Frequency of Cerebral Folate Deficiency in Autism Spectrum Disorder
Cerebral folate deficiency (CFD) occurs in approximately 38% of individuals with autism spectrum disorder, with folate receptor alpha autoantibodies (FRAAs) present in 71-75% of children with ASD. 1, 2
Prevalence Data
CFD in ASD Population
- A systematic review and meta-analysis found that 38% of individuals with ASD have cerebral folate deficiency, though this estimate shows significant variation across studies due to methodological heterogeneity 1
- The pooled prevalence of ASD among individuals diagnosed with CFD is 44%, indicating a strong bidirectional association 1
- In children with low-functioning autism and neurological deficits, CFD prevalence approaches 92% (23 of 25 patients in one study had low CSF 5-methyltetrahydrofolate despite normal serum folate) 3
Folate Receptor Alpha Autoantibodies
- FRAAs are detected in 71-75% of children with ASD, with remarkable consistency across multiple independent studies 1, 2
- Children with ASD are 19-fold more likely to be positive for FRAAs compared to typically developing children without an ASD sibling 1
- FRAAs account for 83% of CFD cases in ASD, representing the primary mechanism of cerebral folate deficiency in this population 1
Clinical Context and Diagnostic Considerations
When to Suspect CFD
- The American College of Medical Genetics identifies CFD as a "low incidence yet high impact" metabolic disorder in ASD and recommends maintaining high clinical suspicion, particularly in children presenting with developmental regression (beyond typical ASD speech loss), seizures, or hypotonia/dystonia 4
- CFD should be strongly considered in low-functioning autism with neurological abnormalities, where prevalence is substantially higher than in the general ASD population 3
Pathophysiology
- FRAAs interfere with folate receptor alpha function at the blood-brain barrier, blocking folate transport into the central nervous system 2, 3
- Higher FRAA serum titers correlate significantly and inversely with lower cerebrospinal fluid 5-methyltetrahydrofolate concentrations 2, 1
- Mitochondrial dysfunction contributes to CFD in 43% of cases, often coexisting with FRAA-mediated mechanisms 1
Important Clinical Pitfalls
Testing Limitations
- Normal serum folate levels do not exclude CFD, as the deficiency is cerebral (CNS-specific) rather than systemic—23 of 25 children in one study had low CSF folate despite normal serum levels 3
- The American College of Medical Genetics does not recommend routine metabolic testing for all ASD cases, but targeted testing based on clinical features is appropriate 4
Variable Presentation
- CFD prevalence varies significantly based on ASD subtype: highest in low-functioning autism with neurological deficits, lower in high-functioning ASD without neurological features 3, 1
- The heterogeneity in reported prevalence (ranging from individual studies) reflects differences in patient selection, diagnostic criteria, and testing methodologies 1