This newsletter is about a book written by Dr. Richard Frye, a medical doctor who also has a PhD in Physiology and Biophysics along with a master’s degree in biomedical science and biostatistics. He has authored more than three hundred peer reviewed articles, and along with board certifications in pediatrics and neurology he is a national leader in autism research. I will attempt to summarize his work over two newsletters.
Folate (vitamin B9) is a water-soluble vitamin discovered in the mid-1900s by Herman K. Mitchell, Esmond E. Snell, and Roger J. Williams when they identified and isolated it from spinach leaves. The name came from the Latin word folium which means leaf. It is also found in brewer’s yeast and in the early 1900s-fifty years earlier, an English physician, Lucy Wills, found that when brewer’s yeast was added to the diet, anemia was cured and prevented. In the 1940s scientists synthesized folate in different forms such as folic acid in 1945 by Yellapragada Subbarow, and Bob Stokstad, and folinic acid in 1948 by Sauberlich and Baumann, and 5-MTHF (5 methyl tetrahydrofolate), in the early 1960s by Merck. Aside from the use of folate to help megaloblastic anemia, it was soon discovered that folate when given to pregnant women helps prevent neural tube defects called spina bifida in babies. In addition, because the neural tube eventually differentiates into different brain regions, we now know that it also has a protective effect on the nervous system, brain development and the myelination of the nervous system which helps with transmission of nerve impulses from the brain throughout the body. During prenatal development cells are reproducing at an extraordinary rate - from one cell to 40 trillion cells by birth of which 100 billion cells become neurons in the brain. Without folate the rapid replication of cells could result in copying errors of DNA and potentially lead to developmental and genetic mutations. Folate also protects the fetus from the adverse effects of prescription drugs. This is why a prescription form of folate was developed to help the side-effects of chemotherapy drugs. Because folate was useful for cell division for normal growth and development, an unfortunate counterbalance has been theorized- that folate could potentially cause an acceleration of existing cancers. However, studies are showing that it is not likely and that folate can have a protective effect on many cancers.
Since folate is a water-soluble vitamin, it cannot be stored like a fat-soluble vitamin. We cannot manufacture it, so we need to regularly ingest it through food or supplementation. Folate can be derived from organ meats, dark leafy greens, legumes such as beans, chickpeas, green peas, lentils, and fruits such as oranges, and grapefruit, avocados, and broccoli. Based on the overwhelming benefits that folate provides to humans, and that we cannot manufacture it, it seemed to be a good idea to begin a fortification program in the U.S. and other countries where it would be added to packaged food products that contained grains such as wheat. This all began in 1998 for both the U.S. and Canada. The form of folate that was being added was folic acid. This is the form that is in most prenatal and multi-vitamins too.
Choosing to use folic acid to fortify foods instead of folate or folinic acid presents some problems. Folic acid is synthetic, less expensive to produce, and harder to absorb form than the original folate that was discovered in the 1940s. Folic acid can be absorbed only if it is transformed with the use of dihydrofolate reductase (DHFR) which is made in the liver and converts folic acid to reduced folate. The form of reduced folate is either folinic acid or 5 methyl tetrahydrofolate (5 MTHF). The liver has a limited ability to manufacture enough DHFR to convert folic acid to the natural forms of folate and the result is the accumulation of unmetabolized folic acid (UMFA) in the body. In some cases, this might be due to a genetic polymorphism of the DHFR enzyme. This defect or excessive exposure to folic acid even without the genetic defect would stress the enzyme system responsible for metabolizing folic acid. Higher levels of UMFA are being linked to increased incidence of asthma, insulin resistance, and autism spectrum disorders and other neurodevelopmental disorders. In animal studies it has been associated with altered cortical and learning development, and an increased seizure susceptibility. This revelatory information raises questions about the fortification of foods with synthetic folic acid because folinic acid and 5 MTHF do not stress the DHFR enzyme system and can be absorbed without raising UMFA.
Cerebral Folate Deficiency (CFD)
About two decades ago a European child neurologist in Germany by the name of Dr. Vincent Ramaekers started observing abnormally low folate levels in the central nervous system with associated neurodevelopmental disorders in these patients. Dr. Ramaekers teamed up with Dr. Blau an expert in cerebrospinal fluid (CSF) and when measuring the cerebrospinal fluid found low levels of 5 MTHF. It was Dr. Ramaekers who coined the term CFD to bring attention to the brain specific nature of the abnormality. To diagnose this condition a lumbar puncture is performed below the end of the spinal cord and a small amount of spinal fluid is extracted for analysis. Dr. Ramaekers suspected that the underlying problem was Folate’s inability to cross the blood cerebrospinal fluid barrier. The main carrier to bring folate across this barrier is the folate receptor alpha (FRa). This hypothesis was supported by the fact that many patients had sufficient levels of folate concentrations in their blood, but abnormally low concentrations in the CSF.
Dr Ramaekers also worked with Dr. Edward Quadros a cellular biologist from the State University of NY (SUNY) at Downstate in Brooklyn. Dr. Quadros discovered that the body’s immune system could produce antibodies that blocked the FRa from working. There are two folate receptor autoantibodies (FRAAs) that can do this. One is a binding autoantibody, and the other is a blocking autoantibody. In 2005 these two doctors published a landmark medical research paper defining CFD in the New England Journal of Medicine (NEJM) along with the symptoms and neurological disorders associated with CFD. A couple of years earlier, Dr. Ramaekers had also published a paper on a genetic form of autism spectrum disorders known as Rett Syndrome. He believed that the cause was a mutation in the FOLR1 gene which is responsible for the production of FRa to transport the folate but was never able to find abnormalities in this gene after examining many patients. This is what led to his realization that CFD was an autoimmune disorder. Two years after the seminal NEJM paper, Dr. Ramaekers found that children with mitochondrial disorders also manifested CFD, even without positive FRAAs. Because the level of folate is 2-3 times higher in the brain than it is in the blood, active transport to bring folate to the brain requires energy from ATP which is made by mitochondria. The transporting of folate by FRa requires healthy mitochondrial function but it also works with an enzyme 10-formyltetrahydrofolate dehydrogenase (FDH) to ensure the brain’s high metabolic demands to distribute folate to the entire brain. Another antibody test is the soluble folate receptor antibody (sFR) which is on the surface membrane of the neuron and helps transport the folate into the cell. A positive antibody test for sFR will also interfere with uptake of folate and lead to the same kind of problems that the binding and blocking antibodies cause. sFR is also heavily expressed cellularly in the placenta, so assessing a woman either before pregnancy or during a pregnancy could identify a risk factor for that fetus in its ability to uptake folate.
Symptoms of CFD are varied and they are not limited to children. Adults can have CFD as well. In children some common symptoms are sleeping problems, irritability, obsessive compulsive disorders, developmental delays, neurodevelopmental regression, seizures, loss of hearing or vision, lack of muscle tone, abnormal gait patterns and autism spectrum disorders including speech delays. In adults, symptoms might be memory loss, cognitive impairments, psychosis, schizophrenia, depression, suicidal ideation, sensory deficits, movement disorders, intellectual disability, and complex neurological disorders.
Cerebral Folate Deficiency is a new diagnosable condition that is causing untold suffering amongst children and adults. In part two, I will try to summarize more of Dr. Frye’s excellent book with more detailed information about how to diagnose this condition and how to treat it.
