What Is Leucovorin And Can It Help My Child With Autism?
I’ve heard about it- but I don’t quite understand.
Alright, let me try to break this down for us.
Folate (vitamin B9) is necessary for neuron (i.e., brain cell) differentiation and proliferation in the brain. Normally, folate is converted in its active form (5-methyltetrahydrofolate) via MTHFR (enzyme/gene) and then transported to the brain via FRalpha (primary receptor/carrier); however, when there is a mutation in MTHFR, deficiencies can lead to reduced active folate, even when folate is present in the blood. Additionally, the MTHFR mutation can cause difficulty converting homocysteine (ending up with too much) to the amino acid methionine (ending up with not enough), which affects cardiovascular function. The the active folate (5-methyltetrahydrofolate) cannot be converted back to its precursor, leading to low levels of methionine and too much homocysteine, which can affect production of DNA and RNA, especially in the womb. The two most common forms of MTHFR mutations are C667T and A1298C. MTHFR mutations seem to be inherited in some cases. Interestingly, most mutations in white, hispanic, and certain middle eastern populations.
FRalpha can be blocked by antibodies or mitochondrial dysfunction. Impaired folate transport is associated with mitochondrial dysfunction (reduced ATP, oxidative stress). Active folate is transported across the choroid plexus via FRalpha (primary carrier) and endocytosis (can be transported by RFC when FRalpha antibodies interfere with transport). Correlation between lower (5-methyltetrahydrofolate) and higher FRalpha antibodies, depending on type of antibody, can be more or less inflammation, thyroid dysfunction, oxidative stress, and b12 malabsorption. There is also a strong relationship between fragile X, Rett’s syndrome, ASD and cerebral folate deficiency (lower amounts of folate in the CSF of the brain) as well as FRalpha antibodies affecting transportation of folate across the blood-brain barrier (bringing folate from the bloodstream to the brain).
MTHFR mutations tied to gastritis and other gastric issues. RFC requires high concentrations of active folate and PCFT transports it in the gut when FRalpha is disrupted. Reduced folate carrier (RFC) is responsible for absorbing folate in the intestines and alterations in RFC linked to ASD (decreased microbial diversity, lower levels of good bacteria often obtained with breastfeeding). B12 malabsorption may be caused by gastrointestinal differences/disorders as well as lack of meat/dairy intake. The exposure to the milk FR antigen (especially in cows) in the gut may contribute to FRalpha antibodies, some recommend animal free milk. Most implications for those with “low-functioning autism” because they have highest rates of FRalpha antibodies, can be exacerbated by picking eating or limited diet because of medical conditions.
When you get a test for MTHFR mutation, they test for homocysteine levels in the blood, if the test is positive it will show which mutation of the gene and partial or full mutation. FRAT (folate receptor antibody test) out of SUNY downstate in NYC. Folinic acid/calcium folinate/leucovorin is able to cross the blood-brain barrier via reduced folate carrier (RFC; secondary carrier), which reportedly has increased verbal communication and reduced repetitive behavioral patterns (measured using ADOS-2 and CARS-2), most significant improvement in those with FRalpha antibodies, significant variability in responses to folinic acid (0% through 88% depending on study and population). Folate supplementation has also been shown to improve mitochondrial function.
Leucovorin (folinic acid) rapidly accumulates in the mitochondria and may improve mitochondrial disease; however, inconsistent evidence of benefit and concern about over-marking of folate-based supplements. Researchers and clinicians are still unsure what may be the optimal folinic acid dose and can be dependent on the microbiome of the individual. Current recommended dosage tends to range from .05 mg once a day to 9mg per day, dose may depend on the amount of fortified food in a specific country (many foods are fortified with inactive folic acid). Treatment with folinic acid may normalize (5-methyltetrahydrofolate) levels via RFC .
High homocysteine can also be the result of low B12, the combination of low B12 and mutations in MTHFR can produce significant negative effects. Thus, Those with this mutation might need additional folate, even if their bloods tests are not indicating so. When folate and B12 are not adequate, cellular metabolism and replication are interrupted. Good options for b12 supplementation include: hydroxocobalamin, adenosylcobalamin, and methylcobalamin (best for children with ASD). Best effects when methylcobalamin was combined with folinic acid (increases glutathione, an antioxidant) but small sample sizes and limited generalization causes some hesitancy to prescribe without further research. It appears there have been minimal adverse effects, as some effects were reported but hard to identify if normal experiences for children with ASD (insomnia, aggression, irritability, reflux, GI distress) and expected 1-3 years for maximal clinical improvement.