What is the relationship between cerebral folate deficiency and autism spectrum disorder (ASD)?

Cerebral Folate Deficiency and Autism Spectrum Disorder

Cerebral folate deficiency (CFD) is recognized as a metabolic condition associated with autism spectrum disorder (ASD) and represents an important treatable cause of ASD symptoms, particularly in children with neurological deficits. 1

Definition and Mechanism

• CFD is characterized by reduced folate transport to the central nervous system despite normal serum folate levels, resulting in low cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF) concentrations 2
• The primary mechanism involves folate receptor alpha autoantibodies (FRAs) that block folate binding sites on choroid epithelial cells, preventing adequate folate transport across the blood-brain barrier 2, 3

Prevalence in ASD

• FRAs have been identified in 58-76% of children with ASD, making it a significant metabolic abnormality in this population 4
• In one study, 75.3% of children with ASD tested positive for FRAs, suggesting a high prevalence of this metabolic abnormality 3
• CFD is listed among recently described metabolic conditions associated with an ASD phenotype in clinical genetics guidelines 1

Clinical Presentation and Diagnosis

• CFD should be suspected in children with ASD who present with:
  • Neurological deficits beyond typical ASD symptoms 2
  • Early-onset low-functioning autism 2
  • Developmental regression outside of typical ASD speech loss at 18-24 months 1
  • Seizures 1
  • Hypotonia/dystonia 1
• Diagnosis involves:
  • Measuring serum folate levels (typically normal in CFD) 2
  • Testing for serum folate receptor autoantibodies 3
  • When clinically indicated, measuring CSF 5-methyltetrahydrofolate levels (reduced in CFD) 2

Treatment Approach

• Oral folinic acid (leucovorin calcium) supplementation is the primary treatment for CFD in ASD 2, 4
• Folinic acid can bypass the folate receptor alpha blockage by using an alternate pathway (the reduced folate carrier) 4
• Recommended dosage is 2 mg/kg/day (maximum 50 mg/day) of folinic acid 5
• Treatment duration of at least 12 months may be needed to see significant clinical improvement 2

Treatment Efficacy

• Recent randomized controlled trial (2024) demonstrated that oral folinic acid supplementation significantly improved ASD symptoms compared to placebo 5
• The improvement in Childhood Autism Rating Scale (CARS) scores was significantly higher in the folinic acid group (3.6 ± 0.8) compared to placebo (2.4 ± 0.7) 5
• Children with high titers of folate receptor autoantibodies showed more pronounced benefits from folinic acid treatment 5
• Previous studies have shown improvements in:
  • Verbal communication 3
  • Receptive and expressive language 3
  • Attention 3
  • Stereotypical behavior 3
  • Approximately one-third of treated children demonstrated moderate to much improvement 3

Metabolic Pathways and Mechanisms

• CFD may interfere with several metabolic pathways in ASD:
  • Serine and lysine metabolism 6
  • Purine metabolism and inosine monophosphate production 6
• These metabolic disturbances may contribute to the neurological and behavioral symptoms seen in ASD 6

Clinical Considerations and Pitfalls

• CFD is considered a "low incidence yet high impact" metabolic disorder in ASD 1
• The American College of Medical Genetics does not recommend routine metabolic testing in all ASD cases but emphasizes maintaining a high index of suspicion for metabolic disorders like CFD 1
• Early detection of FRAs may be crucial for prevention and therapeutic intervention 2
• Treatment with folinic acid appears safe with low incidence of adverse effects 5, 3
• Failure to consider CFD in ASD evaluation may miss an important treatable cause of symptoms, especially in children with neurological abnormalities 2

Monitoring and Follow-up

• Regular monitoring of clinical response is recommended during folinic acid treatment 5
• Assessment tools like CARS and Child Behavior Checklist (CBCL) can be used to measure treatment response 5
• Long-term follow-up is important as some improvements may take months to become apparent 2