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Cerebral Folate Deficiency in Children

Autism spectrum disorders (ASDs)—which include autistic disorder, Asperger’s Syndrome, and pervasive developmental disorder-not otherwise specified (PDD-NOS)—are defined by behavioral observations and characterized by impairments in communication and social interaction, along with restrictive and repetitive behaviors.

The association of ASD with a number of physiological abnormalities, including immune dysfunction and inflammation, mitochondrial dysfunction, oxidative stress and environmental toxicant exposures, has gained increased attention.  An example of a physiological abnormality that might cause ASD is mitochondrial disease.

Recently we reviewed the evidence for children with ASD having abnormal functioning of mitochondria [5].

The mitochondrion is an essential part of each cell, and is responsible for producing energy for the cellular metabolic processes. When this energy engine of the cell does not work correctly, many organs in the body—especially those that require a high amount of energy (like the brain, gastrointestinal tract, and immune system)—may not function correctly, resulting in symptoms seen in mitochondrial disorders.


CFD is characterized by below normal levels of the active metabolite of folate known as 5-methyltetrahydrofolate (5MTHF) in the central nervous system (CNS), despite normal levels of folate metabolites in the blood.

5MTHF is normally transported into the CNS through one of two pathways. The CNS folate receptor protein alpha (FRA) transports 5MTHF directly into the CNS in a process that is dependent on mitochondrial function (ATP production). 5MTHF is also transported into the CNS through the reduced folate carrier (RFC). Impaired transport of 5MTHF into the CNS can lead to reduced levels of 5MTHF in the brain and cause CFD.

One study reported a child with ASD who also had mitochondrial disease and CFD. In most of these cases, autoantibodies to FRA were not found, suggesting that it was the lack of ATP availability secondary to mitochondrial dysfunction that resulted in the impaired transportation of 5-MTHF into the CNS.


To date, three studies have reported a connection between CFD and Rett syndrome [25-27], and seven studies have reported an association with ASD [10, 13, 24, 28-31].


Because FRA autoantibodies appear to be highly prevalent in children with ASD, we recommend that FRA autoantibody testing should be considered in all patients with ASD. Early identification and treatment is paramount, as younger children generally respond more robustly than older children, with “cure” reported in some children.

The test we run is ONLY $200.00 and done via blood testing, results in 6-12 days.


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Dr. Amber Brooks FNP, CACCP, BCIP,

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