. They’re kind of the quirky neurodivergent child that does great things. I have one of those in my family. That’s actually my father.
And then there’s the children that I see. I see more of the severe and profound kids where they were normally developing, most of them, probably about 80% of them. And then there was a triggering event where they lost their eye contact, they lost their words, they went into a world around them, and they could even lose skills like potty training. And everything from banging their head onto the wall, to not sleeping, to not eating. It is quite striking what could happen to a young child when they first get the diagnosis of autism.
Yes, Dr. Gaitanis, he’s one of the board members of the Medical Academy of Pediatric Special Needs. That group would completely agree. Autism needs a new name. We need subtypes of autism. So, I am definitely not here to offend any one group. And I appreciate all neurodiversity and don’t believe because you have any type of label that makes you less than no matter what your label is.
[0:07:37] SCOTT: So let’s then at a high level we’re going to talk about a lot of acronyms and maybe terms that people are not familiar with. So, kind of in a couple of sentences, help us just to establish the concept of cerebral folate deficiency. What are folate receptor alpha autoantibodies? Give us that 30,000-foot view so that you kind of set the stage with the terminology for the discussion to follow.
[0:08:03] DR. GUTIERREZ: In 2004, there was an original research article published in the New England Journal of Medicine that really started to break this science around folate in the brain. And what we have discovered in translation of how long we’ve known this and what’s happening in practice, I’m so excited to talk about. But the basics are sometimes you can see that serum folate, if you look in the blood, is normal. But if you were to look in the cerebral spinal fluid or inside where that folate bathes the brain, it’s quite deficient, and that is cerebral folate deficiency.
And so, there are a lot of reasons for that. And boy, are we going to get into them. And it’s going to get so sciency and so technical. I’m excited. But 30,000-foot view is you can’t always draw blood to say that you don’t have folate deficiency in the brain. And that deficiency can really affect how the brain is developing and functioning.
A folate receptor alpha antibody is when a transport from folate from the body can have some let’s say roadblocks within the way on how it’s getting into the brain. And what we’re discovering is there’s this autoimmune inflammatory process happening in the body that we’re basically making a pathway for folate not as readily available into the brain. I like to compare it to Hashimoto’s thyroiditis where we have free thyroid hormone but it’s not able to get into the cell. And it’s like that is the same. You might have great forms of methylated folate, but transporting it through the choroid plexus into the brain is not as easy.
[0:09:55] SCOTT: So let’s talk then a little bit about the folate side. So, Vitamin B9. Most people have heard of folic acid, folinic acid, and methyl folate. And in the functional integrative medicine world, many of us think about folic acid as a synthetic toxin, which most people don’t think of it that way. I think I first learned about that probably from Dr. Ben Lynch many years ago.
Then we have folinic acid or 5-formyltetrahydrofolic acid. We also have methyl folate or 5-methyltetrahydrofolate which generally in this realm we view more favorably. So, can you help us understand a little bit of the differences between the different types of folate? Why might folic acid potentially cause harm? And as we think about cerebral folate deficiency and this folate receptor alpha autoantibody issue that we’re going to talk about, why is folinic acid typically the treatment of choice? And could methyl folate accomplish the same goals? Or is there something unique about folinic acid?
[0:11:02] DR. GUTIERREZ: Right now, as it stands in 2026, the American College of Obstetrics and Gynecology still recommends that we give our pregnant women 4 milligrams of folic acid a day. And you’re right, in integrative and functional medicine, we kind of get a chill down our spine when we hear that because we understand that the forms of folate are so critically important and they’re complex.
Folic acid is the synthetic derivative. It’s super cheap to put in supplements, like 20-fold cheaper. Supplements like to put folate in the form of folic acid if they want a bigger margin. Some of them do. But folic acid has to be really reduced down to active forms. We do this through NADPH and we take folic acid through certain genomically-encoded enzymes like your dihydrofolate. We make it into a more reduced form of folate. And down the pathway we go through enzyme steps one reduction encoded by genes that we end up with more active forms.
As you said, 5-formyltetrahydrofolate is also known as folinic acid, which is also known as leucovorin is the medication. And then there’s 5-methyltetrahydrofolate which is the form of methylated folate. And these two active forms, folinic acid and methylfolate, have very specific roles of transport into the brain and actually into other tissue types.
[0:12:34] SCOTT: So, we have an option then of making it easier for the body or making it harder for the body and having to take something that’s less beneficial and work through conversion steps to get what we can just exogenously take.
[0:12:49] DR. GUTIERREZ: Exactly. So the question is, is why aren’t we recommending that we take these already broken down methylated, more methylene activated forms? And the mainstream answer to that from what I gather is there’s not enough evidence. But I beg to differ. I beg to differ in my practice. But also, I beg to differ. I think there’s emerging research to show us different things.
In fact, there was a great study by some Italian researchers in 2026 that just came out. And basically, they looked at pregnant women that had these folate antibodies. And what they found is they randomized them into groups and they gave one 15-milligrams of folinic acid a day. And the other group, the standard folic acid a day. And they later followed these children. And what they found is in the cohort that got the folinic acid, there was only 10% of the children that had a diagnosis of autism. And in the folic acid group, it was around 65% that these kids were diagnosed with autism.
Now, this is preliminary research. It was a small sample size. There’s not thousands of people in our N, but it’s emerging and I think it’s exciting to know. And as we dive into this discussion about why are the different forms important, I think listeners will be able to reference back to that and go, “Okay, well, yeah, that makes sense. That makes a lot of sense.”
[0:14:22] SCOTT: So let’s then talk about the role of folate in the brain, in the cerebral spinal fluid, in the nervous system. Why is it so important for brain function? What happens when there’s a deficiency of folate in the brain? I think that’s really the heart of this whole cerebral folate deficiency conversation. So, can you kind of walk us through what cerebral folate deficiency is? What are the typical causes or triggers? And then what symptoms or conditions do you think of as kind of the hallmarks that clinicians should be looking for to consider this as a possibility? And then one more layer, as Dr. Nathan says, that was a nice 10 questions in one. One more layer to that. Do those symptoms tend to look different depending on the person’s age in life? So, if we’re talking about a young child versus maybe an adult, that could also have a deficiency of folate in the brain.
[0:15:18] DR. GUTIERREZ: Folate to me, if there was one nutrient I had to say, was a life-giving nutrient, it is folate. And that is because it has a critical role in so many things. In the brain, it helps with DNA synthesis and cell division. It helps with myelination because you need s-adenosylmethionine to myelinate the basic protein and maturate the oligodendrocytes. It’s important for our monoamines and our neurotransmitters. It’s important to help us in that methionine to homocysteine regulation cycle. It’s even important in lipid metabolism, amino acid metabolism.
So, it’s not just a one nutrient, one pathway. It is pleiotropic. It has so many different indications and the brain requires more folate than the peripheral. So, our central nervous system needs about three times as much folate than our body does. So, when we see that these folate receptor antibodies, what are signs and symptoms that you could see? It definitely does depend on the stage of life, but it’s not just in infancy. It’s not just as a toddler. It’s really across the life spectrum.
In infancy, we might see a small head in a child or something called acquired microcephaly. In toddlers, it can be related to hearing loss or seizures. In small children, it could be related to tics, problems with their gait, a PANS/PANDAS presentation. Adolescents could have PANS/PANDAS as well, or the onset of schizophrenia, or treatment resistant depression. And into the older cohort, we can even see some of the neurodegenerative stuff like Parkinson’s and dementia.
Globally, you might see things like psychomotor decline. In a young child you might see stagnation of development or regression of development. So, they’ve achieved something and then they’ve lost it again. You can see low tone or hypotonia. You can also see dyskinesia, some spasticity. Mood-wise, you can see kids that don’t sleep. You can see OCD. You can see insomnia, depression.
And things that we are discovering what is leading to this, why this is coming about. And cerebral folate deficiency can be from these autoantibodies. There also can be rare pathogenic gene variants. And I can’t wait to talk about that. There can be a lot of mitochondrial dysfunction. Because folate transport actually needs a lot of energy. And different ways that folate gets through the brain, you have different mechanisms. And then there of course is folate deficiency because you have a child that will eat three beige foods or you have a PANS/PANDAS kid that all of a sudden only will eat meat because they have that eating manifestation that can go along with it. So, it can be dietary and it also can be immune mediated.
So, in my work, I truly believe a lot of neurocognitive, neurodevelopmental presentations are intricately tied to the immune system. And this is something that we focus on at our clinic. This is something that we always are trying to uncover. When I have a new patient come in, either they’ve been to see other people and they’ve tried to do everything, or they come in and they’re brand new. I always try to break it down for them as simply as I can, which is this. I’m here to discover with you as my partner on what your child has that they do not need that is stressing out their immune system and what they may be missing that they need to get to homeostasis. So, what are we going to remove and what are we going to replace so we can get back to balance?
[0:19:25] SCOTT: Let’s talk about the intersection of some of these different conditions. So, what percentage of people with cerebral folate deficiency will have an autism diagnosis? And then the reverse, what percentage of people with autism will have cerebral folate deficiency? What percentage of those with cerebral folate deficiency is due to the folate receptor alpha autoantibodies?
And then I’m also interested in the intersection between autism and PANS/PANDAS. So, if a child has autism, how likely is it that they will also have PANS or PANDAS? And if a child has PANS or PANDAS, how likely is it that they’re somewhere on the autism spectrum?
[0:20:10] DR. GUTIERREZ: Here’s the deal is we’ve done this research around the world, not just in the United States, but certainly there are some key researchers in the United States that I know they’re part of the Medical Academy of Pediatric Special Needs and other people that I have not met like the Italian researchers across the pond. Researchers like Dr. Frye, Dr. Rossignol, Vincent Ramaekers, Edward Quadros, and then some of our functional medicine colleagues like Lindsey Wells, and Elizabeth Hinchey, and Nancy O’Hara. Nancy O’Hara did the work with Dr. Wells to figure out what are the incidence of these antibodies in children with PANS/PANDAS, and what they discovered was they found them in about 63.8% of their cohort that they studied had these folate receptor antibodies.
And then if we were going to zoom back and take more of a global look, instead of going to one particular study, I really like to look at meta-analysis because it’s grouping the studies and coming up with a number. It’s not just within that one cohort. And so, I like Rossignol and Frye’s meta-analysis where it was a systematic review published in 2021 in the Journal of Personalized Medicine. And they reported about 44% of those with cerebral folate deficiency also had autism. And among people with autism, about 38% had cerebral folate deficiency. And the folate receptor prevalence in those cohorts was 71%. Which the p value on that’s pretty high. It’s very statistically significant.
And children with autism were about 19 times more likely to have folate receptor alpha antibodies than their typically developing child or sibling. The incidence is quite high and quite significant. And what they’ll see is when they’ve discovered this, what they’re seeing is worsening autism and irritability, all the things that we talked about with signs and symptoms of it. And we’ve even seen this not only in the developing brain and PANS/PANDAS, but in a cohort looking at cerebral folate deficiency in depression and schizophrenia, they found about 36% with treatment resistant depression. But with refractory schizophrenia, there was a study done as well that showed 83.5% of the cohort had these cerebral folate deficiency and antibodies.
So, I think we’re discovering that in the brain when you have something with neurodevelopment, neurocognition and neuropsychiatric needs, right now in practice what I’m doing if you’re coming in, I’m testing you for them no matter what your diagnosis is if there’s any neuroinflammatory stress that we are trying to unravel and treat.
[0:23:18] SCOTT: And then what do you see in terms of your autism population, the overlap with PANS/PANDAS and your PANS/PANDAS population, the overlap with autism? What does that look like?
[0:23:28] DR. GUTIERREZ: Well, that is almost always an indication that we’ve been testing for for many years. If you had a PANS/PANDAS, we talked to the parents about the likelihood of having cerebral folate insufficiency based on these positive antibodies. And I think I’m seeing the same as Dr. O’Hara and Dr. Wells reported. It appears to be around 65%.
Now I am doing a study in my clinic. I have about 70 people in the cohort, and I am looking at correlation of FRAT antibodies with certain genomic variotypes. And maybe I need to also add their secondary diagnosis. I have their primary. But a lot of times, you can have autism and PANS/PANDAS. And that’s a sticky point for me because it’s often missed. It’s often missed.
Scott, a couple of months ago, I had a patient come to me. And they live in Houston, and it’s an 18-year-old that has a profound form of autism, level two to three. And mom said he just became catatonic. He was talking, he was moving, he was engaging. And all of a sudden, he became catatonic. She took him to the neurologist. She took him to the pediatrician and they said, “This is just worsening autism.”
But what induced the catatonia was mom and the child went to Mexico, came back and mom had a severe parasite, was very sick, ended up in the emergency room several times. And so, through an index of suspicion, I empirically treated him. I treated him for parasites. I treated him for possible infection. And six weeks later, his catatonia completely disappeared. Completely. And it could have been missed that it was just worsening autism. So yes, in autism, we’re more likely to see PANS/PANDAS. And in both of those diagnosis, we’re more likely to see folate receptor alpha antibodies.
[0:25:34] SCOTT: So, is autism and PANS/PANDAS the only condition where we should really be thinking about cerebral folate deficiency? You touched on others as well. So, do you think that this also extends beyond autism entirely? If someone had ADD, or ADHD, or what we used to call Asperger’s, or maybe milder autism presentations, should we still be exploring this potential? And then there’s the question again of age. Is this limited to children or are you seeing it in adults as well? Or is the broader community seeing it in adults as well? Do we know whether the prevalence of these autoantibodies differs between children and adults?
[0:26:20] DR. GUTIERREZ: Those are great questions. And we are seeing it outside of PANS/PANDAS, autism, and even outside of depression and schizophrenia. I personally would love to see someone study it in obsessive-compulsive disorder. So that to me is one of the harder neuropsychiatric disorders that I treat and that people suffer with. And I have seen a lot of positive cerebral folate deficiency symptoms and folate receptor alpha antibodies in that population.
Also, in 2026, Dr. Wells, again, with Dr. Hinchey did a study in their Lyme disease patients. And what they found in patients, I think their cohort was N of 68. So, 68 people in their sample. And 42 of them with vector-borne illnesses, about 62% had these folate receptor alpha antibodies. And then some of them had a more severe form of the antibodies which we’re going to get into. The ones with the more severe called the soluble. Or colloquially, we can call it floating, they had Borrelia. But most commonly, the vector-borne illness was Bartonella.
I do believe we’re seeing it beyond just what we’re talking about, but we have more information in these cohorts. But it really opens the question, should we be studying it beyond? Because we also are seeing it in mothers getting pregnant. The Italian study that I referenced to, those women had positive antibodies in the cohort that then they treated with the specific types of folate. How wonderful for preconception and for trying to have a baby and trying to prepare for pregnancy, especially those moms that already have a child with a neurodevelopmental delay? Because once you have one child, it is more likely that you will have a second than if you didn’t in the first place.
And those moms sometimes go into building their family and having that second baby with a lot of hesitation because they don’t know if they’re going to have another child with severe or profound autism. So preparing them and looking for this is something that I think should become routine and standard of care.
[0:28:44] SCOTT: Let’s talk about how folate enters the body and then gets transported into the brain. Are the transport receptors on the choroid plexus? What is the choroid plexus? How’s that different from the blood-brain barrier? And are these folate receptors also in the brain? How does the cerebral spinal fluid come into the discussion as well? And are there receptors in the body in other places that also have impacts in terms of other tissues in the body, other potential symptoms if we’re not getting folate properly transported?
[0:29:22] DR. GUTIERREZ: Okay, so now we’re going to get real sciency. Are you ready? This is so awesome. Actually, when I study biology and biochemistry in this way, it’s just so amazing. It’s amazing. And here’s how it is really I hope that I can paint a picture. And then if you want to dig deeper, there’s lots and lots of data around this.
Folate is an important mechanism to get to many tissue types. In fact, there are folate receptor antibodies on the placenta, in the intestinal epithelium, in the genital tract, in the lungs, the kidney, the thyroid, and the retina. And then we talk about the choroid plexus. Some people think of that as the blood-brain barrier, but it really is more scientifically correct when we say the choroid plexus.
On the choroid plexus, there is a folate receptor alpha. And that is actually encoded by the FOLR1 gene. So, there’s common gene variants around that and there’s pathogenic ones. And we’ll get into that. But this has the highest affinity for methylated folate. And so what happens is methylated folate loves to flow through this receptor into the brain and then it’s further distributed.
When you have this transport happening, it happens through something really awesome called endocytosis. So, what’s happening here is it’s basically a receptor mediated endocytosis. So, your body grabs it, it wraps it up and then it ships it across the brain through the proton coupled folate transport which then gets it out of its bubble so it can be in the CSF.
So, this requires energy and ATP. Those with a lot of mitochondrial dysfunction, those with a lot of neuroinflammatory stress, this process doesn’t work as well. But when you have these folate receptor alpha antibodies, what can happen is I think of this receptor as a Y-shape. And sometimes those antibodies can get in the middle and block the transport and sometimes they can become on the receptor side and bind to it. Either binding or blocking. And then sometimes it can pop off of the choroid plexus and be soluble or floating, the transport is disrupted.
If the transport is disrupted and we’re not using the backdoor to get folate into the brain, then you can see lower amounts of folate in the cerebral spinal fluid. The backdoor is also encoded by a gene called the solute carrier 19A1. And that is the reduced folate carrier. And this is a totally different function on how it gets it through the brain. It gets it through the brain as an anion exchanger which means that it lets folate in while it ships another organic ion out. And this organic ion is the efflux is thiamine. In fact, thiamine pyrophosphate. I think the research is out is if you are low on thiamine, does this efflux transport happen less efficiently? It appears. It makes sense mechanistically. But I don’t know if we have a lot of data out on that.
It’s very technical how folate gets to the brain. And if it’s not getting through the methylated form, that reduced folate carrier has a high affinity for folinic acid. So, it will antiport folinic acid into the cerebral spinal fluid when the methylated form is not getting there. So, once it’s in the brain, then the methylation continues. But there can be some steps and hiccups along the way.
[0:33:20] SCOTT: So, am I understanding correctly though that the folate receptor alpha is only transporting the methyl form? And then it’s that backdoor that can bring in the folinic acid and then convert in the brain? Or can the folate receptor alpha also transport folinic acid and then convert it?
[0:33:42] DR. GUTIERREZ: I don’t believe the affinity is high. I know that the affinity for methylated folate is its primary form. And I read in one article, and I don’t know if this is a thousand percent true, but that it was a thousand times more strongly had an affinity for methylfolate. So, does a little bit of folinic acid get through? I’m not sure. People don’t publish on it. What they do talk about is folinic acid getting through that backdoor-reduced folate carrier.
And when I talk to my parents about it, I try to give them an example. Because when you really talk sciency, you know how people can just kind of fade away and just be kind and listen, but you have them gone. I try to make it this simple. Think of the brain as your house. And sometimes your key doesn’t fit in order to get inside. And that would be because maybe there was like gum in the lock. So, something’s blocking the key from getting in.
And then sometimes the lock just doesn’t unlock, right? So, it’s either blocked or it’s bound. So, a lot of us have a backdoor, a sliding backdoor that you can run around the house and get in the backdoor. And that’s where I think of folinic acid giving in. Because either your lock is broken or it’s just the lock isn’t working at all getting it in.
[0:35:04] SCOTT: So, from a perspective then of the folate receptor alpha, we’re expecting the body is converting the folinic acid into the methyl form before it gets to that receptor in order for it to get into the brain. Or the folinic is using that backup process which is different from the folate receptor itself.
[0:35:25] DR. GUTIERREZ: Yes. And in the brain, unless you have an extremely rare variant, a genomic variant, which is the FDA contraindication with folinic acid, that rare and pathogenic variant is called MTHFS, which we think about 12 people in the entire world has it, you cannot convert the folinic acid into the methylated form. And that is a strong contraindication to give somebody folinic acid because it is so incredibly rare. And I have never seen it in practice. And it’s only 12 patients. It doesn’t prevent me from using folinic acid if I do not know their MTHFS variant result.
[0:36:13] SCOTT: So before we move on from this topic, the folate receptor alpha autoantibodies, if someone has those autoantibodies, does that then automatically mean that the same antibodies are affecting the receptors that are in the intestines, and the lungs, and the kidneys, and the thyroid, and all of these other places? And if so, are there specific symptoms or problems that result from lower folate in those specific tissues, glands, and organs?
[0:36:46] DR. GUTIERREZ: That’s such a wonderful question. And I don’t think we have the research to show that. But those tissue types also have a reduced folate carrier as well. So, they also have backdoors. It would be interesting. I think they would have to study it in vitro to look at the amount of folate in those tissue types. Checking the cerebral spinal fluid is easier, right? Because you’re getting a fluid to look at a nutrient level. So, it’s interesting. It mechanistically makes a lot of sense to me.
And yeah, I mean, think about it fully in the genital tract, in the placenta. I mean, again, we’re talking about fertility and conception. So, we know, and we’ve known forever and ever, that if you want to have a healthy pregnancy, that you need adequate amounts of folate to support that. So, those are great questions, Scott.
[0:37:38] SCOTT: When a child has the antibodies then that develop to the folate receptors, can we say that that is a form of autoimmunity? And if we’re talking then about autoantibodies and the prevalence of these autoantibodies being fairly high in autism, does the research and clinical work to date suggests that autism may be an autoimmune condition?
[0:38:07] DR. GUTIERREZ: Well, for anyone in this space that treats autism, we know it is an immune mediated neuropsychiatric condition that happens from stress in the body. So, autoimmunity, we can call it that. I mean, the antibodies are antigen-antibody complexes that are like the soluble one, it’s not anchored to the membrane. Certainly, that is an autoimmune reaction.
Why are kids developing these? Why are we developing these? I think it’s the amount of oxidative stress. It’s what do you have that’s stressing your body out? And what are we lacking? And that goes back to the functional medicine model. How is your gut balanced? What are you putting in your gut? What is your exposome, your environmental toxicants? What are your coinfections or infections that nobody has treated or hasn’t recognized?
So, I truly believe that autism, there are some genomic variants that are about 10% of autism. And then the other 80% of autism we see more common variants and pathways, like how you make glutathione, how you recognize pathogen clearance through your mannose-binding lectin pathway? It’s very complex, but it’s very biological.
And today, we’re still told it’s bad luck. It’s just a neurodevelopmental behavioral condition, and there’s no physiologic root cause of it. Or you might be told there’s some rare genetic thing that you can’t do anything about. Yes, we have to redefine autism. We have to rename it. We have to redefine it. And this picture of folate autoimmunity or folate transport issues into the brain is a big deal in neurodevelopment.
I think autism is an autoimmune condition in the regards that you are no longer able to tolerate that redox balance, the amount of oxidative stress and the amount that your body can balance it out to get back to homeostasis. I don’t know if I would define it as autoimmune. Certainly, there’s a huge autoimmune component to it, but I think there’s a little bit more complexity than that.
[0:40:34] SCOTT: So, let’s talk then about whether or not this is more commonly seen in families. If mom has antibodies during the pregnancy, does that then increase the potential for the child to have or to develop the same antibodies? I know some antibodies are passed from mom to baby during the pregnancy. Does mom’s folate level or the presence of these folate receptor alpha autoantibodies during a pregnancy play a role as a contributor to the later potential development of autism or cerebral folate deficiency, or to then develop these autoantibodies? And can a child actually be born with a cerebral folate deficiency or already born with folate receptor alpha autoantibodies? And how much of all of that could we minimize with proper folate sufficiency during pregnancy?
[0:41:29] DR. GUTIERREZ: I love the question of are children born with this? Are pregnant mothers carrying these autoantibodies? And what do we know today on what that looks like for the child? And I really think the best research was the one we talked about before, the Italian research where they looked at a cohort of 210 pregnant moms, and 36 of them were positive for the folate receptor alpha antibodies.
And when they randomized them into groups, there was 15 in one and 14 in the other. In those groups, there were folate receptor alpha antibodies in those infants when they were born. So, they were born. And then those that had more folate receptor alpha antibodies were more likely to come into play to have autism versus those that didn’t depending on the type of folate that they were given. Because if they were given folinic acid, there was a lower incidence of autism in that group versus the one that were given folic acid.
We’re learning. We’re still learning about it. Just because you have a folate receptor alpha antibody does not mean you will have autism. Does it mean that there is some signal that the folate transport into your brain could be compromised? Absolutely. What does that look like for that individual? Well, I think we have to put it into context of all the oxidative stress, too. When we think about this process of creating these antibodies, it always begs the question, “Why is this happening?” And I think we can just put it into context with the milieu of what our bodies are experiencing in 2026, all of this oxidative stress. So, the more neuroinflammation the brain has, the more likely this process is going to be happening.
Dr. Quadros in 2018 did the study looking at family clustering, and what they found was autism families, the children’s siblings and parents were 70% more likely than to unaffected controls which were 29% to have these folate receptor alpha antibodies. I do know it’s more common in families. But just because you have that in a sibling does not mean they will have autism.
Example, for some of my patient population, I often see siblings often. So, I might start off seeing a child with autism and then eventually I see their younger sibling because they’re having anxiety. They might have PANS/PANDAS, they have OCD, they have a learning difference. There’s something that is non-autism but neurodevelopmentally catching their attention. So, in those children, I often will do FRAT testing, and because I want to know what is the form of folate that their brain needs. And I also know that they’re more likely to have a positive number because their sibling did.
[0:44:28] SCOTT: When we think about that reduced folate carrier backdoor, is that adequate to make up for the loss in transport from the folate receptor alpha autoantibodies or does it still not enough to make up for that potential inefficiency in transport of the methylfolate? And then how much is this backup system dependent on mitochondrial function? So how much of what you’re exploring and assessing is focused on optimization of mitochondrial function? And if that is important, what markers are you looking at to assess mitochondrial function and also some of the tools that you’re finding most helpful for mitochondrial optimization?
[0:45:14] DR. GUTIERREZ: So is it sufficient if you’re using the reduced folate carrier with folinic acid because you have a binding, blocking, floating result? It depends. It depends on their response. It depends on the dose. It depends on how much oxidation is in the brain, how much redox stress they have. And the folate receptor alpha is the one that requires more energy. But an anion antiporter also does as well, just not as much.
So, what do I see with a child with mitochondrial deficiency? Well, there’s true mitochondrial disease and there’s acquired mitochondrial deficiency. And almost every single child with autism has some mitochondrial deficiency. And I think that work has been well elucidated. What we see in them is acetylcarnitine deficiencies. So, rescuing them with carnitine which sometimes can be very challenging in a child that refuses to eat meat.
The other mitochondrial cocktails like ubiquinol, coenzyme Q10, making sure that they have enough B vitamins for their mitochondria. I’m always zooming in and then zooming out. And zooming out, if you have acquired mitochondrial pathology, it still is like, “Well, what’s happening outside of the cell that’s troubling inside of the cell that’s troubling the mitochondria?” You still have to zoom out and do that work.
Often I’ll be clearing infection. I’ll be reducing inflammatory stress, allergies, what they’re eating, environmental toxicants, heavy metals, mycotoxins, you name it. I’m looking for what is stressing out the cell that the mitochondrial dysfunction is already there. But yes, we need to give them thiamine and we need to give them the B vitamins and the other nutritional cocktail to help their mitochondria have the nutrients to perform better so that that transport into the brain can work better.
[0:47:24] SCOTT: I think a lot of what you were just talking about then also overlaps into the whole cell danger response conversation and how the mitochondria essentially kind of change from energy production factories into sensors of danger and creators of danger signals in response to a given threat.
[0:47:45] DR. GUTIERREZ: Beautifully said. Beautifully said. And I know you’ve had the expert on your podcast talking about this. And I would love in a child to give them things like methylene blue. And sometimes I have some Bartonella patients right now taking high doses of methylene blue. They’re managed by Dr. Amy Offutt. I mean, just the mitochondrial, the fatigue is disappearing, the headaches are disappearing, the muscle tension, the ability to study, the ability not to have to sleep for 12 to 14 hours a day. It’s really quite remarkable.
We don’t always use all those great tools. I’m not going to ask a four-year-old to go get an NAD IV. However, they’re great tools in older adolescents and young adults and adults that you can use. But the cornerstone for mitochondrial, like rescue nutrients would be carnitine for children, and coenzyme Q10, and their B vitamins.
[0:48:45] SCOTT: So, now we’re going to jump into a section on testing. And again, I’m going to throw out a bunch of questions and then let Dr. Emily run with them.
So, are you generally testing a mom during pregnancy for folate levels? Do you also test children for folate levels? And if so, what testing are you looking at? Can the folate blood levels be normal but still have a cerebral folate deficiency because of that autoimmunity to the folate receptors? I think that’s already pretty clear that that can happen. Could higher serum levels be a clue for these autoantibodies in that maybe there’s higher serum levels because of these potential transport issues into the brain, into the spinal fluid, into the nervous system? Or is testing serum folate not helpful because it’s giving us no meaningful insight into what’s happening in the brain itself?
And then if you’re testing someone for folic acid at a lab like Labcorp, how do we know what they’re testing for? Are they testing the various forms? Are they testing just the synthetic toxin form? If they’re really only measuring folic acid, is that test better used as a test for toxicity rather than nutritional sufficiency?
And then maybe building on that, as if I didn’t throw out enough, if we think about the functional medicine tests, we can see something like Vibrant, they will talk about folate, Genova will talk about folic. So how do we know what they’re measuring? And what are you using to explore the various forms of folate in the blood knowing they may not reflect the levels in the brain? And are there cases where you might even look specifically at folate in the spinal fluid?
[0:50:32] DR. GUTIERREZ: Okay. I have never done a cerebral spinal fluid tap on a child in my clinic. Does that happen? Absolutely that can happen. Will the hospitalist or the person tapping the spine because someone’s admitted for encephalopathy check for folate? I don’t know.
I had a very, very sick kid that was in the hospital, and they were there for a couple of weeks, and they did a spinal tap with the normal looking at the encephalopathy panel and they refused to run folate. They refused. And they had the cerebral spinal fluid. So, it’s very hard to say that. I know there’s a couple of the functional physicians from the MAPS group that are thinking about actually opening a practice doing spinal taps on kids because access to care for that is so bleak and so hard unless you’re being followed by one of the big guys like Dr. Frye.
So folic acid, I don’t know if I answered this. Before when we talk about folic acid being this toxic component, there is some literature. The question is why is it toxic? Well, we know it’s synthetic, but there’s been studies correlating when folic acid is higher in the serum that natural killer cytotoxicity cells are low.
So, there’s a cancer correlation. And I think the signal that we’ve seen the most is in GI disorders and GI cancers. But the mainstream gastroenterologists and oncologists probably would still very much disagree with us that it’s still okay. And that’s why ACOG and the American Academy of Pediatrics says, “Oh, just take that folic acid.” But folic acid is hard to test. It’s hard to test.
In Texas, we use Clinical Pathology Labs. I’ll use Quest. And I know there’s Labcorp. And they don’t say is it 5-formyltetrahydrofolate, which is folinic acid, or 5-methylenetetrahydrofolate, which is methylfolate. They say folic acid. I only run folic acid one time. And I run it one time because if it’s high, it’s probably an absorption issue. That’s my deduction, especially if they’re not taking folic acid and they are eating, depending on what their diet looks like.
But if it’s low, I know we have a pretty big problem. I only check it once. Because once you then give someone folate, that level is going to go high. And a lot of well-meaning providers look at that level and they say, “Oh, well, that. And your mean corpuscular volume is right. And so you don’t have any problems with folate.” If they’re smart, they might check B12, but that’s a whole can of worms, too, right? Because B12 can be very high in the serum and be very replete in the cells because B12 has so many transport and absorption issues.
So, could high serum folic acid be a clue of malabsorption? Sure. Is it hard for parents and providers even to wrap their head around that because they don’t understand the nutritional biochemistry, and the genomics behind it, and the autoimmunity behind it? Absolutely. I like to look at ancillary markers for folate more, like homocysteine. But in a three-year-old, your homocysteine, even if they’re a poor methylator and they have folate receptor alpha antibodies, might still be low.
So, there’s some shift in your lifetime. And to me clinically, and I’ve been doing this, I’ve been running homocysteine for about 15 years, the highest I see it trending upward is about six to seven. And nobody’s ever really been able to tell me why you can have low homocysteine in a younger pediatric population. I think the hypothesis is, is they’re just burning up their methionine because they’re so toxic. They’re getting to that transsulfuration pathway and they’re trying to make antioxidants. But I don’t know. Homocysteine can be an ancillary marker. It’s not perfect though.
[0:54:36] SCOTT: So, what I took away from all of that is that when we’re testing folic acid, it’s not really clear what the value might be. We don’t always know whether they’re looking for folinic or methyl folate. So, someone could have low folic acid, but maybe they have sufficient folinic acid or methylfolate. So my takeaway, and correct me if I’m wrong, was testing for folic acid or testing for folate is not driving a lot of value in this conversation.
[0:55:09] DR. GUTIERREZ: That’s true. I think that’s absolutely true. My functional medicine blood panel that I created when I started the practice has folic acid on it. And now when I run them, I just delete it. I delete it. Because I rather get a FRAT test instead. And the conversation of, “Well, my folic acid is high. Why are you putting my child on folate?” Or just if the pediatrician sees the labs and it’s like, “You don’t need folate. Look at how high your folic acid was.” So, it doesn’t have a lot of value. It has a lot of nuance behind it. And I wish there was a different marker. And some of those more functional tests, the SAM/SAH ratio, different pathways that you can, some of the organic acids. I think that’s more valuable.
[0:55:53] SCOTT: So given the overlap then with cerebral folate deficiency and the methylation side of things, how important is it to optimize B12 as well as that B9 or folate? We know that you mentioned that the folate receptor alpha is really transporting methylfolate and not so much folinic acid. So, it seems like this is another reason why the methylation conversation is important. And when you do a serum B12 and it’s elevated when someone is supplementing, does that concern you at all? Does a high level potentially mean that the B12 is not getting from the serum into the cells?
And then talking about some of these other markers like you mentioned, homocysteine potentially related to the folate conversation, but do you find value in mean corpuscular volume or MCV as an indication of a need for B12 or folate? How does methylmalonic acid fit into that conversation? Are you also using homocysteine as a potential surrogate for B12 deficiency? And then are you finding that this population generally does better or better tolerates methylcobalamin, hydroxocobalamin or adenosylcobalamin? I’m guessing you’re not using cyanocobalamin. And what’s the concept of folate trapping if B12 is insufficient?
[0:57:19] DR. GUTIERREZ: So folate trapping is an interesting and important thing to talk about. Before I start any amount of folinic acid in a child or a patient, I really want to make sure that they have enough B12 on board. And as you know, B12 comes from animal protein mostly. There are some other sources of B12. But if you have a vegan family or a very, very picky child that will only eat a couple of packaged processed carbohydrates, you should have a high index of suspicion that their B12 is not going to be in the therapeutic range.
And just like folate, B12 in the serum, if it’s super low, it’s super low. If it’s high, it still could be low. B12 has a lot of genomic influences on how we absorb it within our gut via our intrinsic factor, how we transport it through our transcobalamin genes into the cells and even how our mitochondria is able to uptake it versus some of our genes as well. So that is it’s very, very genomically influenced. It’s influenced by our diet. And high levels, again, can really send providers on the wrong trail. Like, “Oh, your MCV is fine and your B12 is high, you don’t need any of that.”
But if they’re not looking at homocysteine, which I do love looking at homocysteine. Because in the methionine cycle, methionine needs to recycle the homocysteine. Homocysteine back into methionine, as it’s creating S-adenosylmethionine and giving us methyl donors, and that process needs B12.
So, if you give a lot of folinic acid in the brain and the cerebral spinal and that tissue gets it and it can’t remethylate it, then the folate is going to become trapped in the cycle. So, they’ve done a few studies on this. I don’t think it’s robust research, but certainly I will see that kids do better and people do better if their B12 is normal first or supported. Because I think normal is a misleading word, and then you start to give the folinic acid.
In fact, in autism, one of the biggest things that we do in the Medical Academy of Pediatric Special Needs, and it might surprise some people to know that I give B12 injections all the time. And I not only give them in the clinic, I will send them home with the parents. And that child will be getting a good dose of B12. Say a six-year-old might be getting 2 milligrams of B12 every other day. And we do that for 6 months. And they inject their child at home when they’re asleep or after the bath. And we get their B12 very high.
So, if someone were to check their B12, they would be like, “Oh my gosh, you’re maxed out of the range. It’s so high. Quit your B12. Quit your B12.” But B12 is water soluble. It’s not toxic. There’s no signs of toxicity for it. And we are giving heroic doses that support the methylation. So when you add in the folate, we can have proper methylation. And in the homeostatic mechanism of all the biochemistry works in so much greater harmony.
[1:00:39] SCOTT: And do you find in this population that one specific type of cobalamin is better tolerated?
[1:00:45] DR. GUTIERREZ: That’s a great question. You’ll hear it online. You’ll hear it online and you’ll hear it from some people like, “Well, I do better on hydroxocobalamin. Methyl just makes me too agitated and irritable.” And you’re right. There’s cyanocobalamin that you can get from Monster drinks and energy drinks, but we know that is from cyanide. And we know that hydroxocobalamin and those that have cyanide poisoning can actually cleave the cyanide off of cyanocobalamin, which I think is fascinating. And then adenosylcobalamin, there’s more literature out there that that’s more of the mitochondrial form.
In my kids, depending on what we’re doing, if I’m doing injections, it’s almost always methylated. But if we’re not doing injections and say I am going to compound them a personalized nutrient, I might give half adeno, half methyl. And then if we are more sensitive to the methyl B12, I just want to know why. Because you can also have a greater sensitivity to the folinic acid. And that’s a nuance conversation I think we should have on side effects of giving folinic acid because B12 kind of fits in there as well.
[1:01:55] SCOTT: So, let’s talk now about the FRAT test from Religen. The website is fratnow.com. So, is that the only lab where this testing is available? I think that’s always a question for people, like has it been replicated with other labs and that kind of thing? How much does it cost? Can it be ordered directly by the patient or does it have to be through their practitioner? Do you generally find that it’s covered by insurance? And does a patient need to stop supplementing with all forms of folate before the blood collection? And then how long is it taking to get the results back?
[1:02:34] DR. GUTIERREZ: Have you ever met Dr. Sri Ganeshan yet? He’s wonderful. He’s one of the medical directors of Religen who does the FRAT test. He’s always open for questions. He’s a wonderful man. He’s a gastroenterologist, and he’s been in the space in autism for a long time. So, he’s become a friend of mine. And boy, I’ve asked him a lot of questions.
So, when it comes to this type of testing, they’re the only ones that do it. I know of one company in Austin, Texas that is about to produce a test looking for these folate receptor alpha antibodies. Currently to date, right now, I don’t know of anybody else doing it. Will there be lab companies doing it? I’m almost certain that there will be. So, once they really, the company, the FRAT testing company got notification or they really became more publicized, then their operations just really got underwater. And it used to take 3 to four months to get a FRAT test back. But I’m happy to report now my FRAT tests are coming back in four to five weeks. They’ve really kind of caught up.
It does have to be ordered by a medical provider. It costs around 300 bucks. It’s not covered by insurance. And it’s a poke. In pediatrics, kids don’t want to be poked. Most of them. There are some that they’ll surprise you. They’ll be like, “Oh, yeah. It’s real interesting. I can’t wait to get my blood drawn.” But for the most of everyone, it’s a very hard conversation. And I don’t know how to get this test without actually drawing serum.
You get a testing kit and you could take it to your local lab company or any lab test now and get it drawn. And you do need to stay off folate, all folate containing products. And they say 48 hours. I tell my patients 3 days. Just one more day for good measure because that could skew the findings.
[1:04:32] SCOTT: When someone gets those FRAT results back, how do you interpret them and turn that into useful clinical information? Talk to us about the difference between the blocking and binding folate receptor alpha autoantibodies that you alluded to earlier. Are they two different types of antibodies? Is one more clinically important than the other? Are you primarily looking at yes, it was positive, or it’s negative. Or does the quantitative value of the level of autoantibodies influence your clinical decision-making and even how you might dose the folinic acid?
[1:05:12] DR. GUTIERREZ: Yes, those are great questions. So, on the test right now, it’s positive or negative, and it gives you a number but it does not give you a range. And so what I found clinically is the higher the number, the more severe the presentation is with the person that I’ve done the test on. And you can have blocking. Remember, it’s like the key is stuck. There’s gum inside of the key getting folate into the brain. Or you can have binding, which means maybe the handle isn’t working well in the door. That there’s antibodies bound to the receptor but necessarily not blocking the receptor. There’s still receptor dysfunction. Or you can have that floating antigen-antibody complex lacking the membrane to anchor down to the soluble or the floating one.
The most severe that I would see would be a floating; so two positives. So, I think blocking is more severe than binding. And if you have a binding and a soluble, that’s very severe. So, the soluble, when that comes, and in my work, in the study that I’m doing, about 5% of the kids that I’ve done have a soluble. And those inherently have a greater diagnosis at presentation. Maybe they have a comorbidity of a seizure disorder or they have a very severe form of autism. They tend to have more neuropsychiatric symptoms. The severity does tend to correlate.
Now what I also would say is somebody that has a low level of binding versus somebody that has two positives and a floating, I’m going to approach treatment differently. And I’m going to approach it differently. Because if we have the soluble, I’m going to really focus on inflammation for at least a month before I introduce anything like B12 or folinic acid. So, I might give lots of neuroinflammatory calming things first. And then I absolutely will determine how high I want to push the dose.
Scott, right now I have one kid. He had a pretty positive result. And we started off the normal amount of treatment, which is 2 milligrams per kilo, and you max out at 25 milligrams twice a day. And he’s taking 75 milligrams twice a day now because it totally helped with his speech and his ADHD. And mom keeps pushing me to increase the dose. And I’m like, “We’re just going to stay at 75 twice a day.” Yes, the more severe the results, the more likely I am to try to push higher levels to overcome what we’re seeing in the testing.
[1:07:59] SCOTT: So, I could have a positive blocking and a positive binding. But more clinically significant is the soluble folate receptor on the blocking combined with a positive binding. That’s the more significant potential combination. Correct?
[1:08:19] DR. GUTIERREZ: I believe so. So, the soluble one that Dr. Ganeshan and I have talked about tends to be the one that we believe is the most severe form of the result. Anywhere on that. And I do see binding and floating in my population. I haven’t seen it reversed. I don’t know the specific data on that but that’s what I have seen.
[1:08:45] SCOTT: And so, this soluble folate receptor, because you’re saying floating, does that mean that the folate receptor itself then is circulating in the blood and binding folate but it’s not getting transported into the brain? Help us understand where this soluble folate receptor is impacting this process in the body. Is it in the brain? Is it in the systemic circulation?
[1:09:12] DR. GUTIERREZ: Yeah. And the assay that they’re doing, what Dr. Ganeshan and I have talked about is he’s like, “Think about it as it’s floating and it’s not anchored down.” Because there’s so much inflammation that it’s floating that we’re seeing it floating in the blood. That’s what they’re seeing. And you should have him on the show. He would get totally technical and tell you everything about their assay and what they’re doing. But yes, it’s more floating. Folate is binding to it. It’s just not anchored down to transport.
[1:09:49] SCOTT: And that floating soluble folate receptor, it’s not necessarily the case then that there is an autoimmune development against that receptor. It’s that the receptor is floating around essentially sucking up the folate that then is getting transported into the brain at a lower level. Is that a reasonable way to think of it?
[1:10:12] DR. GUTIERREZ: Well, and you also could think about it as it’s more of there’s so much inflammation that it came off of its docking station. So, you can think of it as we really need to focus on inflammation first so that we can quelch the environment. And I might use things like specialized pro-resolving mediators. I know you’ve had Dr. Dayan Goodenowe in here. I love the ProdromeGLIA. I might use a lot of that. You have to dose it pretty high for the neuroinflammatory treatment. I might use high dose omegas. It just depends. But we would do that first.
And then of course, you just can’t throw antioxidants and anti-inflammatories on someone without saying what’s inciting the inflammation. At that point, I might say let’s talk about the diet. Go at least gluten and dairy-free. Let’s reduce the sugar. We’re going to get rid of X, Y, and Z that’s in the home. So, I’m still in the background working on everything that’s inciting it.
And of course, in my patient population, I’m like, “Where is the infection?” Is it strep in the gut? Is it coinfections with Lyme? Is it a non-infectious toxicant like a mycotoxin? I’m still doing that background work so that the inflammatory stress on the brain can normalize this soluble. That’s how I think about it.
[1:11:34] SCOTT: Is it reasonable then to think that this floating folate receptor would have otherwise been at the choroid plexus to help optimize the transport into the brain, but now it’s not there anymore? It’s floating around somewhere else. And so that also then is reducing the potential for folate transport into the brain.
[1:11:59] DR. GUTIERREZ: Wonderful. I think you’ve got it.
[1:12:01] SCOTT: So, in someone who has this folate receptor alpha autoantibodies, if they’re not treated at all and you test them again at a future point in time, do the results generally look consistently the same? Or does a child move in and out of this autoimmunity and have periods of lower and higher transport as a result of waxing and waning autoimmunity?
[1:12:27] DR. GUTIERREZ: Yes. And it surprises a lot of people to hear that, but this is not a fixed result. You can wax and wane based on where your autoimmunity is. The makers of the test say recheck it 6 months to a year to see where you’re at. I have never had a patient that we’re testing monthly to see where these are at. That would be a really interesting test to do. But typically, yes, it’s how much stress, how much autoimmune stress, how much waxing and waning. It’s often like tics in the brain where you see motor tics, vocal tics, those can wax and wane. Well, this process can too. So, yes, I believe the folate transport waxes and wanes as well.
[1:13:10] SCOTT: And I’m guessing it’s fairly uncommon for someone to repeat the test having not done any intervention.
[1:13:18] DR. GUTIERREZ: Well, you would be surprised. Let me tell you why. In the past three years, I have had probably five or six families come to me and they have a FRAT test and they have positive results. And the reason that they came to find our clinic is because they know that we know what to do with those positive results. And their pediatrician or their neurologist ordered the test for the family, got it back, and said, “I have no idea what to do with this. Here you go.” And they received no treatment whatsoever. That’s so heartbreaking to me.
As a provider, as a clinician, if you are going to order a test, please partner with your patient to then support them through whatever the results are. But on the one hand, I’m glad the pediatricians are ordering them. And on the other hand, I hope that there’s more information that they get that they start to feel comfortable with initiating some treatment.
[1:14:13] SCOTT: So do you think that the incidence of folate receptor alpha autoantibodies is increasing or is it increasing awareness and now having the testing? I would personally argue that the increase in autism over the last few decades is not based on better awareness and better diagnostics. I think it’s actually a real increase. So, do you think that the prevalence of cerebral folate deficiency and folate receptor autoantibodies has been the same over time? Or are there potential contributors or reasons in our world that it’s actually increasing?
[1:14:51] DR. GUTIERREZ: I think it’s both. I think that we’re more aware of it and there’s more of it happening just for all the other reasons that I’m sure that you could agree that autism is not just because we’re better at diagnosing it. We’re seeing more autism. We’re seeing more profound autism. We’re seeing more non-speakers. We’re seeing more severe presentations, like non-speaking and all the PANS/PANDAS, all the immune stuff. Our kids are getting sicker. We are seeing more of it. And it’s not just because we have a DSM module or manuscript to diagnose it.
[1:15:28] SCOTT: So, let’s talk now about some of the genetics. First, just briefly at a very high level, I want to get your perspective on these SNPs. So, I think of SNPs as potential and not a representation of function. So, as we step into the potential genetic contributors to folate issues and folate receptor issues, are these deterministic if someone has them? Or how much does epigenetic influences like stress, trauma, toxicity? How much does that impact the function of the genes that we’re talking about in this domain? Is there value in focusing on the optimization of genetic expression as part of your treatment protocols? And is that done by removing or mitigating the stressors in someone’s life that’s influencing the expression of their genes or by introducing nutrients that are essentially bypassing or optimizing that inefficiency or a combination of both?
[1:16:30] DR. GUTIERREZ: I think you’re right about some of the genes. Some of the genes are genes that we have that the odds of an outcome will happen are higher because we have a genomic variant in that pathway. But there are some rare pathogenic genes. In fact, less than 1 in 10,000 people have a rare pathogenic gene. Just like the FOLR1 gene, there is a rare pathogenic gene and that encodes for the folate receptor alpha. It’s a biallelic loss of function variant. So, you have to have a two-copy loss of function. And there have only been 35 cases reported worldwide. And that is on label for leucovorin. That is on label for a treatment.
But there’s also an FOLR1 common variant that I think that would be really fun to get into. And sometimes I use my patients’ genomics and the genomics around folate transport and the genomics around methylation to determine if I think there is a problem with folate transport. So sometimes we’ll do genes and not a FRAT test. Of course, I like both if I can get them, but like we talked about before, there’s just some children that no matter what you do, they will not let you draw blood from them and it would be a trauma to ask them to do so. So, I think we can use some of these common genomic variances that have data that you’re more likely to have folate receptor antibodies as a diagnostic marker or a probability that this is happening. So, we might want to go ahead and start treatment.
[1:18:08] SCOTT: What panel then are you using to look at the genetic associations with folate receptor alpha autoantibodies, cerebral folate deficiency? Is there a specific panel that’s geared for that? Or are you doing a broader genetic panel and pulling that data out yourself?
[1:18:27] DR. GUTIERREZ: I have been using IntellxxDNA for the past five years, and they actually have a folate antibody profile. So, they have genes that are run in that panel. They look at the folate receptor 1 alpha, some of the solute carrier 19A1 which encodes the reduced folate carrier. And believe it or not, even the good old MTHFR C677T, there’s data. If you have a homozygous variant in that pathway, you are more likely to have folate receptor antibodies. That work was done by Dong and associates in 2018. But there’s also the MTHFD2 which encodes for the mitochondrial folate uptake. So, it is a nice panel of certain ones. And I would say maybe the FOLR1 is the star variant, something that I pay very close attention to.
[1:19:22] SCOTT: So that is Dr. Sharon Hausman-Cohen with IntellxxDNA. She’s been on the podcast before. So that’s great to know that she has a specific panel that’s geared towards this conversation.
So, we talked a little bit earlier about that rare MTHFS variant. You just mentioned FOLR1. So why is that called the star gene? How is transport of folate impacted if someone does have this variant? What does that mean for their serum folate levels? And are those that have this variant at higher risk for the development of autism? Does it increase the risk for any other presentations or symptoms associated with autism? And how does the presence of that variant change your approach to treatment? Does it increase the potential for the treatment that you’re implementing to be even more beneficial? And are there multiple variants of FOLR1 that are relevant to the conversation?
[1:20:25] DR. GUTIERREZ: I think the FOLR1 more common genomic variant is very relevant to the conversation. And I think of it as the star gene because it’s on label for folinic acid. But remember, it’s that rare pathogenic variant only in a handful of people. So, the more common variant, a heterozygous variant is found in 11.3% of the population, and a homozygous variant is found in 0.4% of the population. And this encodes for the folate receptor alpha as well.
And we have seen in this, there’s data to show, that if you have this gene variant, your odds ratio of having autism is 6.45. For the listeners that don’t know, an odds ratio of one is average times the risk, and odds ratio of 1.5 is one and a half times the risk. So the higher the odds ratio, the higher the odds that this common gene variant will infer a specific outcome.
Now why would this gene variant have autism? Well, we know that children with autism are more likely to have deficient levels of folate in their brain.
So, I’m actually doing a study with this in my population. I have 79 people in the cohort, and my findings are pretty much the same as what we found with the frequency in the human population. I found that about 13% had a heterozygous and then 6% had a homozygous and of those, 56.3% of them had a FRAT positivity. So that’s what I’m hoping to contribute to science is some of the correlation with these genomic variants and FRAT positivity. Because remember, genomics are important for methylating folic acid, into tetrahydrofolate, into 5-methyltetrahydrofolate, into methylfolate. But then we have to encode the receptors, folate receptor alpha, for that endocytosis through the brain. And then the back door is encoded by the solute carrier 19A1 with that anion exchange.
So, genes do play a role. And sometimes knowing the gene variant, do you have to do the FRAT test? Or can you infer from the genotype. So, if I have somebody with FOLR1, depending on their situation, depending on their diagnosis and their severity, I might even just give them two to two and a half milligrams of folinic acid and not prescribe them leucovorin.
[1:22:56] SCOTT: So, let’s touch a little bit on the dietary considerations for treatment. I know many foods are fortified with folic acid. California recently started requiring fortification of corn and masa tortillas. The fortification of foods, as I understand, is not being done with folinic acid or methylfolate. I mean, wouldn’t that be a great idea? So should we be avoiding foods that are fortified with folic acid in this population? Is it potentially detrimental in this context?
[1:23:31] DR. GUTIERREZ: I do believe we should be avoiding foods that are fortified in folinic acid. There are some people in the population that will eat them and do just fine. And then there are other people that will eat them and it’ll build up. And we have evidence, the higher your folic acid, the lower that your natural killer cytotoxicity cells are working. Yes, avoiding it.
And I also think it’s important for this population in particular to avoid animal dairy. So, they have done studies showing that animal dairy in the form of cow or bovine, camel, sheep, goat, and human can carry folate receptor alpha. Most strikingly, it was highest in bovine milk. And it’s not the excipients of milk. It’s really that milk protein. So, taking away things like A1, A2 really doesn’t matter. It’s really that milk protein.
And even if we do see folate receptor alpha antibodies in human milk, we still are not going to discourage that mom from breastfeeding because of the other benefit. And Scott, I don’t know anybody that’s testing breast milk for folate receptor alpha antibodies but we know that it has been found before.
[1:24:48] SCOTT: So, is the impact then of consuming dairy, is that a real issue impacting the patient, or is it an impact of milk on the assay itself? Should we then be avoiding in this population? Do we need to avoid dairy consumption for life? And do we even then need to be as careful about thinking about supplements like homeopathics that might have lactose as the base for example?
[1:25:17] DR. GUTIERREZ: I think the dose is going to be the poison depending on the individual. Some people will do okay with things like a little bit of lactose in leucovorin which is the manufactured folinic acid. Or they’ll do okay eating some cheese occasionally. What is their autoimmune reaction to dairy? Certainly, we found that some of these antibodies are coming through dairy. So, what is the load going into them? Where are they at? What is their autoimmune response? And what are they doing over time to decrease the autoimmunity so that then they can add back in dairy?
I don’t know about you, but a lot of times when you need to rescue someone because they’re in such a bad state, you have to take away a lot of the inflammatory foods. But as you balance over time, you can incorporate some of them back in. And I truly want children to eat organic, full fat dairy if they can tolerate it, if they don’t have problems with folate absorption.
I think children should have as many foods, healthy foods as they possibly can because they need them for growth, like eggs. But some people just can’t eat eggs. So, I know it is their global recommendation that anybody that has any type of folate receptor alpha antibodies found that you go on a dairy-free diet at least initially.
Camels were also found to have them very high in their milk. And there was a trend in autism about 5 to 10 years ago where parents were giving their children camel milk because it’s supposed to be the closest to human milk. But unfortunately, now we know that maybe that wasn’t the best idea. And I wonder if some people are concerned about EGCG as well. Because in vitro, it can inhibit dihydrofolate reductase. But that’s not a global recommendation, but it’s something interesting to really consider.
[1:27:15] SCOTT: How often do you have the test results to work from versus you empirically are treating given the low risk that comes with folinic acid, knowing it’s not always easy as you mentioned to get a blood draw in this population, knowing the test can take a month or longer? Could we argue that not intervening empirically also carries potential risk and harm for the child?
[1:27:40] DR. GUTIERREZ: Wow. First, do no harm, right? That’s what we’re taught. And I truly believe with or without a test, if you don’t try and you have a classic regressive child that is presenting with profound autism, that you will do more harm than good by not trying. So, do you always have to have a test to treat with folinic acid? Absolutely not. Is it helpful to have a test? Certainly. Is it helpful to have the genotypes? Absolutely. Is it imperative? No. With informed consent so the parents know what you’re doing, why you’re doing it, the benefits and the risk. Most parents are really eager to start treatment and they don’t want to get a test. They don’t want to spend the $300. Or even if it’s negative, we might even still try and see what kind of response we get. So, I think in my practice, I rather initiate treatment and gauge response than just not treating because I don’t believe I have enough evidence. If the evidence presents in their symptoms, that is evidence enough for me.
[1:28:49] SCOTT: So, let’s just touch again, and we’ve hit on several of these, but some of the prerequisite treatment steps that you might explore before starting someone on high dose folinic acid or leucovorin. We’ll talk more about inflammation. We’ve touched on that. We also talked about diet. But what about other cofactors like B2, B6? We touched on B12. Do those need to be in place before starting high-dose folinic acid? Why are those co-actors important? Is it primarily to support the methylation side of things? Are there other reasons? And are there other nutrient deficiencies that we also should be considering? And then I’d like to extend it just broader timeline. If you’re working with a child that has folate receptor autoantibodies but they also have Lyme or mold, where does the incorporation of high doses folinic acid come in? Can we start that at the beginning? Do we address Lyme and mold first? What’s that broader healing timeline?
[1:29:51] DR. GUTIERREZ: I want to address the inflammation and the infection first. I want to. Because you’re going to have a better response to treatment if you do. So, preparing someone for treatment is putting them in that functional medicine matrix and knowing where is the stress. And what do we need to be removing or helping to lessen in the body to prepare it for methylation?
And remember, when that folinic acid gets through into the brain, it still has to be methylated. And methylation is dependent, the methionine to homocysteine via B12. And then that step from folic acid into the methylated form, B6 plays a role and so does riboflavin or B2. I like to make sure that we’ve done the initial assessment. I know what I’m going after and what we’re going to treat with coinfections, infections. Making sure the gut microbiome is in a good place, making sure we have enough antioxidants and we’re supporting inflammation. And then I’ll give them B12. And we’ll do B12 for at least a week before given in the other cofactors. And then we’ll start to slowly titrate in folinic acid.
[1:31:07] SCOTT: So, inflammation, neuroinflammation, that’s another thing that you look at before starting something like leucovorin. We touched on the idea of using things like SPMs or maybe ProdromeGLIA for example, looking at what those things are that might be driving that inflammation or neuroinflammation.
One of the specific points that I wanted to touch on around inflammation and neuroinflammation that I’m thinking you probably see a lot of in this population is glutamate excitotoxicity. How that potentially impacts the microglia. So, what is it that drives glutamate excess in children on the spectrum? And how are you assessing that and then mitigating that to help reduce that overall inflammation, microglia activation, neuroinflammation?
[1:31:58] DR. GUTIERREZ: Mm-hmm. I feel like a lot of times that other than supporting folate status in my patients, I am always managing glutamate excitotoxicity. And glutamate is that excitatory neurotransmitter that can make a child feel agitated, irritable, anxious, stimmi, not sleeping, hand flapping, agitation. So, glutamate also in neuropsychiatric disease is well known for its role in obsessive-compulsive disorder, in seizures.
And the toxicity from glutamate, to me it’s driven by infection. There are certain inflammatory cytokines that once they’re incited, they cross through and then they incite the microglia, which are the primary immune cells of the brain. And that glutamatergic overexcitability is really about the brain trying to get to homeostasis. But what you have is too much glutamate and not enough GABA or inhibition. So you have a really irritable child.
And glutamate modulators can be really impactful driving back to what is the infection. Strep throat in a child certainly can go undetected. In the pediatrician office, we’ll swab the front of the tonsils. But what if the strep is behind the tonsils? What if the strep is in the nose? What if the strep is in the microbiome? What if the strep is around the anus? What if the strep is on the skin? Strep lives outside of the tonsils. And depending on the swab that you get or if you even culture it, a child can have strep and not have any symptoms. They cannot have fever, or a scarlatina rash, or a sore throat, or a headache. They can just be irritable.
And the irritability tends to happen pretty significantly. And the longer that infection is occult and not treated, the more neuroinflammatory stress, the more microglia activation, the more glutamate cytotoxicity, the more you’re dealing with a kid that is angry, that cannot control their behavior, and that needs us to back up and say, “What is driving this behavior?”
I love to use things for glutamate cytotoxicity like magnesium threonate, pyridoxine 5-phosphate, high doses of inositol. But also, there’s some medications. Amantadine can be very helpful. I use that a lot in my practice. Memantine is not as helpful as amantadine. But amantadine can.
And then just backing up again. If you have an irritable child like this, throwing folinic acid on the fire of this irritability and glutamate excitotoxicity. Well, once folinic acid gets into the brain, it increases all your monoamines. So, glutamate is also going to go up. So, you’re going to have a more irritable child. And that’s when the parents are going to be like, “This leucovorin stuff is terrible. I want to go off of it.”
But that response actually can be a predictor of something that’s very great. Wait, back up. We’re getting folate in there now. It’s increasing the things we don’t want it to increase. So, we’re going to try to lower that. And in fact, Dr. Ramaekers, one of the original researchers in this space said, “Oh, don’t worry. Just put them on an antipsychotic. Start leucovorin therapy if they get irritable.” And I typically do not start antipsychotics when children get irritable on leucovorin. We back up and say, “Clear the infection, lower the glutamate, really focus on the inflammation, and start slow with titration.”
[1:35:32] SCOTT: Another thing that you touched on earlier was the need to look at oxidative stress as well. So, is that something I know particularly in those with the soluble folate receptor that we talked about that the oxidative stress exploration is maybe even more important. So how are you assessing the level of oxidative stress? And then are you using NAC or other antioxidants to mitigate those free radicals?
[1:35:56] DR. GUTIERREZ: Yes, I love N-acetylcysteine. I think it’s a wonderful, wonderful thing to use for oxidative stress in the brain. And for children, sometimes I’ll run a cytokine 13 panel. I’m looking at interleukin-6 and tumor necrosis factor-alpha. But remember, it’s in the serum, it’s not in the CSF. So, it has its limitations. I know if it’s high in the serum, it’s likely very high in the brain. I ran one last week, and the TNF-alpha was just sky high.
So, I do like to do things. Lion’s mane has evidence that it can decrease tumor necrosis factor-alpha. Sometimes in a child like that, maybe I do go to medication. Maybe I even would prescribe an anti-steroid. In very, very, very rare cases, I will do that. But in children, the barometer is their symptoms. How severe is their autism? How severe are their behaviors? And then you look for response.
And the most amazing thing about being in pediatrics is your patients typically respond. They’re really sick and they can get really well pretty quickly if you’re doing the right things. So NAC is definitely one of the cornerstones to decreasing oxidative stress in the brain. And you got to do a lot of it. You can’t just do 600 milligrams. The studies on OCD are upwards of 3600 milligrams a day. And the challenge with a child is getting that nutrient into their body if they can’t swallow a pill because it’s terrible tasting.
[1:37:26] SCOTT: Yeah. Fortunately, in kids, you don’t really have a placebo or a nocebo effect. Right?
[1:37:32] DR. GUTIERREZ: Yeah, that’s right.
[1:37:33] SCOTT: In our last few minutes together, we’re going to get into some more details now about the leucovorin, high dose folinic acid. So, you’ve done these prerequisites. You’re ready to start introducing folinic acid often in the form of prescription leucovorin. You talked about the standard dosing being 2 milligrams per kilogram with a max 25 milligrams twice a day. You talked about some scenarios where that could go higher. Do the FRAT results change your dosing? Do you generally start low and titrate up? Is there a recommended titration schedule? Or is that also determined based on the results? And then how quickly do you increase the dose in a given child? Do the benefits also tend to correlate with their FRAT test results? And does a positive blocking result potentially mean that they’ll have a better outcome than only having a positive binding result?
[1:38:35] DR. GUTIERREZ: The treatment, titration, and how we do it depends on how the child is responding. Once I get a FRAT test, it’s information that we take into consideration at that time. But it’s really when we start the treatment for how they’re responding of how we titrate it, how fast we titrate it, and how much we give them. And there’s no standard in how much you do it. If you prescribe it, it’s five milligrams per tablet.
Typically, I say to cut the tablet in half and start with two and a half milligrams in the morning and hold it for 2 to 3 days and then go from 2.5 milligrams to 2.5 milligrams in the afternoon for 3 to 4 days and then up you go. And so, it might take you, depending on how large the child is, to titrate up over 3 months to get to that 25 milligrams BID.
You can see if a parent portal messages me and says, “Emily, I titrated up to 10, and they didn’t sleep all night. And, really, they’re too excitable. They’re stimming more.” I’ll say, “You know what? Let’s go back down to seven and a half and let’s hold there for a couple of weeks, and then try to titrate up a little bit longer.”
I’ve had some parents that it took them a year to get them on a therapeutic dose and they have responded beautifully with their speech. And that’s something we haven’t talked about. What can you see with giving folinic acid? The biggest signal in neurodevelopmental is speech. And it doesn’t mean; speech is the spectrum. Right? Because some children have zero words. Some people have just echolalia, where they’re repeating back. Some have utterances. And some can have somewhat of a back and forth but are not conversational.
So, depending on where they are for the speech spectrum, you will see them increase. If they just had zero words, they might get a few. If they have a few words, they might start speaking in phrases. And we typically treat for 2 to 3 years. So, it’s not, if your child doesn’t respond in 3 months, give up. Keep going. Give it at least a year and try the treatment. If you haven’t seen anything different at all whatsoever after a year, I would say try to come off of it. And sometimes, Scott, when they come off of it, they see the regression and they’re like, “Oh, it actually was doing way more than I thought it would.”
[1:41:03] SCOTT: And have you been able to correlate those children that have the most significant beneficial results from high dose folinic acid to the results of their FRAT test? Are there certain test results that lead you to say this is a child that’s more likely to beneficially respond?
[1:41:25] DR. GUTIERREZ: Yes. And I don’t have the hard data on that. But I would say that’s something I tell myself and often I tell the parents. You have a blocking. It’s pretty high. When we start, you might see a little hyperexcitability. And I always tell them that kind of agitation, insomnia, the hyperexcitability, it’s transient. It will come, it will go. But we’re going to mitigate it with all the work we’re going to do before that. And we’re going to do slow titration.
But it’s a good sign to me. It’s a good sign to me. All of a sudden, you have more of everything, including glutamate, if glutamate was high baseline. So, you have to work on glutamate reduction. But you’re getting the other things. And to me, a little bit of an activation, if you can get through it, you won’t be sorry that you did. Because on the other side, that child has more reduction in their severe autism symptoms. They have better sleep.
He was two and a half. He had never slept through the night before, ever. And we started him on folinic acid. Within a month, he was sleeping 12 hours at night. The mom was over the moon excited. And that was the only thing we had changed.
[1:42:42] SCOTT: The increase in speech, I think, is profound in terms of the potential for the child to be able to communicate. There was actually an article that I saw just this morning where they were talking about leucovorin. And the title of the article was, “My nonverbal autistic son began speaking at age eight after taking wonder drug. He understood everything for years and he had complaints.”
[1:43:08] DR. GUTIERREZ: I love it. Oh, I love it. I love it. It’s like the non-speakers doing the spelling method. What they have to say once they’re open and communicating. This is the most rewarding work I think I could ever do because of that. These kids are not intellectually disabled. They’re smart. They’re aware. They’re in there. They have a communication issue. And they have neuroinflammatory stress that they need providers like us that are looking at them differently and giving them tools to get to this place of being able to say, “You know what, mom, I have complaints. I’m eight. I don’t want to sleep with my brother. And I don’t like this food. Yes, it’s wonderful.
[1:43:50] SCOTT: If the child is negative for both blocking and binding antibodies, is it less likely that they would be a candidate for treatment? Or are there any scenarios where you would still potentially consider high dose folinic acid even if the FRAT test was normal?
[1:44:08] DR. GUTIERREZ: Yes. Possibly we’re looking at genomic variance and correlation with that as well. And with informed consent, just going over with a parent. Here are the risk. Here are the benefits. Do we want to try it? Absolutely, I would try it anyway.
[1:44:24] SCOTT: Touch on the different isomers of folinic acid or leucovorin. What’s the difference between the L and D isomer? What’s in leucovorin? Is one better than the other? And if one is better than the other, can we get a medication that contains only the most beneficial isomer? Does leucovorin have any dyes, fillers, excipients? You mentioned lactose. Are you usually using the prescription leucovorin? Or are you having cases where you’re compounding it? And are you most commonly using a tablet, or a capsule, or a powder?
[1:45:01] DR. GUTIERREZ: So, you ask really smart questions, and that’s why I was so happy to be on this podcast. I don’t think that most providers know about the racemic mixture of leucovorin. So racemic means an inactive and active form. And it’s the levofolinic acid, the l form that’s active. And it’s the dextrofolinic acid that is the inactive form.
PD Labs is here in Austin, Texas, and Ray Solano is a good friend of mine. And I begged Ray to find some levofolinic acid for me. And he looked for 3 months. He found a batch. He was going to have to buy too many kilograms. And he said, “Emily, this is like 10 times as expensive as regular leucovorin.” So, we didn’t end up doing it. But I know that there’s some studies underway that they’re using the levofolinic acid. I think right now, it’s hard to access and it’s super expensive.
It depends on the family which form I will prescribe. Because some families are really watching how much money they’re spending on all the supplements and the medications. And their insurance will cover leucovorin. Others, they don’t want to use it because it does have dyes, and excipients, and fillers in it. And it does have that lactose in it as well.
Now, it doesn’t taste bad. Kids just usually chew it, which is really nice. But if I compound it, I can compound it in a powder. But, really, I compound it in a liquid. And they can make it really concentrated. So, you got to make sure you’re giving the right dose. I think we had a family a couple of months ago that was giving four times the dose accidentally with the liquid. And the child was doing great, by the way. I mean, doing really great. So, I will sometimes compound it.
PD Labs, Ray said, “I’m dedicated to autism. I’m dedicated to this population. And I’m going to source it the cheapest that you can find it in the US.” And he’s made true to that promise. So sometimes I’ll compound it with him, especially when we’re going to a lot of higher doses. Because sometimes insurance might cover 5 milligrams twice a day. But when you get up to 25 milligrams twice a day, they might say, “Hey, you know what? It’s $1,000 a month.” Versus if it’s 10 twice a day, they might say you owe me $5. It just really depends on the insurance, the preference, and can the child swallow a capsule or not.
[1:47:20] SCOTT: So, some people are going to ask about over-the-counter folinic acid. My understanding is generally those are much lower dose. I know there’s been questions that have come up about folinic acid powders. And I know there’s been some questions raised about whether or not there’s stability of the powder over time. So, it sounds like really it is at this point to optimize this intervention that the pharmaceutical prescription route is the way to go. Correct?
[1:47:46] DR. GUTIERREZ: Well, the powdered form, first of all, we have to say. Because leucovorin as a drug is 5 milligrams. Typically, the FDA says if it’s a medical food, it can be half that milligram or less OTC and be legal. If you’re producing something that’s a pharmaceutical dosing, you might get dinged by the FDA. And that’s why I have not made any products greater than half the dose of the 5 milligrams.
That said, leucovorin can oxidize to light. It can be unstable in higher temperatures. Usually, after you take it, the oral peak of the dose is about 1 to 2 hours. And the plasma half-life is about half to one hour. That’s why we dose it twice a day so it stays in your system daily. Active methylfolate has a longer half-life of 3 to 6 hours.
If somebody gets a little stimulated from folinic acid, that’s why I say let’s take it in the afternoon after school versus 30 minutes before bed. Because if you get activated, you’re going to get activated, but it’s going to be out of your system pretty quickly. It is excreted through the kidneys. And so is also our other forms of folate as well.
But it all depends on the family, whether I compound it or I prescribe it. And I do believe even a little bit of folinic acid that’s over the counter is very beneficial. And sometimes I’ll go lower if I’m not treating cerebral folate deficiency, but I’m suspecting that a little bit of folinic acid could also be helpful.
[1:49:21] SCOTT: Are the benefits of this intervention generally observed pretty quickly? Is there a risk that someone doesn’t see immediate benefits? They stop too soon and they miss something that could have been very significantly helpful. Would you repeat testing at some point during this process? And if so, would you expect to see changes on the FRAT test if the issue is less about folate availability and more about autoimmunity? And is the benefit coming from pushing more folinic acid through the transporters? How is increasing the folinic acid bypassing the transport issue if it’s really autoimmune? And does high dose folinic acid resolve the autoantibodies? Or is it primarily increasing the level so much that it’s attempting to bypass inefficient transport?
[1:50:14] DR. GUTIERREZ: Well, remember the reduced folate carrier doesn’t require the mitochondrial energy and how it’s going as an antiporter and ion transporter. You flood the serum with higher doses in exchange towards the brain. So, we don’t know that there’s autoimmunity towards the reduced folate carrier.
Over time with the FRAT test, I would anticipate that the severities of the findings would wane. A lot of families are not real motivated to do another FRAT test when their child is doing better. If they’re doing better, that’s all they need. But there have been some people, we did a FRAT test 5 years ago and we’re repeating them now to see where they’re at. As your homeostasis and your autoimmunity improves, so should your folate transport.
And it’s nice to have a test, but we don’t always have to have a test. It’s really how did they respond? And over time, if you’ve done really well, what I might do is then start titrating back on the dose. And then, this is my practice and my preference, I keep them on a little bit over time. Instead of them being maybe on 50 milligrams, maybe they stay on 2.5 to 5 milligrams a day over their time as part of their maintenance.
[1:51:29] SCOTT: Is this leucovorin treatment working because it’s doing something to the folate receptor alpha autoantibodies or its ability to transport? Or is this treatment primarily working because it’s increasing the folinic acid that then is brought into the brain through that backdoor that you talked about?
[1:51:52] DR. GUTIERREZ: Yes, it’s working because you have availability of folate into the brain that is then further methylated and used as the linchpin for all the things that folate does. Supports methionine, supports transsulfuration, supports DNA, supports tetra biopterin, supports your monoamines. Folate is the linchpin. So, we get enough of the cofactor in, and then the homeostatic mechanisms can work. So, it’s about getting folate where you need to have it. And that’s how the treatment is working.
[1:52:23] SCOTT: But it’s not necessarily doing anything for the production of the autoantibodies, right?
[1:52:30] DR. GUTIERREZ: No. No, it’s not. I don’t believe so. I don’t believe so. I believe that the production of the autoantibodies is all due to doing all the other work of decreasing oxidative stress.
[1:52:43] SCOTT: So what are the potential side effects then that people see with folinic acid? We know it’s water soluble. So, it sounds like you don’t commonly see significant issues. But if you start out too fast, too high of a dose, can that lead to some symptom exacerbations? Why might it not be tolerated in someone who desperately needs it? And then I wanted to tie that into is there also a connection here to BH4 or tetrahydrobiopterin? Many in this population are low in BH4. So, what’s the interaction between leucovorin and BH4? And are there cases where you might be supporting BH4 before adding the leucovorin? Could that potentially minimize some side effects?
[1:53:27] DR. GUTIERREZ: Again, what I said before, and I think it’s encouraging when you have a little bit of side effects, that eventually when you get through those, you’re going to see more of a result in whatever you’re trying to treat, OCD, autism, depression. The hyperexcitability is because of the increase of all of the monoamines. If you have problems with tetra biopterin, if we go upstream, you still need folate to support that pathway.
Now there is the GCH1 variant. I’ve published on this with Dr. Sharon Hausman-Cohen and a few other colleagues, that this variant definitely can decrease your tetrabiopterin. And in those patients, I sometimes will compound BH4 and give it to them. We also know that vitamin C can increase BH4. And then pharmaceutically, they’ve studied lithium carbonate. I think it would be interesting on lithium orotate with BH4. But I just still think of the upstream model. Go upstream, support folate. Folate is going to support BH4. If folate isn’t corrected for first, how is BH4 going to work? Because it’s dependent on the methionine, methylation, and folate.
[1:54:42] SCOTT: So, some of the things that you could potentially see then are agitation, or aggression, or sleep issues that you mentioned. A lot of times that comes back to maybe slowing the titration, pulling things back and then working up slowly. What are some of the troubleshooting scenarios that you’ve encountered with leucovorin?
And so one listener reached out and had a child with binding antibodies. But when they introduce leucovorin, the child’s seizure threshold is lower and he actually has more seizures. So, are there some paradoxical reactions that you find? And then how do you navigate those?
[1:55:20] DR. GUTIERREZ: I like that you use the word paradoxical because we know that cerebral folate deficiency can be actually a root cause of seizures. So, in this child, I wonder where the neuroinflammation is, how much glutamate excitotoxicity has? And for this child in particular, I wonder how much B6 is supported in the brain.
There is a more common gene variant around B6 that has a high odds ratio for seizures. So I can imagine if B6 was not supported and then you recommended folinic acid and you had this reaction, I would kind of pause on the folinic acid back up and make sure that you’ve addressed the other nutrient cofactors.
[1:56:03] SCOTT: And I think also you mentioned earlier the new work from Dr. Lindsey Wells. I tend to think of Bartonella as a potential factor in seizures as well. Are there some vector-borne infections that we maybe need to think about as well?
Is treating with high dose folinic acid treating the symptoms of autism? Is it treating the root cause of autism? Is folate receptor alpha autoantibodies, is that a root cause? And would you consider the root cause then to be the low folate or the autoimmunity? And if it’s the autoimmunity, is the real root cause the driver of that autoimmunity, meaning an infection or a toxin? Is the goal to replete the cerebral folate or to ultimately also resolve the autoimmunity? And is that autoimmune aspect something that someone would potentially then deal with for the duration of their lifetime?
[1:57:05] DR. GUTIERREZ: I do not believe that once the autoimmune switch has been turned, it’s for lifetime. There is a saying in pediatrics that rings true over and over again. The earlier the intervention, the better the outcome. And that is absolutely true. Can I help a 16-year-old improve their severity of autism? Certainly. Can I help a three-year-old do it much more profoundly most of the time? Absolutely.
So, we can reduce the inflammatory immune mediated neuroinflammatory stress in these children which I believe is a very complex interplay of genomics, and environment, and infections, and immune that lead to things like autoimmunity and poor folate. Kind of like when they say, “Well, cerebral folate deficiency is you have more autism. And in autism, you have more cerebral folate deficiency.” So what is the chicken and what is the egg? We have to zoom out and say this is a complex neurodevelopmental condition. And we have to look at the nodes of the functional medicine matrix. And everything matters. Everything matters. It matters their exposome. It matters their parenting. It matters their therapeutic behaviors. It matters their nutrition, and their nutrients, and how much nutrients. And the FRAT test matters, but it’s not the only thing that matters.
There’s so much complexity in autism. I can understand how parents could get super overwhelmed. But I think it’s hard to say, is this the root cause of autism? RFK got up and said, “We’ve found a treatment for autism. It’s leucovorin.” I was thrilled and disappointed at the same time because what they should have said is we’ve discovered in autism there’s a lot of cerebral folate deficiency. And when you can give this special form of folate called folinic acid, it can reverse that and improve somebody’s autism. That’s what they should have said. But it was political, and it got watered down. And that’s when the FRAT testing company just had so many more orders, all of a sudden. And I’m so grateful for the amount of attention it got. But as we’ve talked about this for the last couple of hours, it’s super complex. It’s not just as simple as, “Hey, you have a severe form of autism. We’re going to give you folinic acid at 25 milligrams twice a day. And let’s see how you go.” It’s more complex.
[1:59:32] SCOTT: So my last question then before the final wrap-up question, and that is the overlap with inflammation and autoimmunity is really clear here. So, do interventions that are aimed at immune modulation and autoimmunity have a role? Things like low-dose naltrexone, black seed oil, maybe Dr. Ty Vincent’s low-dose immunotherapy. Are there any signals that are suggesting that immune modulating interventions are showing promise in this population? And then building on that, what about other ways to remove auto antibodies like plasmapheresis or EBOO? Could that removal of those autoantibodies then have a positive effect on the transport and utilization of folate?
[2:00:23] DR. GUTIERREZ: Great questions. I think in regards to plasmapheresis and EBOO, I don’t know that we have that data yet. That would be very, very interesting to see. I think that’s a great question. And somebody should study that. And I would love to see the outcomes.
Immunomodulation and autism, absolutely. We use all kinds of tools. I mean, the biggest gun that somebody might use is IVIG for PANS/PANDAS that can decrease that and also improve the autism at the same time. That’s intravenous immunoglobulins. That’s a very, very big therapeutic. But there’s other therapeutics like low-dose naltrexone, low-dose immunotherapy. If they have tons of allergies, maybe some sublingual immunotherapy. Some people do good on some homeopathy. I’m not an expert in those fields, but somebody do. It’s all about training the immune system to tolerance.
But our system gets overwhelmed when there’s too much to tolerate. So, it comes back to just removing what is stressing out the immune system, giving these functional tools. And peptides are coming on board with that too. There’s some interesting peptides around immune modulation and autism. And we throw them the rope in the hole that they’re in and they climb out. And then eventually, hopefully, you don’t need the ropes to be able to go forward and develop and have a more normal life.
[2:01:49] SCOTT: I love that. My last question is the same for every guest, and that is what are some of the key things you do on a daily basis in support of your own health?
[2:01:59] DR. GUTIERREZ: Well, you better bet I take my supplements. I always protect my sleep, too, no matter what’s going on in my life. I am a cranky Emily if I don’t sleep well. And I like to rise early. And I rise early, and that’s when I study, and I have some alone time. And that’s really special time to me. But I also make sure I’m in nature. I love my animals. I love taking my animals for a walk. I love being in the forest. I try to work on the basics. I try to work on the basics.
I could do better at cooking at home. I’ve been doing a lot of eating out lately. I’m kind of convicted of that lately. But yeah, I try to pay attention to the basics. I try to engage in things that I love and really weed out the things that are taking away from my life and are not healthy for me and relationships or saying yes to too many things. Saying yes to this wasn’t hard. I was very excited about coming on. So, thank you for asking. It’s a daily journey to health.
[2:03:02] SCOTT: You are amazing. This was such a fantastic and amazing conversation. You’re super generous with your time and sharing your knowledge to help other people. So, it’s been an honor to have you. And I just really thank you and honor you for your work and your focus on improving the lives of children who desperately need you. So, thank you so much, Dr. Emily. This was fantastic.
[2:03:24] DR. GUTIERREZ: Oh, it’s my privilege. Thank you so much for having me on.
[2:03:30] ANNOUNCER: Thank you for listening to today’s episode of the BetterHealthGuy podcast. You can learn more about today’s guest, including relevant links and resources in the show notes. This podcast may provide community discounts and occasionally share links from affiliate partners. You can find this and other episodes on YouTube, Spotify, Apple Podcasts, Amazon Music, iHeart, and more. To learn more about Scott’s personal journey to better health, visit BetterHealthGuy.com. Join us next time on the BetterHealthGuy podcast.
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