Folate receptor autoantibodies (FRAA) bind or block the receptors that allow folate to cross the blood brain barrier. These antibodies have been found to be elevated in 70% of children with autism resulting in low levels of folate within the brain. Because folate is critical for multiple physiologic systems associated with neurodevelopment it can easily be seen how low levels of folate within the brain would result in symptoms associated with autism. The symptoms of cerebral folate deficiency secondary to folate receptor autoantibodies include:
- lack of or very limited speech development
- sleep disturbance
- low muscle tone
- developmental regression
- seizures
- cerebellar ataxia (sudden, uncoordinated muscle movement)
- dyskinesia (involuntary movement)
Testing:
The following lab processing centers are not contracted with FRATNow but are familiar with FRAT testing. We recommend you contact your local branch of either of these processing centers to ask if this test can be done for your child with the kit you bring to them before taking your child for a blood draw.
Treatment:
Click this image to open a pdf that includes links to folinic acid options.
Leucovorin is the pharmaceutical form of folinic acid available in tablet form, offering a much higher concentration than over-the-counter capsules. This increased potency means only two tablets are needed daily, reducing the number of doses compared to multiple capsules or drops. The tablets can be crushed and mixed into food, applesauce, juice, or other suitable mediums, making administration easier. Leucovorin is available at most general pharmacies, including CVS and Walgreens.
If your insurance will not cover the cost of Leucovorin and you have to pay out-of-pocket we recommend that you use GoodRx.com to check for the best price in your area. Be sure to check that the city matches your location, and adjust it if necessary. Select the pharmacy and price you want. This will adjust the image on the right that looks like an insurance card. You can send this to yourself via email, text or print. Show this to your pharmacist to get this price.
Leucovorin can also be compounded into a liquid formula through Lee Silsby Pharmacy. Please discuss with your physician along with the cost of doing this before the prescription is initiated.
If your insurance will not cover the cost of Leucovorin and you have to pay out-of-pocket we recommend that you use GoodRx.com to check for the best price in your area. Be sure to check that the city matches your location, and adjust it if necessary. Select the pharmacy and price you want. This will adjust the image on the right that looks like an insurance card. You can send this to yourself via email, text or print. Show this to your pharmacist to get this price.
Leucovorin can also be compounded into a liquid formula through Lee Silsby Pharmacy. Please discuss with your physician along with the cost of doing this before the prescription is initiated.
Side Effects
Potential side effects of Leucovorin may include increased excitement, agitation, and insomnia. Experiencing these effects does not necessarily mean Leucovorin isn’t suitable for your child. These symptoms are often temporary and may indicate beneficial changes occurring in the brain. As shown in the table below, children who received Leucovorin experienced these side effects between weeks 3 and 6 of treatment, but by week 9, these effects decreased to 0%.
Dr. Richard Frye discusses side effects in the lecture below at 30:41
Dairy:
Another important aspect of treatment is strictly avoiding all sources of animal-derived milk products including those from cow, camel, goat and sheep. Research has shown that milk proteins may trigger an immune response in the gut that results in the presence of these folate receptor antibodies. Dr. Frye discusses this at 32:16 in the above video as well.
A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome
A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome
Reduced Folate Carrier Upregulation
Two studies in mice suggest that additional factors may contribute to the upregulation of reduced folate receptor, the secondary receptors through which folinic acid enters the brain. One factor is vitamin D, which is often low in children with autism and Down syndrome. An optimal serum vitamin D level is 60-80 ng/mL.
Upregulation of reduced folate carrier by vitamin D enhances brain folate uptake in mice lacking folate receptor alpha
The other factor that may contribute to increased reduce folate receptors is PQQ. The chart below is from this study: Nuclear respiratory factor 1 (NRF-1) upregulates the expression and function of reduced folate carrier (RFC) at the blood-brain barrier. These researchers showed that the SLC19A1 gene that codes for the reduced folate receptor (RFC) was upregulated when exposed to PQQ.
Upregulation of reduced folate carrier by vitamin D enhances brain folate uptake in mice lacking folate receptor alpha
The other factor that may contribute to increased reduce folate receptors is PQQ. The chart below is from this study: Nuclear respiratory factor 1 (NRF-1) upregulates the expression and function of reduced folate carrier (RFC) at the blood-brain barrier. These researchers showed that the SLC19A1 gene that codes for the reduced folate receptor (RFC) was upregulated when exposed to PQQ.
Studies:
Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorders: Diagnosis, Treatment and Prevention
"Autoantibodies against folate receptor alpha (FRα) are present in about 70% of the children with a diagnosis of ASD, and a significant number of these children respond to oral folinic acid with overall improvements in speech, language and social interaction."
Treatment of Folate Metabolism Abnormalities in Autism Spectrum Disorder
"Autoantibodies against folate receptor alpha (FRα) are present in about 70% of the children with a diagnosis of ASD, and a significant number of these children respond to oral folinic acid with overall improvements in speech, language and social interaction."
Treatment of Folate Metabolism Abnormalities in Autism Spectrum Disorder
Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial
"Thus, in this small trial of children with non-syndromic ASD and language impairment, treatment with high-dose folinic acid for 12 weeks resulted in improvement in verbal communication as compared with placebo, particularly in those participants who were positive for FRAAs."
"Thus, in this small trial of children with non-syndromic ASD and language impairment, treatment with high-dose folinic acid for 12 weeks resulted in improvement in verbal communication as compared with placebo, particularly in those participants who were positive for FRAAs."