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

Abstract

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)

Treatment of the psychiatric problems associated with fragile X syndrome

“…These findings are compelling because such supplements are easy to recommend, although studies of patients with FXS have not been completed. A randomized controlled trial of alpha tocopherol (10 mg/kg/day) combined with vitamin C (10 mg/kg/day) is currently being carried out in Spain by de Diego-Otero et al [31] lasting 12–24 weeks for boys with FXS aged 6–18 years (ClinicalTrials.gov Identifier: NCT01329770).…”

An Abnormal Nitric Oxide Metabolism Contributes to Brain Oxidative Stress in the Mouse Model for the Fragile X Syndrome, a Possible Role in Intellectual Disability

“…Thus, the cross-talk of iNOS, nNOS, and NF- κ B is suggested in neurological processes. Several neurological and inflammatory disorders have been linked to NF- κ B, therefore restoring the nitric oxide/nitrosative status, and also to REDOX equilibrium on the FXS which addresses a promising approach for further investigation on treatment trials for the disease as has been also suggested in previous recent publications [ 45 , 46 ].…”

Avances en investigación de la discapacidad intelectual de origen genético: tratamientos experimentales en el síndrome X frágil

“…También se ha propuesto una posible disfunción colinérgica en el síndrome X frágil que podría estar implicada en la sintomatología y han descrito que el ensayo con donezepil, un inhibidor de la acetilcolinesterasa, mejora Mejoría tanto en el placebo como en el tratamiento (Paribello et al, 2010;Leigh et al, 2013) NTC 01120626 No hay mejoría en los test de inteligencia y comportamentales (Sahu et al, 2013) Fuente: actualizado del artículo de De Diego Otero et al, 2014. significativamente funciones cognitivas y de comportamiento en pacientes afectados. Ensayos de tratamiento han comprobado la efectividad parcial de distintos compuestos, como el litio, que ha demostrado eficacia para mejorar el comportamiento y el aprendizaje (Ligsay y Hagerman, 2016: 158).…”

“…En modelos animales FMR1-KO se observan exceso de radicales libres dependientes de NADPH-oxidasa que provoca elevación del estrés oxidativo a nivel del sistema nervioso central. Estas alteraciones podrían estar relacionadas con la hiperactividad, el trastorno ansioso y el déficit cognitivo o del lenguaje, pues con la utilización de compuestos reguladores de esta vía fisiopatológica se consigue revertir parcialmente el fenotipo (De Diego Otero et al, 2009: 1011Romero-Zerbo et al, 2009: 224;De Diego Otero et al, 2014).…”