Research Article: Effect of Leucovorin (Folinic Acid) on the Developmental Quotient of Children with Down’s Syndrome (Trisomy 21) and Influence of Thyroid Status

Date Published: January 11, 2010

Publisher: Public Library of Science

Author(s): Henri Blehaut, Clotilde Mircher, Aimé Ravel, Martine Conte, Veronique de Portzamparc, Gwendael Poret, Françoise Huon de Kermadec, Marie-Odile Rethore, Franck G. Sturtz, Joel Gagnier.

Abstract: Seven genes involved in folate metabolism are located on chromosome 21. Previous studies have shown that folate deficiency may contribute to mental retardation in Down’s syndrome (DS).

Partial Text: The symptoms of Down’s syndrome (DS) result from a trisomy of chromosome 21 [1], [2]. A gene dosage effect [3], [4], resulting from the presence of three chromosomes 21, rather than the usual two, is responsible for symptoms and mild to severe mental retardation [5], [6]. There is currently no effective way to reduce this gene dosage effect. However, some of the metabolic disturbances have been studied and could be targeted pharmacologically [2], [7]. The correction of these dysfunctions by treating DS patients with active molecules may improve the mental condition and quality of life of these patients.

Folates, including folic acid, in particular have been administered to DS patients based on a preliminary study conducted some time ago and not meeting current protocol standards [29], [30]. Assessments of the efficacy and safety of this treatment were required. Our intention-to-treat analysis showed no positive effect of leucovorin. However, the per-protocol analysis of a restricted group examined by the same psychologist at the beginning and end of trial revealed a positive effect of leucovorin. In the per-protocol analysis, the DA of DS children was significantly higher on leucovorin treatment than on placebo (53.1% vs. 44.4%, p = 0.031) (Figure 3). The per-protocol analysis also identified several cofactors, including thyroid treatment. DS patients receiving leucovorin and thyroxin treatment had a DA of 59.7%, whereas those receiving thyroxin only had a DA of 40.3% (p = 0.041).



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