Folates in Health and Disease
Latest Developments Regarding Folates
At the "Folates in Health and Disease" symposium held on September 26, 2022, at the University Hospital Zurich (USZ), renowned experts discussed various current research findings concerning folates. The discussions revealed that certain established medical views require revision.
Folate Transport and the Significance of Autoantibodies
As explained by PD Dr. Michele Visentin—a leading researcher in this field from the USZ Institute of Clinical Pharmacology and Toxicology—various receptors and active folate transporters are essential for folate uptake (e.g., into liver cells), reabsorption in the renal tubules, and, crucially, transport into the brain against the concentration gradient. It is important to note that there are multiple forms of folate, which are metabolized differently among individuals due to polymorphisms in the enzymes involved. Folate transport—particularly into the brain—can be impaired by autoantibodies against folate receptors ("folate receptor autoantibodies" or FRAAs). Consequently, Dr. Michele Visentin, with support from the Baylor College in Houston, became the first in Europe to establish a method for quantifying FRAAs. Determining the concentration of these autoantibodies is of great clinical importance, as they can cause cerebral folate deficiency even when serum folate levels appear normal. For instance, Prof. Robert Cabrera of Baylor College in Houston, a pioneer in FRAA research, found that 70% of autistic children suffer from cerebral folate deficiency due to FRAAs, despite having normal serum folate levels.1
Folate Deficiency and Spina Bifida
Through his research over the past 30 years, Prof. Richard H. Finnell of Baylor College in Houston has demonstrated, among other things, that the neural tube closes between the 20th and 28th day of embryonic development only if sufficient folate accumulates at that site. However, supplementation with synthetic folates before and during pregnancy does not always prevent spina bifida. A primary cause of this is the aforementioned FRAAs.
Folate Deficiency or Excess Can Lead to Problems
A new study presented at the event by Martin Ulmann, CEO of the company Aprofol, shows that in Switzerland, approximately 20% of women of childbearing age suffer from erythrocyte folate deficiency (< 340 nmol/L), and over 90% exhibit folate concentrations below 906 nmol/L—levels that, according to the WHO, indicate an increased risk of neural tube defects.2 However, most dietary supplements contain folic acid—a synthetic, inactive form of folate—and there is growing evidence that intakes exceeding 1 mg per day can actually be harmful. Consequently, natural forms of folate, such as L-methylfolate or levoleucovorin, are becoming increasingly important. This not only ensures greater independence from polymorphisms but also allows for plasma concentrations at which folates can enter the brain via alternative receptors unaffected by FRAAs.1 Clinical studies have already demonstrated that leucovorin and levoleucovorin (folinic acid/levofolinic acid) improve the communication skills of children with autism.1 This therapeutic success was dependent on FRAA levels.1 Currently, three publicly funded clinical trials are underway in the USA using a Swiss-developed formulation of a nature-identical folate.1,3-5
Folates also differ biologically
As Gerd Wiesler from the company Aprofol pointed out during the symposium, there are not only chemical but also biologically significant differences between the various types of folate. He offered the following take-home message for clinicians: "Bioactive, nature-identical forms of folate are not only more beneficial but also safer for some patients, as they can be easily metabolized by the body." However, developing high-quality dietary supplements and medications requires extensive expertise, given the often complex chemical formulas involved.
From theory to practice
In a case study, Prof. Robert Steinfeld (University Hospital Zurich) presented a family with three children, all of whom had a genetic defect affecting the folate receptor. While the defect in the eldest child was only discovered after clinical symptoms had appeared, the diagnosis was made at age three for the second child and immediately after birth for the third. Consequently...