Folic acid therapy in the fragile X syndrome

Brown, W. Ted; Jenkins, EdmundC.; Friedman, Erwin; Brooks, Judith; Cohen, Ira L.; Duncan, Charlotte J.; Hill, A. Lewis; Malik, Mazhar N.; Morris, V.; Wolf, E.; Wisniewski, K. E.; French, Joseph H.; Opitz, John M.

doi:10.1002/ajmg.1320170121

Cited by 41 publications

(15 citation statements)

References 9 publications

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“…Moreover, patients with inherited defects affecting t h e folate pathways, such as methylenetetrahydrofolate reductase deficiency, a r e often mentally retarded. Treatment with folic acid or folic acid derivatives in fragile X syndrome has been a t t e m p t e d by several groups (Lejeune, 1981;Harpey, 1982;Brown et al, 1983), and clinical studies of its efficacy a r e underway in several additional centers.…”

Section: Discussionmentioning

confidence: 97%

Folate metabolism in cells from fragile X syndrome patients and carriers

1984

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The in vitro folate sensitivity of the fragile site at Xq27 and the claims of a beneficial response of patients given folic acid prompted us to examine the folate metabolism in cells cultured from fragile X syndrome patients and carriers. Using Epstein-Barr virus we established permanent lymphoblastoid lines from 4 fragile X syndrome males and 3 carriers from 7 families. All these lines expressed the fragile site when 0.1 microM 5-fluorodeoxyuridine (FUdR) was added to the cultures 24 hr prior to harvest; thus, the lines seemed suitable for seeking an intrinsic defect. Fragile X syndrome patient and carrier lines and normal control cell lines did not differ in regard to folate requirement for growth, the ability to use homocysteine in place of methionine, the ability to utilize reduced folates as the sole folate source, or methotrexate sensitivity. These results suggest that no intrinsic defect in folate metabolism is present in fragile X syndrome cells.

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Section: Discussionmentioning

confidence: 97%

Folate metabolism in cells from fragile X syndrome patients and carriers

1984

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“…In subsequent controlled and uncontrolled trials, some investigators have found little or no evidence of behavioral or performance improvement (Brown et al 1986, Fisch et al 1988, Froster-Iskenius étal. 1986, Madison et al 1986, Rosenblatt et al 1985, Webb et al 1990); limited evidence of improvement has been reported by others (Brown et al 1984, Carpenter et al 1983, Gillberg et al 1985, Gustavson et al 1985, Hagerman et al 1986). Gustavson et al (1985) reported that one adult manifested increased aggressiveness and hyperactivity when treated with folie acid (2 mg/kg) in an open trial, and that the behaviors returned to pretreatment levels one month after the folate treatment was discontinued.…”

Section: Folate Supplementation In Fragile X Syndromementioning

confidence: 88%

Megavitamin Treatment of Mental Retardation in Children: A Review of Effects on Behavior and Cognition

Kozlowski¹

1992

Journal of Child and Adolescent Psychopharmacology

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Many forms of vitamin supplementation have been proposed for the treatment of behavioral and cognitive disorders in children with mental retardation. Except for nutrient deficiencies and selected inborn errors of metabolism, the efficacy of these treatments has not been established. Therapeutic supplementation with vitamin B(6) in Down syndrome and folie acid in fragile X syndrome was attempted following the identification of apparent biochemical aberrations involving the nutrients. Double-blind controlled trials have revealed no evidence that B(6) treatment was effective in Down syndrome. Very limited evidence, only among prepubertal subjects, suggested that behaviors improved with folie acid treatment in fragile X syndrome. There is less clarity of the scientific rationales for various combinations of vitamins (or vitamins and minerals) that have been promoted according to the concept of orthomolecular medicine. Well-designed controlled studies, with data presented in conformity with generally accepted scientific standards, have not supported the efficacy of megadose supplementation with 1) multivitamins in cognitive disabilities or attention deficit disorders, or 2) multivitamins and minerals in Down syndrome or other forms of mental retardation. Insufficient data are available to support claims made for vitamin B(6) and magnesium supplementation in autism. Research in the larger field of nutrient-behavior research has reinforced the need for studies to be more rigorously designed and to draw on the expertise of multiple disciplines. Evidence of toxic effects of nutrients continues to accrue, reinforcing the fact that megadoses should not be used indiscriminately or without physician monitoring. For children with mental retardation generally, assuring that established nutritional needs are met warrants primary consideration.

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“…The first vitamin used for the treatment of the FXS was folic acid. Several publications describe the efficacy and safety of treatment with folic acid in people with FXS [70–73]. …”

Section: Discussionmentioning

confidence: 99%

A combination of ascorbic acid and α-tocopherol to test the effectiveness and safety in the fragile X syndrome: study protocol for a phase II, randomized, placebo-controlled trial

Diego-Otero

Medina

Quintero-Navarro

et al. 2014

Trials

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BackgroundFragile X syndrome (FXS) is an inherited neurodevelopmental condition characterised by behavioural, learning disabilities, phisical and neurological symptoms. In addition, an important degree of comorbidity with autism is also present. Considered a rare disorder affecting both genders, it first becomes apparent during childhood with displays of language delay and behavioural symptoms.Main aim: To show whether the combination of 10 mg/kg/day of ascorbic acid (vitamin C) and 10 mg/kg/day of α-tocopherol (vitamin E) reduces FXS symptoms among male patients ages 6 to 18 years compared to placebo treatment, as measured on the standardized rating scales at baseline, and after 12 and 24 weeks of treatment.Secondary aims: To assess the safety of the treatment. To describe behavioural and cognitive changes revealed by the Developmental Behaviour Checklist Short Form (DBC-P24) and the Wechsler Intelligence Scale for Children–Revised. To describe metabolic changes revealed by blood analysis. To measure treatment impact at home and in an academic environment.Methods/DesignA phase II randomized, double-blind pilot clinical trial. Scope: male children and adolescents diagnosed with FXS, in accordance with a standardized molecular biology test, who met all the inclusion criteria and none of the exclusion criteria. Instrumentation: clinical data, blood analysis, Wechsler Intelligence Scale for Children–Revised, Conners parent and teacher rating scale scores and the DBC-P24 results will be obtained at the baseline (t0). Follow up examinations will take place at 12 weeks (t1) and 24 weeks (t2) of treatment.DiscussionA limited number of clinical trials have been carried out on children with FXS, but more are necessary as current treatment possibilities are insufficient and often provoke side effects. In the present study, we sought to overcome possible methodological problems by conducting a phase II pilot study in order to calculate the relevant statistical parameters and determine the safety of the proposed treatment. The results will provide evidence to improve hyperactivity control and reduce behavioural and learning problems using ascorbic acid (vitamin C) and α-tocopherol (vitamin E). The study protocol was approved by the Regional Government Committee for Clinical Trials in Andalusia and the Spanish agency for drugs and health products.Trial registrationClinicalTrials.gov Identifier: NCT01329770 (29 March 2011)

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Folic acid therapy in the fragile X syndrome

Cited by 41 publications

References 9 publications

Folate metabolism in cells from fragile X syndrome patients and carriers

Folate metabolism in cells from fragile X syndrome patients and carriers

Megavitamin Treatment of Mental Retardation in Children: A Review of Effects on Behavior and Cognition

A combination of ascorbic acid and α-tocopherol to test the effectiveness and safety in the fragile X syndrome: study protocol for a phase II, randomized, placebo-controlled trial

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