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Homocysteine and related genetic polymorphisms in Down’s syndrome IQ
  1. J-L Guéant2,*,
  2. G Anello1,*,
  3. P Bosco1,*,
  4. R-M Guéant-Rodríguez2,*,
  5. A Romano3,
  6. C Barone1,
  7. P Gérard2,
  8. C Romano1
  1. 1IRCCS, Oasi Maria SS—Institute for Research on Mental Retardation and Brain Aging, Troina (EN), Italy
  2. 2Cellular and Molecular Pathology in Nutrition, EMI—INSERM 0014, Faculté de Médecine, Vandoeuvre lès Nancy, France
  3. 3Department of Internal Medicine and Geriatrics, UCSC, CI Columbus, Rome, Italy
  1. Correspondence to:
 Professor J L Guéant
 EMI—INSERM 0014, Faculty of Medicine BP 184, 54500, Vandoeuvre lès Nancy, France;


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 B12, 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 B12, 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 μmol/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 μmol/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).

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.

  • AD, Alzheimer’s disease
  • ApoE, Apolipoprotein E
  • BMI, body mass index
  • DS, Down’s syndrome
  • IQ, intelligence quotient
  • MTHFR, methylenetetrahydrofolate reductase
  • MTR, methionine synthase
  • MTRR, methionine synthase reductase
  • t-Hcys, homocysteine
  • TCN, transcobalamin

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  • * The four first authors contributed equally to this article

  • Competing interests: none declared