What is the relationship between Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal (PANDAS) infections, Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), cerebral folate deficiency, and autism?

Relationship Between PANDAS/PANS, Cerebral Folate Deficiency, and Autism Spectrum Disorder

Cerebral folate deficiency (CFD) represents a significant metabolic link between PANDAS/PANS and autism spectrum disorder (ASD), with folate receptor alpha autoantibodies (FRAAs) being a common pathophysiological mechanism that may contribute to neuropsychiatric symptoms across these conditions. 1, 2

Pathophysiological Connections

• PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections) is characterized by sudden-onset obsessive-compulsive symptoms precipitated by streptococcal infection, while PANS (Pediatric Acute-onset Neuropsychiatric Syndrome) represents a broader disorder with similar symptoms triggered by various infections and insults 3

• A high prevalence (63.8%) of folate receptor alpha autoantibodies (FRAAs) has been found in children with PANS/PANDAS, suggesting folate metabolism abnormalities may contribute to their neuropsychiatric symptoms 2

• CFD is recognized as a metabolic condition associated with ASD and represents an important treatable cause of ASD symptoms, particularly in children with neurological deficits 1

• The pooled prevalence of ASD in individuals with CFD is approximately 44%, while the prevalence of CFD in ASD is around 38%, indicating significant overlap between these conditions 4

Autoimmune Mechanisms

• FRAAs interfere with folate transport across the blood-brain barrier, leading to cerebral folate deficiency which can manifest as neuropsychiatric symptoms 5

• Children with ASD are 19 times more likely to be positive for FRAAs compared to typically developing children, with approximately 75% of children with ASD testing positive for these autoantibodies 5, 4

• In PANS/PANDAS patients, binding FRAAs are more common (83.3%) than blocking FRAAs (6.7%), with some patients (10%) having both types 2

• Interestingly, higher binding FRAA titers have been associated with severe tics in PANS/PANDAS patients, suggesting a potential relationship between folate metabolism and movement disorders 2

Clinical Manifestations and Overlap

• CFD should be suspected in children with ASD who present with developmental regression outside of typical ASD speech loss, seizures, or hypotonia/dystonia - symptoms that may also be present in some PANS/PANDAS cases 1

• Both PANDAS/PANS and ASD with CFD can present with obsessive-compulsive behaviors, although the onset pattern differs (sudden in PANDAS/PANS versus more gradual in typical ASD) 3, 5

• Neurological manifestations including movement disorders, ataxia, and pyramidal signs can be present in both CFD-related ASD and PANDAS/PANS 4

Treatment Implications

• Leucovorin (folinic acid) treatment has shown benefits in both ASD patients with CFD and PANS/PANDAS patients who are FRAA-positive 2, 5, 6

• Meta-analysis has found that leucovorin treatment in ASD patients with CFD can improve overall ASD symptoms (67%), irritability (58%), ataxia (88%), pyramidal signs (76%), movement disorders (47%), and epilepsy (75%) 4

• A case report of a FRAA-positive PANS/PANDAS patient showed symptom improvement with leucovorin treatment, suggesting this may be a promising therapeutic approach for this subgroup 2

• Animal studies have demonstrated that exposure to FRAs during gestation can produce communication, learning, and cognitive deficits that can be prevented by folinic acid and dexamethasone treatment 7

Clinical Approach

• For children presenting with symptoms of ASD, PANDAS, or PANS, consider testing for FRAAs, particularly if there are neurological symptoms, developmental regression, or movement disorders 1, 2

• The American College of Medical Genetics considers CFD a "low incidence yet high impact" metabolic disorder in ASD and emphasizes maintaining a high index of suspicion, although they do not recommend routine metabolic testing in all ASD cases 1

• For FRAA-positive patients with ASD or PANS/PANDAS, leucovorin calcium treatment (typically 2 mg/kg/day; maximum 50 mg per day) may be beneficial and is generally well-tolerated 5, 4

• Monitor for potential adverse effects of leucovorin treatment, which are generally mild but may include aggression (9.5%), excitement or agitation (11.7%), headache (4.9%), insomnia (8.5%), and increased tantrums (6.2%) 4