Folic acid treatment of fragile X males: a further study. Oral folic acid versus placebo in the treatment of males with the fragile X syndrome. Folic acid treatment in males and females with fragile-(X)-syndrome. High dose folic acid treatment of fragile (X) males. Double-blind, placebo-controlled crossover study of folinic acid (Leucovorin for the treatment of fragile X syndrome.
Investigations of the effect of high dose folic acid treatment of fragile X syndrome in males has produced mixed results. However, no study had examined the possible drug effects of folic acid on non-fragile X control males. Therefore, we examined the effect of folic acid on fragile X males using non-fragile X control males. Subjects were assigned randomly to an ABA or BAB design. Duration of either folic acid or placebo condition was 4 months. Folic acid or placebo was given in a double-blind fashion. At the end of each condition, the subjects' behavior was assessed. At the end of the study, parents were asked to complete a questionnaire. Using parents' responses, we examined 22 items on the Autistic Descriptors Checklist and two subscales from the Vineland Adaptive Behavior Scale which corresponded to areas of behavior parents' noted to have shown improvement. We did not find significant differences between fragile X males and control males, within subjects, nor across folic acid and placebo conditions. Thus, our follow-up study confirms and extends our original findings, as well as those of other researchers: namely, that no dramatic changes in behavior result from high dose folic acid. Moreover, subtle improvements observed in earlier investigations were not confirmed. A double-blind, crossover study of a 10 mg folic acid per day (vs. placebo) treatment was carried out in 25 fra(X) males (ages 1-31 years). Each treatment period lasted 6 months. Before, during and after the study, the patients were assessed blindly with psychological, language and behavioral evaluations, and parent or caretaker reports were collected. Standardized testing did not show statistically significant changes in the group as a whole; psychological testing demonstrated a statistically significant improvement on folic acid in the prepubertal males. After uncoding, caretaker or parent reports also demonstrated behavioral improvements in the prepubertal males while being treated with folic acid. Ten males with the fragile X (fra(X] syndrome were treated with folic acid (10 mg/day) for 4 months in a double-blind design study. To eight heterozygotes with mental impairment and fra(X), folic acid was given for 4 months (10 mg/day) in an effort to study possible beneficial effects of folic acid. Psychological and cytogenetic testing were carried out during the trial. There was no improvement in concentration, fine motor co-ordination, or comprehension in the adult male and female patients of the study. One patient showed improvement under a control medications. In the females, improvement was seen only in the youngest patient, a 5-year-old girl. Folate treatment does not seem to be effective in fra(X) adults, but may have some effect in children of both sexes with the disorder. Cytogenetic studies using peripheral lymphocytes showed that the fra(X) frequency decreased significantly (t = 0.00856; 1% level) only in cells cultured in a folic acid-free medium but not in cells cultured in a medium with added antifolate (methotrexate). This shows a "contamination effect" of folate-free culture medium after oral folic acid treatment of these patients. The decrease of fra(X) involves primarily the early-replicating X when culturing with folic acid-free medium. A synergistic suppression effect of "external folate" and BrdU is the most likely explanation of this phenomenon. We conducted an experimental trial of high-dose folic acid given to five males, ages 8 to 26 years, with the fra(X) syndrome. In this double blind study, each subject received 250 mg per day of folic acid for 3 months, followed by placebo for 3 months, and folic acid again for an additional three months. Based on IQ tests, behavior ratings, the Autistic Descriptors Checklist, and parental ratings, there was little evidence to suggest any positive effects seen during the administration of high-dose folic acid. Therefore, this study has provided little support for a hypothesis of benefit of high-dose folic acid in the treatment of the fra(X) syndrome. We conducted a randomized, double-blind, placebo-controlled crossover study of folinic acid therapy (dl-Leucovorin, 15 mg/day) or placebo for males with Fragile X (fra(x)) syndrome. Twenty-one patients were enrolled in the study. The treatment periods were 3 months in length. Patients were followed with chemistry panels and complete blood counts. No differences between placebo and treatment phases were noted in any laboratory parameter. Instruments to measure functioning were the Vineland Adaptive Behavioral Scales, Peabody Picture Vocabulary Test-Revised, Conners Parent and Teaching Rating Scales, the ADD-H: Comprehensive Teacher's Rating Scales (ACTeRS), and a questionnaire designed by the investigators. At the crossover point, 2 parents requested to withdraw from the study because they felt their children had made dramatic gains during the first half of the study and had lost those gains after the crossover point. Both parents had accurately predicted that their sons were receiving folinic acid during the first half of the study. However, no statistically significant differences could be demonstrated between the treatment and placebo phases of the study with any instrument when the results were averaged over the entire cohort. After the conclusion of the study, approximately one-half of the parents believed that their children had benefitted from the folinic acid therapy and elected to continue treatment. Thus far, no significant side effects have been noted from long-term folinic acid therapy so we are offering all Fragile X patients a 3-month trial of medication.
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.