Abstract: We included five trials, which were published between 1986 and 1992. Overall, they included 67 patients, all male, with ages ranging from one to 54 years. Intellectual disability in participants varied from borderline to severe and some studies included patients with an additional diagnosis of autism or autistic behaviour. Four of the studies were placebo-controlled cross-over trials and one study was a parallel design. The duration of follow-up ranged from two months to 12 months and the period on folic acid or placebo ranged from two to eight months. Doses of folic acid ranged from 10 mg to 250 mg per day, 10 mg per day being the most common. Most of the younger patients involved were also taking part in special education programmes (usually involving language and occupational therapy). We were not able to perform meta-analysis to combine results but none of the individual studies found evidence of clinical benefit with the use of folic acid medication in fragile X syndrome patients on any of the areas of interest, either psychological and learning capabilities or behaviour and social performance, as measured with standardised tools. Separate analysis of evidence for patients of different age groups, i.e. prepubertal children and postpubertal young people, found some statistically significant results, but did not show clear evidence of benefit for either group. Adverse effects of folic acid treatment were rare, not serious and transient. Studies were generally poorly reported and we classified only one study as being at low risk of bias. The quality of available evidence is low and not suitable for drawing conclusions about the effect of folic acid on fragile X syndrome patients. It consists of few studies with small samples of patients, all of them male, with little statistical power to detect anything other than huge effects.

Plain-language summary: This review asks whether folic acid helps improve symptoms in people with fragile X syndrome and whether it has any side effects. We found five randomised controlled trials, all of which were published between 1986 and 1992. These studies included 69 people, all male. One of the studies compared a folic acid group with a control group; the other four used a cross-over design (i.e. participants received first one treatment and then the other). The quality of reporting of the trials was generally poor, particularly the methods used, which made it difficult to assess the risk of bias in the studies. The results of the few published studies did not find significant differences in the effects of folic acid or placebo on psychological or learning capabilities, behaviour or social performance, as measured by standardised tools. There is therefore no evidence to support the recommendation of supplementing dietary intake with folic acid medication for people with fragile X syndrome. However, due to the number and quality of the studies, it is not possible to conclude with any certainty that folic acid does not help. Given that intellectual, behavioural, emotional and/or learning performance in people with fragile X syndrome are strongly influenced by different social factors, future studies should also pay attention to the evaluation of non-pharmacological interventions, such as modifications in the home environment, tailored behavioural interventions and classroom environments, or language and occupational therapy.