Important Breakthrough Folate in Autism
by Jeffrey Dach MD
Autistic kids have disrupted folate metabolism due to autoantibodies to the Folate Receptor.
Just published, this report in the March, 2013 issue of Molecular Psychiatry, “Cerebral Folate Receptor Autoantibodies in Autism Spectrum Disorder”, represents a major breakthrough in Autism.
Above Left image: autistic behavior stacking cans, courtesy of Wikimedia Commons.
Folate is Essential
Folate, also called Vitamin B9, is an essential nutrient needed for synthesis of brain neurotransmitters, Serotonin, Dopamine and Norepinephrine.
Folate deficiency is associated with depression, Attention Deficit Disorder (ADD), and other neuropsychiatric disorders.
Disturbed folate metabolism is also a risk factor for blood clots (thromboembolism) and increased risk of all cancers.
5MTHF is the Active Form of Folate
Folate itself cannot enter the brain. It must first attach to Folate Receptors (FR) in the choroid plexus and then be converted to the active form, MTHFR, which then may cross the blood brain barrier to enter the brain tissue.
The active form of folate is 5MTHF, (also called 5-Methyl-Tetra Hydro-Folate) This form of the vitamin can easily cross the blood brain barrier, enter the brain and promote neurotransmitter production.
Folate Receptor Antibodies
In Autism, the Folate Receptor is non-functioning because of auto-antibodies. This is a form of autoimmune disease in which an immune response is mounted against the Folate Receptor. This is a bad thing because the Folate Vitamin is not working and cannot get into the brain where it is needed.
75% of Autistic Children Have Folate Receptor Antibodies
Dr. Frye’s study found that Folate Receptor Antibodies were present in 75% of the 93 autistic children studied. In 16 children in which spinal fluid samples were studied, the presence of Folate Receptor Antibodies correlated with reduced cerebrospinal fluid 5-MTHF levels.
Treatment with Activated Folate
The autistic children were treated with up to 50 mg per day of Leucovorin over 4 months. This is an activated folate vitamin. One third of treated children were deemed “Moderate” to “Much Improved” in verbal communication, receptive and expressive language, attention and stereotypical behavior. The authors recommended empiric treatment of all autistic children with activated Folate supplements (5MTHF)
Leucovorin is Folinic acid, a 5-formyl derivative of Tetra-Hydo-Folate. Regular folic acid is not effective and not recommended for MTFHR patients.
A Major Breakthrough
This is truly a major breakthrough in our understanding of Autism, and other neuropsychiatric disorders associated with disrupted Folate metabolism.
Previous Work in 2007 Also Showed Similar Findings
This new study by Dr Frye confirms a previous 2007 study by Dr Ramaekers from Belgium who found Folate receptor autoimmunity and cerebral folate deficiency in 23 of 25 autism patients.
MTHFR Genetic Mutation
Another patient group with disrupted folate metabolism is the MTHFR Mutation. In this genetic mutation, conversion of Folate to its active form (5MTHF) is reduced by 20-70 % efficiency, depending on whether the mutation is heterozygous or homozygous.
These patients have a genetic inability to utilize Folate, since they cannot convert folate to its active form, or conversion is inefficient. This MTHFR genetic mutation is associated with various neuropsychiatric conditions such as Attention Deficit Disorder, (ADHD), Depression and a host of others as you might expect from the inability of the brain to produce sufficient quantities of neurotransmitters, Serotonin, Dopamine and Norepinephrine.
Poly Drug Psych Meds for MTHFR ??
Without realizing there is a Folate problem, the mainstream medical system will treat many of these MTHFR patients with a poly-drug approach with Adderal, Ritalin, SSRI antidepressants, and Atypical Anti-psychotics like Respiradol and Zyprexa. However, none of these drugs address the underlying cause which is a Folate conversion problem.
As these patients need Methyl-Folate, the correct treatment for these patients is not a Psycho-Stimulant Drug which obviously contains no Methyl-Folate. If the MTHFR genetic mutation is present, these patients should be given 5-Methyl-Tetra-Hydro-Folate (the active form of the vitamin) which is widely available at the health food store without a prescription.
Routine Testing for MTHFR
Patients may also self-test with anonymous online genetic testing with a home test kit ordered online. For more on this, see my previous article:
Understanding Online Genetic Testing
Article on ADHD by David Perlmutter MD- Are Drugs Really the Way to Go for ADHD ?
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Links and references
Mol Psychiatry. 2013 Mar;18(3):369-81. doi: 10.1038/mp.2011.175. Epub 2012 Jan 10.
Cerebral folate receptor autoantibodies in autism spectrum disorder. Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA. Source Department of Pediatrics, Arkansas Children’s Hospital Research Institute, University of Arkansas for Medical Sciences, Little Rock,
Abstract Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood-brain barrier. Autism spectrum disorders (ASDs) and improvements in ASD symptoms with leucovorin (folinic acid) treatment have been reported in some children with CFD. In children with ASD, the prevalence of FRAs and the response to leucovorin in FRA-positive children has not been systematically investigated. In this study, serum FRA concentrations were measured in 93 children with ASD and a high prevalence (75.3%) of FRAs was found. In 16 children, the concentration of blocking FRA significantly correlated with cerebrospinal fluid 5-methyltetrahydrofolate concentrations, which were below the normative mean in every case. Children with FRAs were treated with oral leucovorin calcium (2 mg kg(-1) per day; maximum 50 mg per day). Treatment response was measured and compared with a wait-list control group. Compared with controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior. Approximately one-third of treated children demonstrated moderate to much improvement. The incidence of adverse effects was low. This study suggests that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from leucovorin calcium treatment. Given these results, empirical treatment with leucovorin calcium may be a reasonable and non-invasive approach in FRA-positive children with ASD. Additional studies of folate receptor autoimmunity and leucovorin calcium treatment in children with ASD are warranted.
Neuropediatrics. 2007 Dec;38(6):276-81.
Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits.
Ramaekers VT, Blau N, Sequeira JM, Nassogne MC, Quadros EV.SourceDivision of Child Neurology, University Hospital Liège, Belgium.
Reduced folate transport to the CNS was identified in two autism spectrum disorders, i.e., Rett syndrome and infantile low-functioning autism with neurological abnormalities. Twenty-five patients with early-onset low-functioning autism with or without neurological deficits, were evaluated for serum folate, cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF), and serum FR autoantibodies of the blocking type to determine the significance of folate receptor (FR) autoantibodies with respect to folate transport across the blood-CSF barrier. In spite of normal serum folate, CSF 5MTHF was low in 23 of 25 patients. The reduced CSF folate in 19 of these 23 patients could be explained by serum FR autoantibodies blocking the folate binding site of the membrane-attached FR on the choroid epithelial cells. Oral folinic acid supplements led to normal CSF 5MTHF and partial or complete clinical recovery after 12 months. Serum FR autoimmunity appears to represent an important factor in the pathogenesis of reduced folate transport to the nervous system among children with early-onset low-functioning autism associated with or without neurological deficits. Early detection of FR autoantibodies may be a key factor in the prevention and therapeutic intervention among this subgroup of patients with autism.
Andrew Farah, MD, FAPA
CNS Spectr. 2009;16:1(Suppl 2):1-7 Dr. Farah is chief of Psychiatry at High Point Regional Health Systems, High Point NC, and is clinical faculty at Wake Forest University, Winston-Salem NC. Disclosures: Dr. Farah serves as consultant to and receives honoraria from Pamlab.Abstract Major depressive disorder (MDD) is a debilitating and often recurrent illness. An initial antidepressant trial is effective at achieving remission for ~30% of patients when prescribed as monotherapy, with the majority of patients returning as partial or non-responders. Switching antidepressants or adding augmentation agents are standard therapeutic options used to achieve and maintain remission. Suboptimal serum and red blood cell folate levels have been associated with a poorer response to antidepressant therapy, a greater severity of symptoms, later onset of clinical improvement, and overall treatment resistance. This Expert Review Supplement reviews the evidence for L-methylfolate as an augmentation agent in depression and discusses its clinical use elaborated by three clinical presentations.
J Clin Psychiatry. 2009;70 Suppl 5:12-7.
Folate in depression: efficacy, safety, differences in formulations, and clinical issues. Fava M, Mischoulon D. Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, 55 Fruit Street, Bulfinch 351, Boston, MA 02114, USA.
Altern Med Rev. 2008 Sep;13(3):216-26.
The methylation, neurotransmitter, and antioxidant connections between folate and depression. Miller AL. Source Thorne Research, PO Box 25, Dover, ID 83825, USA.
An ADD Family Success Story.
An ADD family story with a drug free solution. I have 4 children ranging in age from 11-26 with ADD. I’m sharing my experience and solutions, hopefully to bring balance into the lives of ADD families Here is the name of the blood test to order: MTHFR, DNA Mutation.
MTHFR Mutation: A Missing Piece in the Chronic Disease Puzzle June 2012 00:43 By Bianca Garilli, ND, Contributing Writer – Vol. 13, No. 2. Summer, 2012
Int J Med Sci 2011; 8(7):523-528.
Methylenetetrahydrofolate Reductase Gene Polymorphisms in Children with Attention Deficit Hyperactivity Disorder
Cem Gokcen1 Corresponding address, Nadir Kocak2, Ahmet Pekgor3 1. Department of Child and Adolescent Psychiatry, Medicine Faculty of Gaziantep University, Gaziantep, Turkey
2. Department of Genetics, Medicine Faculty of Selcuk University, Konya, Turkey 3. Department of Statistics Faculty of Science, Selcuk University, Konya, Turkey
FINDING THE ROOT CAUSE
Folate Metabolism Gene 5,10-Methylenetetrahydrofolate Reductase (MTHFR) Is Associated with ADHD in Myelomeningocele Patients Catherine J. Spellicy, Hope Northrup, […], and Kit Sing Au
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