Important Breakthrough Folate in Autism

Autism-stacking-cans_2nd_editImportant Breakthrough Folate in Autism

by Jeffrey Dach MD

Autistic kids have disrupted folate metabolism due to autoantibodies to the Folate Receptor.

Just published, this report in the March, 2013 issue of Molecular Psychiatry, “Cerebral Folate Receptor Autoantibodies in Autism Spectrum Disorder”,  represents a major breakthrough in Autism.

Above Left image: autistic behavior stacking cans, courtesy of Wikimedia Commons.

Folate is Essential

Folate, also called Vitamin B9, is an essential nutrient needed for synthesis of brain neurotransmitters, Serotonin, Dopamine and Norepinephrine.

Folate deficiency is associated with depression, Attention Deficit Disorder (ADD),  and other neuropsychiatric disorders.

Disturbed folate metabolism is also a risk factor for blood clots (thromboembolism) and increased risk of all cancers.

5MTHF is the Active Form of Folate

Folate itself cannot enter the brain.  It must first attach to Folate Receptors (FR) in the choroid plexus and then be converted to the active form, MTHFR, which then may cross the blood brain barrier to enter the brain tissue.

The active form of folate is 5MTHF, (also called 5-Methyl-Tetra Hydro-Folate) This form of the vitamin can easily cross the blood brain barrier,  enter the brain and promote neurotransmitter production.

Folate Receptor Antibodies

In Autism, the Folate Receptor is non-functioning because of auto-antibodies.  This is a form of autoimmune disease in which an immune response is mounted against the Folate Receptor.  This is a bad thing because the Folate Vitamin is not working and cannot get into the brain where it is needed.

75% of Autistic Children Have Folate Receptor Antibodies

Dr. Frye’s study found that Folate Receptor Antibodies were present in 75% of the 93 autistic children studied.  In 16 children in which spinal fluid samples were studied, the presence of Folate Receptor Antibodies correlated with reduced cerebrospinal fluid 5-MTHF levels.

Treatment with Activated Folate

The autistic children were treated with up to 50 mg per day of Leucovorin over 4 months.  This is an activated folate vitamin.   One third of treated children were deemed “Moderate” to “Much Improved”  in verbal communication, receptive and expressive language, attention and stereotypical behavior.   The authors recommended empiric treatment of all autistic children with activated Folate supplements ( Such as 5mg caps 5MTHF from Thorne)

Leucovorin is Folinic acid, a 5-formyl derivative of Tetra-Hydo-Folate.  Regular folic acid is not effective and not recommended for MTFHR patients.  Also available is prescription Deplin, a 15 mg methyl folate tablet.

A Major Breakthrough

This is truly a major breakthrough in our understanding of Autism, and other neuropsychiatric disorders associated with disrupted Folate metabolism.

Previous Work in 2007 Also Showed Similar Findings

This new study by Dr Frye confirms a previous 2007 study by Dr Ramaekers from Belgium who found Folate receptor autoimmunity and cerebral folate deficiency in 23 of 25 autism patients.

Useful Lab and Book for Autism

William Shaw PhD of the Great Plains Lab has written a number of useful book on treatment of autism.   Click Here to buy on Amazon: Biological Treatments for Autism and PDD3rd Edition.

MTHFR Genetic Mutation

Another patient group with disrupted folate metabolism is the MTHFR Mutation.   In this genetic mutation, conversion of Folate to its active form (5MTHF) is reduced by 20-70 % efficiency, depending on whether the mutation is heterozygous or homozygous.

These patients have a genetic inability to utilize Folate, since they cannot convert folate to its active form, or conversion is inefficient.   This MTHFR genetic mutation is associated with various neuropsychiatric conditions such as Attention Deficit Disorder, (ADHD), Depression and a host of others as you might expect from the inability of the brain to produce sufficient quantities of neurotransmitters, Serotonin, Dopamine and Norepinephrine.

Poly Drug Psych Meds for MTHFR ??

Without realizing there is a Folate problem, the mainstream medical system will treat many of these MTHFR patients with a poly-drug approach with Adderal, Ritalin, SSRI antidepressants, and Atypical Anti-psychotics like Respiradol and Zyprexa.  However, none of these drugs address the underlying cause which is a Folate conversion problem.

As these patients need Methyl-Folate, the correct treatment for these patients is not a Psycho-Stimulant Drug which obviously contains no Methyl-Folate.   If the MTHFR genetic mutation is present, these patients should be given 5-Methyl-Tetra-Hydro-Folate (the active form of the vitamin) which is widely available at the health food store without a prescription.

Routine Testing for MTHFR

We routinely test all patients for this genetic mutation called MTFR Reductase available through Quest, and Labcorp. 

Patients may also self-test with anonymous online genetic testing with a home test kit ordered online.

For more on this, see my previous article: Understanding Online Genetic Testing

Article on ADHD by David Perlmutter MD- Are Drugs Really the Way to Go for ADHD ?

Update 2011: Cerebral-folate-deficiency-in austism-spectrum-disorders-richard-frye-2011  Frye, RICHARD E., and DANIEL A. ROSSIgNOL. “Cerebral Folate Deficiency in Autism Spectrum Disorders.” Autism Sci. Dig. J. Autsmone (2011).

Buy Methyl Folate 5 mg Capsules from Thorne on Amazon.

Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Florida 33314

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Links and references

Mol Psychiatry. 2013 Mar;18(3):369-81. doi: 10.1038/mp.2011.175. Epub 2012 Jan 10.
Cerebral folate receptor autoantibodies in autism spectrum disorder.  Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA.  Source  Department of Pediatrics, Arkansas Children’s Hospital Research Institute, University of Arkansas for Medical Sciences, Little Rock,
Abstract  Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood-brain barrier. Autism spectrum disorders (ASDs) and improvements in ASD symptoms with leucovorin (folinic acid) treatment have been reported in some children with CFD. In children with ASD, the prevalence of FRAs and the response to leucovorin in FRA-positive children has not been systematically investigated. In this study, serum FRA concentrations were measured in 93 children with ASD and a high prevalence (75.3%) of FRAs was found. In 16 children, the concentration of blocking FRA significantly correlated with cerebrospinal fluid 5-methyltetrahydrofolate concentrations, which were below the normative mean in every case. Children with FRAs were treated with oral leucovorin calcium (2 mg kg(-1) per day; maximum 50 mg per day). Treatment response was measured and compared with a wait-list control group. Compared with controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior. Approximately one-third of treated children demonstrated moderate to much improvement. The incidence of adverse effects was low. This study suggests that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from leucovorin calcium treatment. Given these results, empirical treatment with leucovorin calcium may be a reasonable and non-invasive approach in FRA-positive children with ASD. Additional studies of folate receptor autoimmunity and leucovorin calcium treatment in children with ASD are warranted.

Neuropediatrics. 2007 Dec;38(6):276-81.
Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits.
Ramaekers VT, Blau N, Sequeira JM, Nassogne MC, Quadros EV.SourceDivision of Child Neurology, University Hospital Liège, Belgium.
Reduced folate transport to the CNS was identified in two autism spectrum disorders, i.e., Rett syndrome and infantile low-functioning autism with neurological abnormalities. Twenty-five patients with early-onset low-functioning autism with or without neurological deficits, were evaluated for serum folate, cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF), and serum FR autoantibodies of the blocking type to determine the significance of folate receptor (FR) autoantibodies with respect to folate transport across the blood-CSF barrier. In spite of normal serum folate, CSF 5MTHF was low in 23 of 25 patients. The reduced CSF folate in 19 of these 23 patients could be explained by serum FR autoantibodies blocking the folate binding site of the membrane-attached FR on the choroid epithelial cells. Oral folinic acid supplements led to normal CSF 5MTHF and partial or complete clinical recovery after 12 months. Serum FR autoimmunity appears to represent an important factor in the pathogenesis of reduced folate transport to the nervous system among children with early-onset low-functioning autism associated with or without neurological deficits. Early detection of FR autoantibodies may be a key factor in the prevention and therapeutic intervention among this subgroup of patients with autism.

3) Role of L-methylfolate in Depressive Disorders. Andrew Farah, MD, FAPA

CNS Spectr. 2009;16:1(Suppl 2):1-7 Dr. Farah is chief of Psychiatry at High Point Regional Health Systems, High Point NC, and is clinical faculty at Wake Forest University, Winston-Salem NC.  Disclosures: Dr. Farah serves as consultant to and receives honoraria from Pamlab.Abstract

Major depressive disorder (MDD) is a debilitating and often recurrent illness. An initial antidepressant trial is effective at achieving remission for ~30% of patients when prescribed as monotherapy, with the majority of patients returning as partial or non-responders. Switching antidepressants or adding augmentation agents are standard therapeutic options used to achieve and maintain remission. Suboptimal serum and red blood cell folate levels have been associated with a poorer response to antidepressant therapy, a greater severity of symptoms, later onset of clinical improvement, and overall treatment resistance. This Expert Review Supplement reviews the evidence for L-methylfolate as an augmentation agent in depression and discusses its clinical use elaborated by three clinical presentations.

J Clin Psychiatry. 2009;70 Suppl 5:12-7.
Folate in depression: efficacy, safety, differences in formulations, and clinical issues.  Fava M, Mischoulon D.  Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, 55 Fruit Street, Bulfinch 351, Boston, MA 02114, USA.

Supplementation with folate may help reduce depressive symptoms. Folate, a naturally occurring B vitamin, is needed in the brain for the synthesis of norepinephrine, serotonin, and dopamine. Three forms of folate are commonly used: folic acid, 5-methyltetrahydrofolate (5-MTHF) (also known as methylfolate and L-methylfolate), and folinic acid. Some forms may be more bioavailable than others in patients with a genetic polymorphism and in those who take particular medications or use alcohol. Folic acid augmentation in depressed patients may reduce residual symptoms. The 5-MTHF formulation indicated efficacy as adjunctive therapy or monotherapy in reducing depressive symptoms in patients with normal and low folate levels, improving cognitive function and reducing depressive symptoms in elderly patients with dementia and folate deficiency, and reducing depressive and somatic symptoms in patients with depression and alcoholism. Adjunctive folinic acid reduced depressive symptoms in patients who were partially responsive or nonresponsive to a selective serotonin reuptake inhibitor. Evidence for the efficacy of folate in improving cognitive symptoms is equivocal, but most studies used folic acid. Although the studies reviewed have limitations and, historically, concerns have been raised about the role of folate in increasing cancer risk, masking B(12) deficiency, and worsening depressive symptoms, folate is generally well tolerated, and 5-MTHF may be less likely to incur some of these risks. Several forms of folate appear to be safe and efficacious in some individuals with major depressive disorder, but more information is needed about dosage and populations most suited to folate therapy.(pdf file downloaded) my pdf download area

Altern Med Rev. 2008 Sep;13(3):216-26.
The methylation, neurotransmitter, and antioxidant connections between folate and depression.  Miller AL. Source  Thorne Research, PO Box 25, Dover, ID 83825, USA.

Depression is common – one-fourth of the U.S. population will have a depressive episode sometime in life. Folate deficiency is also relatively common in depressed people, with approximately one-third of depressed individuals having an outright deficiency. Folate is a water-soluble B-vitamin necessary for the proper biosynthesis of the monoamine neurotransmitters serotonin, epinephrine, and dopamine. The active metabolite of folate, 5-methyltetrahydrofolate (5-MTHF, L-methylfolate), participates in re-methylation of the amino acid metabolite homocysteine, creating methionine. S-adenosylmethionine (SAMe), the downstream metabolite of methionine, is involved in numerous biochemical methyl donation reactions, including reactions forming monoamine neurotransmitters. Without the participation of 5-MTHF in this process, SAMe and neurotransmitter levels decrease in the cerebrospinal fluid, contributing to the disease process of depression. SAMe supplementation was shown to improve depressive symptoms. 5-MTHF also appears to stabilize, enhance production of, or possibly act as a substitute for, tetrahydrobiopterin (BH4), an essential cofactor in monoamine neurotransmitter biosynthesis. There are few intervention studies of folic acid or 5-MTHF as a stand-alone treatment for depression related to folate deficiency; however, the studies that have been conducted are promising. Depressed individuals with low serum folate also tend to not respond well to selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Correcting the insufficiency by dosing folate along with the SSRI results in a significantly better antidepressant response.

An ADD Family Success Story. MTHFR mutation addressed
An ADD family story with a drug free solution. I have 4 children ranging in age from 11-26 with ADD. I’m sharing my experience and solutions, hopefully to bring balance into the lives of ADD families Here is the name of the blood test to order: MTHFR, DNA Mutation.

MTHFR Mutation: A Missing Piece in the Chronic Disease Puzzle  June 2012 00:43 By Bianca Garilli, ND, Contributing Writer – Vol. 13, No. 2. Summer, 2012

Methylenetetrahydrofolate reductase (MTHFR) is one of the most important enzymes in human physiology, having influence on at least as many biochemical processes as it has syllables in its nearly unpronounceable name.

Deficiencies in production or function of this enzyme have been associated with increased risk of myocardial infarction, stroke, venous thrombosis, several types of cancer, congenital defects, inflammatory bowel disease, and several neuropsychiatric conditions. In practice, MTHFR function is an important predictor of predispositions to chronic disease states, and interventions aimed at optimizing MTHFR function can often be preventive or therapeutic

Int J Med Sci 2011; 8(7):523-528.
Methylenetetrahydrofolate Reductase Gene Polymorphisms in Children with Attention Deficit Hyperactivity Disorder 
Cem Gokcen1 Corresponding address, Nadir Kocak2, Ahmet Pekgor3  1. Department of Child and Adolescent Psychiatry, Medicine Faculty of Gaziantep University, Gaziantep, Turkey
2. Department of Genetics, Medicine Faculty of Selcuk University, Konya, Turkey  3. Department of Statistics Faculty of Science, Selcuk University, Konya, Turkey


Folate Metabolism Gene 5,10-Methylenetetrahydrofolate Reductase (MTHFR) Is Associated with ADHD in Myelomeningocele Patients  Catherine J. Spellicy, Hope Northrup, […], and Kit Sing Au

11) Cerebral-folate-deficiency-in austism-spectrum-disorders-richard-frye-2011  Frye, RICHARD E., and DANIEL A. ROSSIgNOL. “Cerebral Folate Deficiency in Autism Spectrum Disorders.” Autism Sci. Dig. J. Autsmone (2011).

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Jeffrey Dach MD
7450 Griffin Road, Suite 180/190
Davie, Fl 33314

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Last updated on by Jeffrey Dach MD

Important Breakthrough Folate in Autism
Article Name
Important Breakthrough Folate in Autism
Autistic kids have disrupted folate metabolism due to autoantibodies to the Folate Receptor.
Jeffrey Dach MD
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About Jeffrey Dach MD

Medical Director of TrueMedMD, a Clinic in Davie Florida specializing in Bioidentical Hormones and Natural thyroid. Office address 7450 Griffin Road Suite 190, Davie, Florida 33314 telephone 954-792-4663

17 thoughts on “Important Breakthrough Folate in Autism

  1. For a better understanding of MTHFR defects and Autism, check out the work of Dr. Amy Yasko [].

    For a better understanding of MTHFR defects and various illnesses, check out the work of Dr. Benjamin Lynch at

  2. For those wanting a better understanding of why we become stressed (physical, mental, chemical) and can’t return to “normal” due to lack of methylation, I recommend you read Dr Jack Tips’ article on Methylation at [] .
    B6-B9-B12 is part of the Folate pathway, and when the latter is disrupted, Autism is one possible outcome.

  3. Pingback: Disrupted Folate in Autism by Jeffrey Dach MD - Jeffrey Dach MD

  4. Pingback: Attention Deficit Disorder Exposed as Drug Marketing Ploy - Jeffrey Dach MD

  5. Thanks for sharing this! This may have implications for me and my daughter, because I have a known mthfr mutation and low folate levels and depression. These dots have never been connected. I was tested for mthfr after a severe miscarriage and I struggled with folate deficiency throughout that pregnancy and subsequent attempts at fertility treatments. My daughter has severe infant onset autism, but I have never had any testing done for mthfr or for the antibodies. I am wondering if I should just supplement right away or show this to her doctor. I wonder if can even help her because she is older now… she is 19. Do you think this is worthfurther investigation?

  6. Hi Jennifer –

    You can help both your daughter – and yourself – quite significantly.

    Testing could be useful – but more importantly – taking action – and how to do it.

    Please read this article:

    It’s also about expression of your genes – and balancing methylation:

    You can also read through this and start making some changes here:

    Lots of other information at those two sites – you can start by finding a doctor at Seeking Health Educational Institute. Need to work with someone who’s had training.

    Dr Lynch

  7. Pingback: Mthfr Dementia And Antidepressants | The Brain Improvement

    • Deplin has food colorings and additives that can cause that type of behavior in sensitive individuals.

      Hypoallergenic versions of Methylfolate are available at the health food store without the colorings and additives. Regards from dr d

  8. Pingback: Gut health and autism | healthecologyblog

  9. I didn’t see any links or recommendations on pediatric doses of the 5-mthf supplements. I have two MTHFR genes, we haven’t had my son tested as pretty much all the doctors here seem to think that’s just Made up stuff. Not going into what doctors have said but my son is autistic and I would love to get info on vitamins and minerals to introduce. He takes Doterra (all natural sources) now and I have seen improvement but I would love to break him out of autism completely. I am convinced its because of our Auto Immune diseases that is like he is especially when I was un diagnosed celiac when pregnant and very ill. He has Celiac and I have Celiac and MTHFR.

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