Leucovorin and ASD
Cerebral Folate Deficiency (CFD) and Autism
What is it?
Cerebral folate deficiency (CFD) is defined as any neurological syndrome associated with a low cerebrospinal fluid (CSF) concentration of 5-methyltetrahydrofolate (5MTHF) in the presence of normal peripheral folate status (in blood). CFD has a wide clinical presentation, with reported signs and symptoms generally beginning at around 4 months of age with irritability and sleep disturbances. These can be followed by psychomotor retardation, dyskinesia, cerebellar ataxia, and spastic diplegia. Other signs may include deceleration of head growth (small head circumference), visual disturbances, and sensorineural hearing loss. Identification of CFD is achieved by determining 5MTHF concentration in CSF. However, 2 studies have reported a correlation between elevated levels of folate receptor antibodies and folate deficiency in the brain. Clinically, a clinician may empirically treat for presumed CFD if antibodies are positive.
What Causes it?
1. Less frequent causes of CFD are FOLR-1 genetic mutations, mitochondrial disorders and inborn errors affecting folate metabolism.
2. Folate Receptor Alpha Autoantibodies (FRAAs)- (More Common)
The folate receptor alpha (FRα) is essential for folate transportation across the blood-brain barrier. Folate Receptor Antibodies are closely associated with cerebral folate deficiency, a syndrome that commonly presents with autism spectrum disorder (ASD) features.
FR antibodies in either one or both parents increase the risk of an offspring with infantile autism.
One likely mechanism for autoantibody production could be that exposure to soluble FR from milk elicits an immune response.
There are both blocking and binding FRAAs, and both are found to be prevalent in ASD compared to controls.
What are Associated Conditions?
·Blocking FRAAs, not binding, were associated with reduced thyroid function and suggest that thyroid function should be examined in children with ASD who are positive for the blocking FRAAs.
Both binding and blocking folate receptor antibodies were found to be positive in over 60% of children with PANS in one study. Therefore, it may be associated with OCD and anxiety disorders.
What Treatments are Available?
Once identified, CFD can often be treated with oral folinic acid. As a prescription, this can be in the form of leucovorin calcium or compounded folinic acid. There are also over-the-counter folinic acid supplements. Supplementation with folic acid is contraindicated and, if used, may exacerbate the CSF 5MTHF deficiency.
Decreasing the autoantibody titer with a milk-free diet in conjunction with folinic acid therapy may be advocated.
Treatment of this condition with folinic acid, with a dose of 0.5 to 2 mg/kg body weight folinic acid (racemic mixture of the DL-form) or half of this dose for the levo-form of folinic acid a day, for at least a year, has resulted in significant improvement of clinical symptoms and normalization of 5-methyltetrahyrofolate in the CSF.
For individuals with ASD and CFD, meta-analysis also found improvements with d,l-leucovorin in overall ASD symptoms (67%), irritability (58%), ataxia (88%), pyramidal signs (76%), movement disorders (47%), and epilepsy (75%).
WHAT TIPS HELP WHEN starting LEUCOVORIN?
Starting calming supplements before folinic acid may be helpful, such as magnesium, omega-3 fatty acids, sulforaphane, and taurine. This may reduce the side effects of increased hyperactivity and repetitive behaviors sometimes seen during the first several weeks of leucovorin treatment.
Taking active vitamin B12 is also essential when increasing the dose of folinic acid to avoid “folate trapping.”
Lastly, most clinicians start at a small dose of leucovorin and increase slowly over weeks to months until the target dose is achieved.
It is important to note that while leucovorin may improve core functioning, the underlying cause of the folate deficiency, such as an abnormal microbiome, metabolic deficiency, and mitochondrial dysfunction, will still be present and also need ot be addressed for optimal health and recovery.