AbstractDown syndrome (DS) is the most common chromosomal disorder, and it is caused by trisomy of chromosome 21 (Hsa21). Subjects with DS can show a large heterogeneity of phenotypes and congenital defects and the most constant clinical features present are typical facies and intellectual disability (ID). Jérôme Lejeune was the first who hypothesized that DS could be a metabolic disease and he noted an alteration of the folate pathway (part of the one-carbon cycle) in trisomic cell lines and subjects with DS. Comparing DS with other metabolic diseases characterized by ID and altered folate pathway he hypothesized a possible correlation among them. Recently, a nuclear magnetic resonance (NMR) analysis of the detectable metabolic part in plasma and urine samples was performed, comparing a group of subjects with DS and a group of control subjects. The data showed a clear difference in the concentration of some metabolites (all involved in central metabolic processes) for the DS group, which was sometimes in agreement with gene dosage expected proportions (3:2). The aim of this work is to underline metabolic differences between subjects with DS and control subjects in order to better understand the dysregulation of the folate pathway in DS. For the first time, we performed enzyme-linked immunosorbent assays (ELISAs) to identify the concentration of 4 different intermediates of the one-carbon cycle, namely tetrahydrofolate (THF), 5-methyl-THF, 5-formyl-THF and S-adenosyl-homocysteine (SAH) in plasma samples obtained from 153 subjects with DS and 54 euploid subjects. Results highlight specific alterations of some folate pathway related metabolites. The relevance of these results for the biology of intelligence and its impairment in trisomy 21 is discussed leading to the proposal of 5-methyl-THF as the best candidate for a clinical trial aimed at restoring the dysregulation of folate pathway in trisomy 21 and improving cognitive skills of subjects with DS.
Folate pathway metabolites are altered in the plasma of subjects with Down syndrome: relation to chromosomal dosage
