Abnormal folate metabolism and genetic polymorphism of the folate pathway in a child with Down syndrome and neural tube defect

Am J Med Genet. 2001 Oct 1;103(2):128-32. doi: 10.1002/ajmg.1509.


The association of neural tube defects (NTDs) with Down syndrome (trisomy 21) and altered folate metabolism in both mother and affected offspring provide a unique opportunity for insight into the etiologic role of folate deficiency in these congenital anomalies. We describe here the case of a male child with trisomy 21, cervical meningomyelocele, agenesis of corpus callosum, hydrocephaly, cerebellar herniation into the foramen magnum, and shallow posterior cranial fossa. Molecular analysis of the methylenetetrahydrofolate (MTHFR) gene revealed homozygosity for the mutant 677C-->T polymorphism in both the mother and child. The plasma homocysteine of the mother was highly elevated at 25.0 micromol/L and was associated with a low methionine level of 22.1 micromol/L. Her S-adenosylhomocysteine (SAH) level was three times that of reference normal women, resulting in a markedly reduced ratio of S-adenosylmethionine (SAM) to SAH and significant DNA hypomethylation in lymphocytes. The child had low plasma levels of both homocysteine and methionine and a reduced SAM/SAH ratio that was also associated with lymphocyte DNA hypomethylation. In addition, the child had a five-fold increase in cystathionine level relative to normal children, consistent with over-expression of the cystathionine beta synthase gene present on chromosome 21. We suggest that altered folate status plus homozygous mutation in the MTHFR gene in the mother could promote chromosomal instability and meiotic non-disjunction resulting in trisomy 21. Altered folate status and homozygous TT mutation in the MTHFR gene in both mother and child would be expected to increase the risk of neural tube defects. The presence of both trisomy 21 and postclosure NTD in the same child supports the need for an extended periconceptional period of maternal folate supplementation to achieve greater preventive effects for both NTD and trisomy 21.

Publication types

  • Case Reports

MeSH terms

  • Amino Acids, Sulfur / blood
  • Consanguinity
  • DNA / genetics
  • DNA / metabolism
  • DNA Methylation
  • Down Syndrome / enzymology
  • Down Syndrome / genetics
  • Down Syndrome / pathology*
  • Folic Acid / metabolism*
  • Genotype
  • Humans
  • Infant
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Mutation
  • Neural Tube Defects / enzymology
  • Neural Tube Defects / genetics
  • Neural Tube Defects / pathology*
  • Oxidoreductases Acting on CH-NH Group Donors / genetics*
  • Oxidoreductases Acting on CH-NH Group Donors / metabolism
  • Polymorphism, Genetic


  • Amino Acids, Sulfur
  • DNA
  • Folic Acid
  • Oxidoreductases Acting on CH-NH Group Donors
  • Methylenetetrahydrofolate Reductase (NADPH2)