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PAPERS: Márcia R Amorim, Eduardo E Castilla, and Iêda M Orioli Is there a familial link between Down's syndrome and neural tube defects? Population and familial survey BMJ 2004; 328: 84 [Abstract] [Full text]

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IS THERE A LINK BETWEEN DOWN’S SYNDROME, NEURAL TUBE DEFECTS AND MTHFR MUTATIONS?

Sebastiano Bianca, Nunzio Cutuli , Marco Bianca, Gabriella Milana , Carmela Ingegnosi , Giuseppe Ettore   (17 December 2003)

IS THERE A LINK BETWEEN DOWN’S SYNDROME, NEURAL TUBE DEFECTS AND MTHFR MUTATIONS? 17 December 2003
Sebastiano Bianca, medical geneticist Medical Genetics - Garbaldi Hospital, Catania, Italy, Nunzio Cutuli , Marco Bianca, Gabriella Milana , Carmela Ingegnosi , Giuseppe Ettore Send response to journal: Re: IS THERE A LINK BETWEEN DOWN’S SYNDROME, NEURAL TUBE DEFECTS AND MTHFR MUTATIONS?	Recently a link between Down’s syndrome (DS) and Neural Tube Defects (NTD) was supposed1 with an epidemiological evidence of a coexistence of the two conditions in the same family. On the contrary Amorim et al2 within a large sample size demonstrated that no association occurred between the two conditions. Moreover both studies conclusion are not backed up by molecular analysis for folate metabolism genes that would point to a common genetic and biological mechanism. The extra 21 chromosome in DS derives from the mother in 93% of cases and is due to abnormal chromosome segregation during meiosis (nondisjunction). Except for advanced age at conception, maternal risk factors for meiotic nondisjunction are not well established. There is evidence that mutations in 5, 10 methylenetetrahydrofolate reductase (MTHFR) gene, that is involved in folate metabolism, may play a role in the pathogenesis of NTD3 and DS4, moreover while the link between MTHFR and NTD is well established, the exact mechanisms associated with DS are uncertain, even if it was suggested4, that the possibility that gene- nutrient interactions associated with abnormal folate metabolism and DNA hypomethylation might increase the risk of chromosome nondisjunction. In fact, maternal MTHFR gene mutations could be responsible of an increase in NTD risk and promote chromosomal instability and meiotic non- disjunction resulting in trisomy 21. We tested a woman with a reproductive history characterized by two voluntary terminated pregnancies after prenatal diagnosis of DS in the first pregnancy and isolated spina bifida in the second. She was heterozygous (CT) for the C677T polymorphism of MTHFR gene her husband's genotype was wild type (CC). Our case, then, should support the reported epidemiological evidence of a link between DS and NTD in the same family even if a single case with a common gene mutation did not represent a certain link with conditions. Moreover, while the reported association between the two conditions raises the question of the reduction of the risk of DS through folic acid supplementation, MTHFR mutations alone is, probably, not enough to produce both anomalies and other biological evidence are needed to understand this association. A criticism to the previously reported papers1,2 is that in both cases no mutation search was made in families with the two conditions to demonstrate a possible link with MTHFR. Additional studies also on other candidate genes in the folate pathway, as well as a systematic study of interactions with other micronutrients involved in folate/methyl metabolism in women with DS and/or NTD affected pregnancies, may suggest opportunities to improve public health strategies for the primary prevention of congenital anomalies. References 1. Barkai G, Arbuzova S, Berkenstandt M, Heifetz S, Cuckle H.. Frequency of Down’s Syndrome and neural-tube defects in the same family. Lancet 2003; 361: 1331-1335 2. Amorim MR, Castilla EE, Orioli IM. Is there a link between Down’s syndrome and neural tube defects? Population and family survey. BMJ, doi:10.1136/bmj.37945.610914.EE (published 8 December 2003) 3. Posey DL, Khoury MJ, Mulinare J, Adams MJ Jr, OU CY. Is mutated MTHFR a risk factor for neural tube defects? Lancet 1996; 347: 686- 687 4. James SJ, Pogribna M, Pogribny IP, melnyk S, Hine RJ, Gibson JB, Yi P, Tafoya DL, Swenson DH, Wilson VL, Gaylor DW. Anormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome. Am J Clin Nutr 1999; 70: 495-501 Competing interests: None declared