Effect of leucovorin (folinic acid) on the developmental quotient of children with Down's syndrome (trisomy 21) and influence of thyroid status

Abstract

Background: 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).

Methodology: We investigated the effect of oral folate supplementation (daily dose of 1.0+/-0.3 mg/kg) on cognitive functions in DS children, aged from 3 to 30 months. They received 1 mg/kg leucovorin or placebo daily, for 12 months, in a single-centre, randomised, double-blind study. Folinic acid (leucovorin, LV) was preferred to folic acid as its bioavailability is higher. The developmental age (DA) of the patients was assessed on the Brunet-Lezine scale, from baseline to the end of treatment.

Results: The intent-to-treat analysis (113 patients) did not show a positive effect of leucovorin treatment. However, it identified important factors influencing treatment effect, such as age, sex, and concomitant treatments, including thyroid treatment in particular. A per protocol analysis was carried out on patients evaluated by the same examiner at the beginning and end of the treatment period. This analysis of 87 patients (43 LV-treated vs. 44 patients on placebo) revealed a positive effect of leucovorin on developmental age (DA). DA was 53.1% the normal value with leucovorin and only 44.1% with placebo (p<0.05). This positive effect of leucovorin was particularly strong in patients receiving concomitant thyroxin treatment (59.5% vs. 41.8%, p<0.05). No adverse event related to leucovorin was observed.

Conclusion: These results suggest that leucovorin improves the psychomotor development of children with Down's syndrome, at least in some subgroups of the DS population, particularly those on thyroxin treatment.

Trial registration: ClinicalTrials.gov, NCT00294593.

Figure 1. Folate metabolic pathways and methylation cycle.

Gene names are shown in italics and according to the HGNC approved names. Genes in boxes are located on chromosome 21. Abbreviations used are: DHF: dihrofolate; THF: tetrahydrofolate; 5,10-CH2 THF: N5,N10-methylene THF; 5,10-CH THF: N5,N10-methenyl THF; 5-CH3 THF: N5-methyl THF; GAR: glycinamide ribonucleotide; FGAR: formyl-GAR; GSH: reduced form of glutathione; GSSG: oxidised form of glutathione; ROS: reactive oxygen species.

Figure 2. Flow chart of participants in the clinical trial.

N = number of patients. Not eligible: patients with no efficacy and safety data after V₁. Early premature V₁ discontinuation: patients with no efficacy and safety data after V₁. Late premature V₂ discontinuation: patients not evaluated after V₂ (6 months). Per protocol analysis: patients assessed by the same psychometric examiner during at least 2 visits. Major protocol violation: patients not assessed by the same psychometric examiner at 2 consecutive visits. Completed: patients without protocol violation and with 12 months of efficacy and safety data.

Figure 3. Effect of leucovorin treatment on change in global developmental age (DA).

DA was measured for the patients receiving placebo or LV, in the per protocol population (87 patients) and as a function of a thyroxin treatment (N = number of patients, % change in developmental age with respect to a non-DS age-matched population).