People with fragile X syndrome (or FXS) have intellectual limitations that can range from mild to severe. Fragile X syndrome is considered the most common form of inherited intellectual disability and it has been estimated that it affects approximately 1 in 4000 males and 1 in 8000 females. Folate is particularly important during the early development of the brain and in later life is involved in methylation processes that are essential for the maintenance of normal brain function. It was observed that cells from patients with fragile X syndrome cultured in solutions deficient in folic acid revealed a fragile site at the X chromosome; consequently it was thought that individuals with fragile X syndrome had low folate levels in their bodies, which may be due to insufficient dietary intake, inefficient absorption or impaired metabolic utilisation. It was argued that supplementing their dietary intake might help improve the adverse developmental and behavioural effects of the condition.
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.