Autism and Cerebral Folate Deficiency


I work with a family with two young sons, both diagnosed with autism. They live in a large, West Coast city. No one else in their immediate or extended family has an Autistic Spectrum Disorder (ASD) or autoimmune disorder (the latter is sometimes associated with ASD). Understandably, one of the first questions the father of these two boys asked me was, “Why do my sons have autism?” It’s a heartbreaking question that any physician wants to be able to answer with surety, but there are many potential contributing antecedents, triggers, and mediators.

One thing is certain, however—environmental exposures play a massive role in autism spectrum disorders, given the meteoric rise in incidence since the 1980s.

The boys in this family are first generation Americans. This fact provides us with a unique window because Mom and Dad were born in and spent their earliest years in the Middle East with different environmental exposures. The parents recall that the older son developed ASD very early on, before the usual 18-24 month timeframe commonly seen today. Despite their best efforts, it took some time before he was given the correct diagnosis and treatments were started.  Because of the later treatment start, he didn’t respond to biomedical and behavioral interventions as well as his younger brother. With their second son, both parents spotted the signs of autism immediately and initiated treatment. He responded very well and demonstrates fewer autistic features today.

One key intervention for both boys that resulted in a significant reduction of behavioral symptoms was the removal of bovine dairy and gluten-containing grains. Both are big problems for many kids with ASD, and their removal is a common first step.

The older boy recently started a trial of high-dose folinic acid (1mg/kg body weight). This intervention appears to have made a remarkable difference in him. Both parents noted that rather quickly after starting, his expressive language greatly improved—he began articulating his needs and desires—in a way he’s never done before. (In all fairness, we cannot rule out benefit from his various other treatments. This trial, like life, wasn’t controlled.)

Given the above history, and the favorable folinic acid trial, is it possible for us to form a hypothesis around a potential causative factor in this case? Yes we can.

I strongly suspect that Cerebral Folate Deficiency is an underlying etiologic factor with these boys. Here’s why:

CFD was characterized a mere 10 years ago by Ramaekers et al.1 They describe five patients with normal development until approximately six months of age, when developmental regression, irritability, psychomotor retardation, ataxia,  and other problems developed. Central nervous system 5-methyltetrahydrofolate (5-MTHF) levels were found to be very low, although serum and RBC 5-MTHF were normal. The patients responded favorably to the addition of folinic acid.

Ramaeker’s group later investigated mutations in a blood-brain barrier folate-transport-associated protein (folate receptor 1, or FR1), and found none. They did, however, find high affinity autoantibodies to FR1 in a group of 25 children with CFD.2,3

Research by other groups found an association of CFD and a wide variety of mitochondrial diseases (MD). Individuals with MD/CFD may not, apparently, have FR1 autoantibodies. 4-8

Further research found that a subset of individuals diagnosed with autism had either MD-associated CFD or FR1 autoantibody-associated CFD.2,3,9

Ramaeker identified in 2008 that human folate receptors potently cross react with folate receptors found in bovine or goat’s milk. They noted that a dairy-free diet reduced production of FR1 autoantibodies.10 It was also observed that folic acid (also called synthetic, oxidized, or unmetabolized folic acid {UMFA}) competes with natural folates for the binding site on FR1. Not surprisingly, folic acid is toxic to those with CFD, associated with seizures and symptom regression.2,11

The fact that so many individuals with ASD respond very favorably with the removal of dairy from their diet is an interesting correlation. Do these children have CFD? Is the action of removing dairy allowing increased transport of active folates into the central nervous system? And, likewise, is the removal of gluten-containing grains (which yields clinical improvement for many) reducing exposure to synthetic folic acid? All very valid questions.

Monitoring UMFA in the serum of individuals with diagnosed or suspected CFD could make good sense, given the ubiquitous presence of synthetic folic acid in the food supply, and its toxic ramifications in those with CFD. My goal for these individuals would be to minimize the presence of UMFA in the serum, not unlike anti-gliadin antibodies in celiac patients.

Now, back to the case study:

It’s compelling that Mom and Dad both spent their early years in a country that didn’t participate in folic acid enrichment (Egypt). Additionally, the father reports ingesting less cow’s dairy prior to coming to the West. However, both boys were born and raised in the West on a diet deemed healthy by most, which invariably includes much synthetic folic acid and dairy. Both boys developed autism. Both developed it earlier than the commonly seen 18-to-24-month window, which fits Ramaeker’s description. Both boys responded favorably to the removal of dairy and gluten. Since the younger son’s treatment started earlier, he demonstrated a fuller resolution, as presumptively his CNS folate levels were restored sooner.

If these boys have CFD, we’d expect something like this, would we not? The youngest boy does well because both toxic components to CNS folate transport—dairy and synthetic folic acid—have been removed very early on in his development. The older boy’s favorable response to folinic acid, a bioidentical folate, seems apparent. There is no history of such problems in this family because there is no previous exposure to these elements in the same way.

I would argue that a careful, monitored, therapeutic trial with folinic acid is indicated for most children on the spectrum, regardless of whether they fit the pattern of the boys in this case or not. Mitochondropathy is very common in this population and is also an underlying factor for CFD. Interestingly, the boys in my case didn’t have the classic pattern of mitochondropathy on laboratory analysis.

Next treatment steps: Check serum UMFA levels in both boys (and anyone with ASD or suspected CFD.) Consider a trial of folinic acid for the younger boy, as he continues to have some autistic features. If the boys have higher serum UMFA, I would strongly suggest to the parents that we investigate the occult exposure sources, and remove them. 

Many questions remain regarding CFD and autism, and the impact of folic acid, dairy, gluten, and the myriad environmental toxins we are all exposed to daily. Of course, folic acid fortification has reduced the incidence of birth defects in this country and others. No one, however, metabolizes synthetic folic acid into its active counterparts very efficiently. And some of us activate it much more slowly, allowing for a pronounced accumulation and increasing vulnerability to toxicity.12,1

(Originally published on


1.      Ramaekers VT, Hausler M, Opladen T, Heimann G, Blau N. Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydrofolate in cerebrospinal fluid: a novel neurometabolic condition responding to folinic acid substitution. Neuropediatrics. Dec 2002;33(6):301-308.

2.      Ramaekers VT, Blau N. Cerebral folate deficiency. Developmental medicine and child neurology. Dec 2004;46(12):843-851.

3.      Ramaekers VT, Rothenberg SP, Sequeira JM, et al. Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. The New England journal of medicine. May 12 2005;352(19):1985-1991.

4.      Frye R. Complex IV hyperfunction in autism spectrum disorder: a new mitochondrial syndrome. J Ped Neurol. 2012.

5.      Garcia-Cazorla A, Quadros EV, Nascimento A, et al. Mitochondrial diseases associated with cerebral folate deficiency. Neurology. Apr 15 2008;70(16):1360-1362.

6.      Hasselmann O, Blau N, Ramaekers VT, Quadros EV, Sequeira JM, Weissert M. Cerebral folate deficiency and CNS inflammatory markers in Alpers disease. Molecular genetics and metabolism. Jan 2010;99(1):58-61.

7.      Pineda M, Ormazabal A, Lopez-Gallardo E, et al. Cerebral folate deficiency and leukoencephalopathy caused by a mitochondrial DNA deletion. Annals of neurology. Feb 2006;59(2):394-398.

8.      Ramaekers VT, Weis J, Sequeira JM, Quadros EV, Blau N. Mitochondrial complex I encephalomyopathy and cerebral 5-methyltetrahydrofolate deficiency.Neuropediatrics. Aug 2007;38(4):184-187.

9.      Ramaekers VT, Blau N, Sequeira JM, Nassogne MC, Quadros EV. Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits. Neuropediatrics. Dec 2007;38(6):276-281.

10.   Ramaekers VT, Sequeira JM, Blau N, Quadros EV. A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome. Development al medicine and child neurology. May 2008;50(5):346-352.

11.   Gordon N. Cerebral folate deficiency. Developmental medicine and child neurology. Mar 2009;51(3):180-182.

12.   Bailey RL, Mills JL, Yetley EA, et al. Unmetabolized serum folic acid and its relation to folic acid intake from diet and supplements in a nationally representative sample of adults aged > or =60 y in the United States. The American journal of clinical nutrition. Aug 2010;92(2):383-389.

13.   Bailey SW, Ayling JE. The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. Proceedings of the National Academy of Sciences of the United States of America. Sep 8 2009;106(36):15424-15429.

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Comments 2

  1. Great article!
    Have you looked at the diversion by folic acid of DHFR activity? I just spent a couple of weeks of intensive research, and no one seems to be connecting the dots I just did, and I’m wondering why…
    1) Before such widespread folic acid fortification of food, one study found 98% of autistic children to have an MTHFR polymorphism.
    2) High folic acid intake can cause a pseudo-MTHFR deficiency. (online at Recent studies that don’t find the MTHFR gene connected to autism are dealing with populations that typically have folic acid fortification of the food supply and/or health care initiatives to promote folic acid.
    3) Folic acid is now ingested in such large quantities that probably half the USA has unmetabolized folic acid in their bloodstream. Children can easily ingest 200 mcg–half of the adult RDA, and children are much smaller–or more in just one little bowl of breakfast cereal. So now you have folic acid in the bloodstream and reaching the blood-brain barrier, where it pushes reduced folate out of the way (folate receptor alpha, for example, has ten times the affinity for folic acid as it does for reduced folate; that same folate receptor is the one that people who drink a lot of milk develop autoantibodies against).
    4) Folic acid gets into the brain easily, where it significantly diverts the DHFR enzyme from its other jobs. One substrate for DHF is DHFR. Another enzyme that uses DHF is MTHFR. Diverting DHFR from doing its work on DHF would logically be likely to impact MTHFR’s activity.
    5) DHF levels drop off during infancy, indicating that DHFR’s role likely alters during that period, right around the time that autism starts to manifest.
    6) “Global methylation profiling of lymphoblastoid cell lines reveals epigenetic contributions to autism” ( and “Genomic DNA Methylation Changes in Response to Folic Acid Supplementation in a Population-Based Intervention Study among Women of Reproductive Age” (; MTHFR is involved)
    I’m not a doctor. But I studied math, so I see patterns. I studied law, so I know what constitutes evidence. You’re a doctor. Please, look into this and tell me if I’m missing something. Too many kids and their families and communities are suffering from autism these days.
    The worst of it is, no one needs to take folic acid anymore. There are other forms of folate that are available as supplements such as folinic acid and 5-MTHF.

    1. Looked over my comment and saw a couple of sentences I need to fix:
      “One substrate for DHF is DHFR. Another enzyme that uses DHF is MTHFR. ”
      should read “One substrate for DHFR is DHF. Another enzyme that acts on DHF is MTHFR. “

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