Table 4.

Studies on the frequency of serum FRAA in ASDs children.

No	Study	Type of Study	Sample Size	Treatment	Age	Study Outcome Parameters	Outcomes
1	Ramaekers V et al., (2007) [31]	Case-control study	n = 25 patients early-onset low-functioning autism vs. 25 controls age match	Folinic acid supplementation dose of 1–3 mg/kg/day3–6 months following	2.8–12.3 years old	Serum and cerebrospinal fluid (CSF) folate level analysis and autoantibodies against FRs assay. Serum FA, vitamin B12, homocysteine, and amino acids concentrationFR1 and FR2 genotyping	Reduced CSF folate levels were observed in 19 of these 23 patients. Oral folinic acid supplementation led to normal CSF 5-MTHF levels and partial or complete clinical recovery after 12 months. Serum FR autoimmunity appears to represent an important factor in the pathogenesis of reduced folate transport to the nervous system among children with early-onset low-functioning autism associated with or without neurological deficits [31].
2	Zhou J et al., (2018) [62]	Cohort study	n = 40 ASDs children vs. 42 gender and age matched TD children	No supplementation	Younger than 14 years old (2–6 years old)	Serum FRAA concentrations	Serum FRAA are more prevalent in children with ASDs than in TD children, suggesting that children with ASDs may have defects in folic acid absorption that play a role in the onset of ASDs [62].
3	Frye RE et al., (2018) [63]	Double-blind randomized placebo-controlled parallel study	n = 48 ASDs children	Folinic acid (2 mg/kg) (maximum 50 mg) per day for 12 weeks	±7 years old	Improvement of verbal communication. Development of language and communication skills	Improvement in verbal communication was significantly greater for the participants on folinic acid compared with participants on placebo with a medium-to-large effect size, particularly in those participants who were positive for FRAAs [63].