Author: Richard E Frye, MD, PhD, FMAPS, Autism Discovery and Treatment Foundation, Phoenix AZ
Many physicians are becoming more aware of the problems with abnormally low levels of folate in the central nervous system (CNS), which, when severe, is known cerebral folate deficiency (CFD), in children with neurodevelopmental disabilities such as autism spectrum disorder (ASD). Normally folate is transported into the CNS using a special mechanism known as the folate receptor alpha (FRα). One of the main causes of problems transporting folate into the CNS are two antibodies known as the blocking and blinding FRα antibodies. Over the last decade we have luckily been able to order a test for these antibodies known as the Folate Receptor Antibody Test (FRAT). The wonderful thing about diagnosing an individual with FRα antibodies is that the standard treatment, leucovorin, is safe and well tolerated.
Over the last few years, we have learned more about the biomarkers for diagnosing central folate abnormalities. This blog will provide an update on some of the new findings.
About two years ago, we published a paper demonstrating a third biomarker of folate abnormalities in children with ASD known as soluble folate binding proteins (sFBPs). sFBPs have been described in cancer research but they have not been discussed in neurologic or developmental disorders. Essentially sFBPs are proteins in the blood which bind to folate, making it less available. For the FRAT test, these proteins were primarily thought of as an annoyance because they interfere with the assay that measures blocking FRα antibodies. This results in an inability to measure blocking FRα antibodies on the FRAT. What we found is that the patients with sFBPs are some of the most severely affected individuals and they require higher than usual doses of leucovorin to respond. We found patients who had not responded to any treatment improving on high doses of leucovorin and finally showing show improvement. We do not know what exactly what the sFBPs are, but some have suggested that they might be FRα proteins that have dislodged from the cell surface. Over the next year or so, we aim to investigate what exactly these proteins are in our new lab at the Autism Discovery and Treatment Foundation. We are excited because we believe this is yet a third biomarker of central folate abnormalities in ASD.
At the beginning of this year, we published a study demonstrating that the blocking FRα antibody could be used to predict the amount of improvements in ASD symptoms with leucovorin treatment. In general, we found that scores on the Social Responsiveness Scale (SRS), a scale that measures ASD symptoms, were higher (worse) as the blocking FRα antibody titer increased and that treatment with leucovorin resulted in a greater decrease (improvement) in the SRS for individuals with higher the blocking FRα antibody titers. We also found that concurrent treatment with subcutaneous injected methylcobalamin and fatty acids further improved scores on the SRS. This now provides a guide to predict how much improvement will occur with leucovorin treatment. However, the dosing of leucovorin is still understudied, so further research is needed to better understand the response to the optimal dose of leucovorin.
Earlier this year, along with Drs Lindsey Wells and Nancy O’Hara, we published our results on the investigation into the prevalence of the FRα antibodies in Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). Surprisingly, we found that about 64% of children with PANS and/or PANDAS from the clinics of Drs O’Hara and Wells were positive for one of the two FRα antibodies, with the majority positive for the binding FRα antibody. Interestingly, PANS/PANDAS patients with ASD had lower binding FRα antibody titers than the PANS/PANDAS patients without ASD. In addition, severe tics were a predictor of higher binding FRα antibody titers. This now opens other biomarkers for individuals with PANS/PANDAS as well as puts a new treatment in the armamentarium for PANS/PANDAS patients.
We have known that some children with ASD do not react well to the commercial brands of leucovorin, requiring a compounded form of the medication but we have started to become aware that specific commercial brands of leucovorin, not only are less effective, but may resulted in worsening behavior and regression in some patients. This is very important as I have found that many children who do not respond to leucovorin are simply using one of the brands that is suboptimal. This provides support for developing a safer brand of leucovorin that we know is well tolerated and effective. Over the last several years we have been researching a special form of leucovorin called levoleucovorin. Levoleucovorin is the L isomer of leucovorin. Most drugs contain two mirror images of themselves. This is called the racemic mixture of the drug. In racemic mixtures, one of the forms is the active form while the other form is inactive and only can result in adverse effects. Thus, a Swiss company called Aprolol has developed a liquid form of the L isomer of leucovorin which only has the active form of leucovorin. We have several clinical trials ongoing to learn more about this formulation as a potential standard treatment for ASD.
Central folate abnormalities and their treatment is an exciting and emerging area of treatments for children with neurodevelopmental disorders. Hopefully further research will continue to improve our ability to diagnose these disorders and apply the optimal treatment.
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