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

The association of neural tube defects (NTDs) with Down syndrome (trisomy 2 1) and altered folate metabolism in both mother and affected offspring prov ide a unique opportunity for insight into the etiologic role of folate defi ciency in these congenital anomalies. We describe here the case of a male c hild with trisomy 21, cervical meningomyelocele, agenesis of corpus callosu m, hydrocephaly, cerebellar herniation into the foramen magnum, and shallow posterior cranial fossa. Molecular analysis of the methylenetetrahydrofola te (MTHFR) gene revealed homozygosity for the mutant 677C-->T polymorphism in both the mother and child. The plasma homocysteine of the mother was hig hly elevated at 25.0 mu mol/L and was associated with a low methionine leve l of 22.1 mu mol/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 lymp hocytes. The child had low plasma levels of both homocysteine and methionin e and a reduced SAM/SAH ratio that was also associated with lymphocyte DNA hypomethylation. In addition, the child had a five-fold increase in cystath ionine level relative to normal children, consistent with over-expression o f the cystathionine beta synthase gene present on chromosome 21. We suggest that altered folate status plus homozygous mutation in the MTHFR gene in t he 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 th e risk of neural tube defects. The presence of both trisomy 21 and postclos ure NTD in the same child supports the need for an extended periconceptiona l period of maternal folate supplementation to achieve greater preventive e ffects for both NTD and trisomy 21. (C) 2001 Wiley-Liss, Inc.