Homocysteine and related genetic polymorphisms in Down's syndrome IQ.
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 micromol/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 micromol/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 677T allele. The MTHFR 677T 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).


CONCLUSIONS
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.
Guéant
J-L
JL
IRCCS, Oasi Maria SS-Institute for Research on Mental Retardation and Brain Aging, Troina (EN), Italy. Jean-Louis.Gueant@medecine.uhp-nancy.fr
Anello
G
G
Bosco
P
P
Guéant-Rodríguez
R-M
RM
Romano
A
A
Barone
C
C
Gérard
P
P
Romano
C
C
D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004314:Down Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D005492:Folic Acid / Q000235:genetics / Q000378:metabolism; D006710:Homocysteine / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007360:Intelligence; D007621:Karyotyping; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D014155:Transcobalamins / Q000235:genetics / Q000378:metabolism; D014805:Vitamin B 12 / Q000235:genetics / Q000378:metabolism
D001057:Apolipoproteins E; D014155:Transcobalamins; D006710:Homocysteine; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D014805:Vitamin B 12