Designs for Health Research & Education Blog

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Assessing and Supporting Methylation Pathways

The topic of methylation has become more and more popular over the past few years. Methylation is a crucial biochemical process that is essential for the normal function of almost all of our body’s systems. It helps repair our DNA on a daily basis and regulates homocysteine metabolism. In addition, methylation is needed for detoxification and keep inflammation under control. Methylation requires certain cofactors such as B vitamins. When we are deficient in certain B vitamins methylation breaks...Read more

How Much Vitamin D Do You Need to Prevent Osteoporosis?

Vitamin D is essential to keep our bones from developing osteoporosis, but how much do we need? Studies published in the New England Journal of Medicineshow that we need more than 800 IU per day to lower the risk of developing osteoporosis. A study published in the NEJM in June of 2012 showed that there were 30% fewer hip fractures and 14% of all fractures in people in the highest quartile of vitamin D level than the lowest. While the Institute of Medicine and the US Preventive Services...Read more

Fat does not necessarily make you fat

Supplementation with both CLA and omega 3 fatty acids in a recent study helped prevent increased abdominal fat mass and raised fat-free mass and adiponectin levels in younger obese individuals without deleteriously affecting insulin...Read more

Manufactured on Dating use on Designs for Health Products

The US Food & Drug Administration (FDA) is responsible for the regulation of dietary supplements manufactured in, and sold within the United States. Involved in this regulation is the establishment of good manufacturing practices (GMPs) for the production of dietary supplements. Parts of these GMPs address issues related to the shelf life. Specifically, in regard to expiration dating of dietary supplements, FDA has published this comment quoted from the Final Rule on GMPs for supplements,...Read more

Supplementation with lutein found to increase biological antioxidant potential

In a study involving 20 healthy term newborns, supplementation with lutein at 12 and 36 hours after birth was found to be associated with increases in biological antioxidant potential, a marker of antioxidant power, and a reduction in total hydroperoxides, a marker of oxidative stress, 48 hours after...Read more

Did you know? Prostate health is best addressed proactively.

Prostate health is best addressed proactively. Several natural compounds including nettle leaf and saw palmetto can provide tremendous preventative health...Read more

So many calcium options, so very confusing

Calcium carbonate, calcium hydroxapetite, calcium citrate…There are so many different forms of calcium available to both the consumer and the clinician that it is difficult for most of us to answer the questions as to which form is best or which is the most absorbable, and so on.New science has come to the rescue, providing us with answers to the vexing questions of calcium metabolism. First up is the most common form of commercially available calcium, calcium carbonate. This is the form found...Read more

Can't Take the Pressure? 1 in 4 Suffer from High Blood Pressure

According to the Agency for Healthcare Research and Quality, one in four Americans suffers with the potential destructive effects of high blood pressure (HBP). In spite of this significant number, what may be more disconcerting is that… One in five of those who have HBP don’t even know they have it, and Three-quarters of people diagnosed with HBP were overweight, obese, or morbidly obese. The good news is proper diagnosis and treatment can cut the risk of stroke by up to 40% and heart attack by...Read more

Did you know? Carotenoids can modulate the immune system

Carotenoids, the powerful antioxidants found in many colorful fruits and vegetables can also modulate the immune system and help optimize the health of the gastrointestinal...Read more

Depression: not all in your head

Have you been diagnosed with depression because of one or more of the following symptoms? Suffering a depressed mood most of the day nearly every day Markedly diminished interest in activities Significant weight loss (when not dieting) or weight gain Sleeping more than usual or having difficulty sleeping Feeling fatigued nearly every day Feeling worthless or inappropriately guilty Having difficulty concentrating or making decisions Thinking about death or attempting suicide Believe it or not,...Read more

Did you know? Post-menopausal Women Low in Vitamin D

A Spanish study determined that a significant proportion of post-menopausal women are chronically low in vitamin D, a nutrient known for its anti-cancer and pro-immune...Read more

Why Menopause Disrupts Quality Sleep

Eight Hours? The concept of eight hours of uninterrupted sleep for women in the midst of menopause may be more wishful thinking than actual reality. According to a comprehensive report on menopause and sleep by the National Sleep Foundation, 61 percent of women between the ages of 45 and 60 say they suffer from sleeplessness and other sleep problems.  This may be a more serious concern than these sufferers may realize, as recent research shows that poor sleep or lack of sleep can raise...Read more

Health Promotion with Periobiotic Toothpaste

Imbalance bacteria and poor dental hygiene can lead not only to cavities and gum disease, but also to elevated levels of inflammation in the body causing heart disease and other inflammatory conditions.  This inflammation can be measured by a blood test called CRP, short for C-Reactive Protein.  Results of a study published May 27, 2010 in the online British Medical Journal showed, after adjustment for established risk factors, that participants who reported less frequent tooth...Read more

Love is a many splendored thing

You may be wondering why an alternative health care blog would be discussing the finer points of love and romantic relationships. Well, it’s a well established fact that a happy, supportive, nurturing and thriving partnership can be an essential and vital part of creating a healthy mind, spirit and body. As most of us at one time or another have experienced, the bloom of a new romance and its initial excitement will eventually wear off. When that occurs, a firm foundation based on certain...Read more

Manufactured on Dating use on Designs for Health Products

The US Food & Drug Administration (FDA) is responsible for the regulation of dietary supplements manufactured in, and sold within the United States. Involved in this regulation is the establishment of good manufacturing practices (GMPs) for the production of dietary supplements. Parts of these GMPs address issues related to the shelf life. Specifically, in regard to expiration dating of dietary supplements, FDA has published this comment quoted from the Final Rule on GMPs for supplements,...Read more

Metabolic Syndrome and Nutrient Deficiencies: What You Should Know

Metabolic Syndrome is a condition comprised of a group of physical and pathological markers which include central obesity defined by hip and waist measurements, together with at least two of the four following metabolic risk factors: raised triglycerides, reduced high-density lipoprotein (HDL) cholesterol, raised blood pressure, and raised fasting plasma glucose (blood sugar). One way to help counteract the development of this chronic condition that many times leads to diabetes and...Read more

How our home's air quality can impact our overall health

While maintaining a healthy home environment means promoting a healthy lifestyle, many Americans aren’t aware of how indoor air quality can influence their vitality and well being. The truth is that improved indoor air quality can lead to a healthier standard of living for you and your family. For instance, studies have demonstrated that indoor air quality of the home can have either positive or negative effects on cardiovascular health. Breathing in allergens and air particulates can cause...Read more

Health Benefits of Fish Oils

The importance of fish oils in human health cannot be overstated. These omega 3 fatty acids carry with them an expansive range of health benefits, including: Anti-inflammatory – useful for any inflammatory condition, such as arthritis, bursitis, tendonitis, cystitis Immune system support – useful in the inflammatory condition, such as arthritis, bursitis, tendonitis, cystitis Supports a healthy lipid profile (total cholesterol, LDLs, HDLs) Essential for a healthy pregnancy and for the healthy...Read more

Bio-identical Nutrients: A Designs for Health Commitment

Many nutrients occur in various forms, and not all are created equally. Nutrients that occur in nature, from plants and animals, are in specific forms that are optimally bioactive when ingested when foods are eaten, or supplements containing them are taken. In fact, it is often the form of the nutrient that determines both its effectiveness and its safety. However, many nutrients found in nutritional supplements are not in the exact bio-identical form found in nature. This occurs for various...Read more

ADHD and the food connection

According to the CDC and the American Psychiatric Association 3%-7% of school-aged children have ADHD (Attention Deficit Hyperactivity Disorder). However, studies have estimated higher rates in community samples. As of 2007, approximately 9.5%, or 5.4 million children, 4-17 years of age have been diagnosed with ADHD. The percentage of children with a parent-reported ADHD diagnosis increased by 22% between 2003 and 2007 while rates of ADHD diagnosis increased an average of 3% per year from 1997...Read more

Insights into the genesis of diabetes.

Most newly diagnosed type 2 diabetics tend to have one thing in common: obesity.Exactly how diet and obesity trigger diabetes has long been the subject of intense scientific research. As the science pertaining to diabetes continues to evolve, insights into the mechanisms of its genesis become clearer and more defined. Pancreatic beta cells, which are responsible for creating and releasing insulin, appear to be a significant center of attention of the disease’s onset and its severity. In healthy...Read more

The spice of life.

The more that researchers and scientists investigate the health benefits of various foods and naturally occurring consumable substances, the more amazing is the profundity of how what we eat impacts: Our health Mood, and Propensity towards certain disease states. It is also equally amazing, in light of this cutting edge information, how much we as consumers take for granted the impact seeming innocuous foods have on our bodies. Herbs and spices for instance, contain high amounts of polyphenols...Read more

Exercise. It's better than you thought.

For many of us who may exercise less than what experts recommend, the last thing we want to hear is more annoying prodding and cajoling as to why we should get off of our lazy duffs and hit the gym or pavement. But, while most of us realize and understand the fundamental health gains of long term, habitual training,  like improving our cardiovascular health and the signs and symptoms of metabolic syndrome    (which also includes obesity, insulin resistance and type 2...Read more

Welcome to the new Designs for Health Research & Education Blog.

Just when you think you know a real lot about nutrition, you realize how much more there is to know.  Never in my lifetime has there been so much information shared from so many sources, and so fast.  Rather than considering it overwhelming, we should consider it exciting.  We all want to keep up with the science – those of us on the information front and those of you in the trenches, helping to mend people back to health.  We need to team up.   DFH is dedicated to...Read more

Autism and Cerebral Folate Deficiency

Posted on Fri, Dec 07, 2012 @ 01:00 PM

autism boyI 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 (learn about testing for mitochondrial dysfunction and other imbalances using organic acids here).   

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

by Dr. Kara Fitzgerald

10 2012 KF head shot


Dr. Fitzgerald received her doctorate of naturopathic medicine from National College of Natural Medicine in Portland, Oregon. She completed the first CNME-accredited post-doctorate position in nutritional biochemistry and laboratory science at Metametrix Clinical Laboratory under the direction of Richard Lord, Ph.D. Her residency was completed at Progressive Medical Center, a large, integrative medical practice in Atlanta, Georgia. Dr. Fitzgerald is lead author and editor with J. Alexander Bralley, Ph.D. of The Metametrix Institute’s Case Studies in Integrative and Functional Medicine. She is a contributing author to Laboratory Evaluations for Integrative and Functional Medicine and the Institute for Functional Medicine’s updated Textbook for Functional Medicine. She has also published in a number of peer reviewed journals. Dr. Fitzgerald is on faculty and a Curriculum Advisory Committee member at Institute for Functional Medicine. She is an adjunct faculty member at University of Bridgeport in the school of Human Nutrition and a member of The Institute for Therapeutic Discovery. Dr. Fitzgerald regularly lectures internationally for several organizations. Formerly at Advanced Diagnostic Pain Treatment Center at Yale-New Haven, she is now in private practice in Sandy Hook, Connecticut. She may be reached at or



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