Homocysteine and related genetic polymorphisms in Down's syndrome IQ

Abstract

Objective: Down's syndrome (DS) is the most frequent genetic cause of Alzheimer-type dementia. Its metabolic phenotype involves an increased trans-sulphuration of homocysteine. The aim of the present study was to investigate the influence of homocysteinaemia (t-Hcys), folate, vitamin B 12 , and related polymorphisms on intelligence quotient (IQ) in DS. Methods: The IQ of 131 patients with trisomy 21 from a specialist centre in Sicily was determined and classified according to DMS-IV. The effects of age, folate, vitamin B 12 , t-Hcys, and genetic polymorphisms on IQ were evaluated separately and in combination using regression analyses. Results: IQ was significantly lower in DS patients with t-Hcys .7.5 mmol/l (median) and in those who were carriers of methylenetetrahydrofolate reductase (MTHFR) 677 T allele and of methylenetetrahydrofolate reductase 677 T and transcobalamin 776 G combined alleles (p = 0.0013, p = 0.0165, and p = 0.0074, respectively). The IQ correlated significantly with t-Hcys and folate in single and multiple regression analyses, independently of age. In addition, t-Hcys .9.6 mmol/l (upper quartile) was found to be associated with low IQ (,40, median of study group) with an odds ratio of 2.61 (p = 0.0203). The odds ratio was increased by threefold in carriers of MTHFR 677 T allele. The MTHFR 677 T allele/ transcobalamin 776 G allele combination was associated with the risk of DS patients to have an IQ less that the median with an odds ratio of 2.68 (95% CI 1.26 to 5.70, p = 0.0104). Conclusion: This study found evidence of an association between t-Hcys and MTHFR 677 T and transcobalamin 776 G alleles with IQ in patients with DS. The association may be related to a defective remethylation of homocysteine, affecting IQ.

The MTR A2756G polymorphism is associated with an increase of plasma homocysteine concentration in Brazilian individuals with Down syndrome

“…Several studies failed to confirm reduced Hcy concentrations in DS patients (11,25,26). Furthermore, in a study with elderly DS patients, Licastro et al (27) observed that their plasma Hcy was higher and their folate lower than in controls; blood concentrations of vitamin B12 were also lower in DS patients than in controls.…”

“…Elevated Hcy concentrations may be harmful since they have been associated with elevated risk of cardiovascular disease, neurodegenerative disorders, psychiatric disorders, and decline of cognitive performance (13,25,38). Guéant et al (25) observed that a lower intelligence quotient was associated with higher Hcy concentrations in DS patients, and this association was also observed in the presence of the MTHFR 677T allele alone and in combination with the transcobalamin 776G polymorphic allele.…”

Infant C677T MTHFR polymorphism and severe mental retardation

“…One gene variant in particular, the C677T/C677T genotype, of the 5,10 methylenetetrahydrofolate reductase (MTHFR) gene, has been associated with Down syndrome as well as being a risk factor for other complex congenital anomalies (Botto and Yang, 2000). Moreover, a recent study reported an association between MTHFR and intelligence quotient in patients with Down syndrome (Gueant et al, 2005). The variant form of MTHFR codes for a thermolabile enzyme with reduced activity and has been linked to elevated plasma homocysteine levels in C677T individuals under conditions of folate deficiency (Frosst et al, 1995).…”

A functional variant in the cystathionine β-synthase gene promoter significantly reduces congenital heart disease susceptibility in a Han Chinese population

“…In Down syndrome patients carrying three copies of CBS, the plasma homocysteine level increased with age. Various studies of Down syndrome children showed consistently decreased plasma homocysteine levels compared with the same age controls [20][21][22]31], while trisomy 21 adults showed no difference in homocysteine levels [23], and elderly patients even had increased homocysteine levels compared with controls [32]. Thus the correlation between CBS −4673 genotypes and plasma homocysteine level during embryonic development cannot be truly reflected in the tested undergraduate students.…”