Is there a familial link between Down's syndrome and neural tube defects? Population and familial survey
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《英国医生杂志》
1 ECLAMC at Departamento de Genética, Universidade Federal do Rio de Janeiro, Caixa Postal 68 011, 21944-970, Rio de Janeiro, Brazil, 2 ECLAMC at Departamento de Genética, Instituto Oswaldo Cruz, Caixa Postal 926, 20001-970, Rio de Janeiro, and at Cemic, Buenos Aires, Argentina
Correspondence to: Iêda M Orioli orioli@centroin.com.br
Abstract
An association between abnormal intake or metabolism of folate and neural tube defects has been proved.1-3 At the molecular level, the 677CT (alanine to valine) polymorphism in the gene encoding the folate metabolising enzyme methylenetetrahydrofolate reductase constitutes a genetic risk for neural tube defects in some parts of the world but not in others.4 5 The same type of association involving folate intake and metabolism, including increased frequency of the 677T allele of methylenetetrahydrofolate reductase, has been found for Down's syndrome in some studies,6-8 but has not consistently been found in others.9-14 The effect of this polymorphism depends on individual folate status, mainly related to intake.15 Several other interactions involve maternal and fetal genotypes for methylenetetrahydrofolate reductase and other enzymes of the folate pathway.5
Barkai et al recently proposed that as neural tube defects and Down's syndrome are both associated with disturbances in the folate pathway, at least some cases of neural tube defects and Down's syndrome could be expected to have a common aetiology.16 They verified that families at risk of neural tube defects had an excess of Down's syndrome cases and that families at risk of Down's syndrome had an excess of neural tube defects cases, establishing a link between the two conditions. They described links between neural tube defects and Down's syndrome in two different populations, an Israeli population of families at risk of neural tube defects and a Ukranian population of families at risk of Down's syndrome.16 To discover if this reported link between Down's syndrome and neural tube defects could be replicated in other conditions, we looked for it in a South American population.
Methods
We found 5404 full and half siblings previous to 3373 probands with neural tube defects or hydrocephalus and 8066 full and half siblings previous to 3095 probands with Down's syndrome (tables 1 and 2). We observed five cases of Down's syndrome among siblings of infants with neural tube defects, compared with 5.13 cases expected according to maternal age distribution (table 1). We observed 12 cases of neural tube defects or hydrocephalus among siblings of infants with Down's syndrome, compared with 17.18 cases expected on the basis of the birth prevalence of neural tube defects plus hydrocephalus; 12 is within the 95% Poisson confidence limits (8 to 27) for a figure of 17. When we used observed and expected prevalences adjusted by calendar year, 11.21 cases of neural tube defects or hydrocephalus were expected (12 observed) among siblings of infants with Down's syndrome. The two expected numbers are not significantly different, but the second one corrects possible bias introduced by the combination of older age of previous siblings with Down's syndrome and increasing time trends for prevalence of neural tube defects.
Table 1 Observed and expected number of cases of Down's syndrome in sibships at risk of neural tube defects or hydrocephalus and cases of neural tube defects or hydrocephalus in sibships at risk of Down's syndrome
Table 2 Prevalence of neural tube defects, hydrocephalus, and Down's syndrome in newborn population (probands) (n=1 583 838) and siblings of probands
Table 2 shows the observed numbers of affected siblings separately for neural tube defects and hydrocephalus, showing the same results. This table also shows how many times more often () siblings were affected than the general population, for each diagnostic category. The risk observed for neural tube defects in maternal half siblings of infants with neural tube defects was half of that observed for full siblings, as expected with a decrease of one degree of relationship in multifactorial diseases.18 The same was true for the risk of hydrocephalus in siblings and maternal half siblings of infants with hydrocephalus. Crossed recurrences (neural tube defects in siblings of infants with hydrocephalus) showed the same risk for full siblings or maternal half siblings, and these risks did not differ from the general population risk.
Discussion
MRC Vitamin Study Research Group. Prevention of neural tube defect: results of the Medical Research Council vitamin study. Lancet 1991;338: 131-7.
Czeizel AE, Dudas I. Prevention of first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327: 1832-5.
Mills JL, McPartlin JM, Kirke PN, Lee YJ, Conley MR, Weir DG, et al. Homocysteine metabolism in pregnancies complicated by neural-tube defects. Lancet 1995;345: 149-51.
Van der Put NMJ, Steegers-Theunissen RP, Frosst P, Trijbels FJ, Eskes TK, van den Heuvel LP, et al. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 1995;346: 1070-1.
Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGe review. Am J Epidemiol 2000;151: 862-77.
James SJ, Pogribna M, Pogribny IP, Melnyk S, Hine RJ, Gibson JB, et al. Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factor for Down syndrome. Am J Clin Nutr 1999;70: 495-501.
Hobbs CA, Sherman SL, Hopkins SE, Hopkins SE, Torfs CP, Hine RJ, et al. Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. Am J Hum Genet 2000;67: 623-30.
Al-Gazali LI, Padmanabhan R, Melnyk S, Yi P, Pogribny IP, Pogribna M, et al. 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;103: 128-32.
Petersen M, Grigoriadou M, Mikkelsen M. A common mutation in the methylenetetrahydrofolate reductase gene is not a risk factor for Down syndrome. Am J Hum Genet 2000;67(suppl 2): 141.
Hassold TJ, Burrage LC, Chan ER, Judis LM, Schwartz S, James SJ, et al. Maternal folate polymorphism and the etiology of human nondisjunction. Am J Hum Genet 2001;69: 434-9.
Chadefaux-Vekemans B, Coude M, Muller F, Oury J, Chali A, Kamoun P. Methylenetetrahydrofolate reductase polymorphism in the etiology of Down syndrome. Pediatr Res 2002;51: 766-7.
O'Leary VB, Parle-McDermott A, Molloy AM, Kirke PN, Johnson Z, Conley M, et al. MTRR and MTHFR polymorphism: link to Down syndrome? Am J Med Genet 2002;107: 151-5.
Stuppia L, Gatta V, Gaspari AR, Antonucci I, Morizio E, Calabrese G, et al. C677T mutation in the 5,10-MTHFR gene and risk of Down syndrome in Italy. Eur J Hum Genet 2002;10: 388-90.
Yanamandra K, Bocchini Jr JA, Thurmon TF. Absence of association of fetal MTHFR C677T polymorphism with prenatal Down syndrome pregnancies. Eur J Hum Genet 2003;11: 5.
Jaques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996;93: 7-9.
Barkai G, Arbuzova S, Berkenstadt M, Heifetz S, Cuckle H. Frequency of Down syndrome and neural-tube defects in the same family. Lancet 2003;361: 1331-5.
Castilla EE, Lopez-Camelo JS. The surveillance of birth defects in South America: the search for time clusters: epidemics. Adv Mutagen Res 1990;2: 191-210.
Risch N. Linkage strategies for genetically complex traits. I: multilocus models. Am J Hum Genet 1990;46: 222-8.
K?llén B, Mastroiacovo P, Robert E. Major congenital malformations in Down syndrome. Am J Med Genet 1996;65: 160-6.(Márcia R Amorim, PhD stud)
Correspondence to: Iêda M Orioli orioli@centroin.com.br
Abstract
An association between abnormal intake or metabolism of folate and neural tube defects has been proved.1-3 At the molecular level, the 677CT (alanine to valine) polymorphism in the gene encoding the folate metabolising enzyme methylenetetrahydrofolate reductase constitutes a genetic risk for neural tube defects in some parts of the world but not in others.4 5 The same type of association involving folate intake and metabolism, including increased frequency of the 677T allele of methylenetetrahydrofolate reductase, has been found for Down's syndrome in some studies,6-8 but has not consistently been found in others.9-14 The effect of this polymorphism depends on individual folate status, mainly related to intake.15 Several other interactions involve maternal and fetal genotypes for methylenetetrahydrofolate reductase and other enzymes of the folate pathway.5
Barkai et al recently proposed that as neural tube defects and Down's syndrome are both associated with disturbances in the folate pathway, at least some cases of neural tube defects and Down's syndrome could be expected to have a common aetiology.16 They verified that families at risk of neural tube defects had an excess of Down's syndrome cases and that families at risk of Down's syndrome had an excess of neural tube defects cases, establishing a link between the two conditions. They described links between neural tube defects and Down's syndrome in two different populations, an Israeli population of families at risk of neural tube defects and a Ukranian population of families at risk of Down's syndrome.16 To discover if this reported link between Down's syndrome and neural tube defects could be replicated in other conditions, we looked for it in a South American population.
Methods
We found 5404 full and half siblings previous to 3373 probands with neural tube defects or hydrocephalus and 8066 full and half siblings previous to 3095 probands with Down's syndrome (tables 1 and 2). We observed five cases of Down's syndrome among siblings of infants with neural tube defects, compared with 5.13 cases expected according to maternal age distribution (table 1). We observed 12 cases of neural tube defects or hydrocephalus among siblings of infants with Down's syndrome, compared with 17.18 cases expected on the basis of the birth prevalence of neural tube defects plus hydrocephalus; 12 is within the 95% Poisson confidence limits (8 to 27) for a figure of 17. When we used observed and expected prevalences adjusted by calendar year, 11.21 cases of neural tube defects or hydrocephalus were expected (12 observed) among siblings of infants with Down's syndrome. The two expected numbers are not significantly different, but the second one corrects possible bias introduced by the combination of older age of previous siblings with Down's syndrome and increasing time trends for prevalence of neural tube defects.
Table 1 Observed and expected number of cases of Down's syndrome in sibships at risk of neural tube defects or hydrocephalus and cases of neural tube defects or hydrocephalus in sibships at risk of Down's syndrome
Table 2 Prevalence of neural tube defects, hydrocephalus, and Down's syndrome in newborn population (probands) (n=1 583 838) and siblings of probands
Table 2 shows the observed numbers of affected siblings separately for neural tube defects and hydrocephalus, showing the same results. This table also shows how many times more often () siblings were affected than the general population, for each diagnostic category. The risk observed for neural tube defects in maternal half siblings of infants with neural tube defects was half of that observed for full siblings, as expected with a decrease of one degree of relationship in multifactorial diseases.18 The same was true for the risk of hydrocephalus in siblings and maternal half siblings of infants with hydrocephalus. Crossed recurrences (neural tube defects in siblings of infants with hydrocephalus) showed the same risk for full siblings or maternal half siblings, and these risks did not differ from the general population risk.
Discussion
MRC Vitamin Study Research Group. Prevention of neural tube defect: results of the Medical Research Council vitamin study. Lancet 1991;338: 131-7.
Czeizel AE, Dudas I. Prevention of first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327: 1832-5.
Mills JL, McPartlin JM, Kirke PN, Lee YJ, Conley MR, Weir DG, et al. Homocysteine metabolism in pregnancies complicated by neural-tube defects. Lancet 1995;345: 149-51.
Van der Put NMJ, Steegers-Theunissen RP, Frosst P, Trijbels FJ, Eskes TK, van den Heuvel LP, et al. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 1995;346: 1070-1.
Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGe review. Am J Epidemiol 2000;151: 862-77.
James SJ, Pogribna M, Pogribny IP, Melnyk S, Hine RJ, Gibson JB, et al. Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factor for Down syndrome. Am J Clin Nutr 1999;70: 495-501.
Hobbs CA, Sherman SL, Hopkins SE, Hopkins SE, Torfs CP, Hine RJ, et al. Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. Am J Hum Genet 2000;67: 623-30.
Al-Gazali LI, Padmanabhan R, Melnyk S, Yi P, Pogribny IP, Pogribna M, et al. 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;103: 128-32.
Petersen M, Grigoriadou M, Mikkelsen M. A common mutation in the methylenetetrahydrofolate reductase gene is not a risk factor for Down syndrome. Am J Hum Genet 2000;67(suppl 2): 141.
Hassold TJ, Burrage LC, Chan ER, Judis LM, Schwartz S, James SJ, et al. Maternal folate polymorphism and the etiology of human nondisjunction. Am J Hum Genet 2001;69: 434-9.
Chadefaux-Vekemans B, Coude M, Muller F, Oury J, Chali A, Kamoun P. Methylenetetrahydrofolate reductase polymorphism in the etiology of Down syndrome. Pediatr Res 2002;51: 766-7.
O'Leary VB, Parle-McDermott A, Molloy AM, Kirke PN, Johnson Z, Conley M, et al. MTRR and MTHFR polymorphism: link to Down syndrome? Am J Med Genet 2002;107: 151-5.
Stuppia L, Gatta V, Gaspari AR, Antonucci I, Morizio E, Calabrese G, et al. C677T mutation in the 5,10-MTHFR gene and risk of Down syndrome in Italy. Eur J Hum Genet 2002;10: 388-90.
Yanamandra K, Bocchini Jr JA, Thurmon TF. Absence of association of fetal MTHFR C677T polymorphism with prenatal Down syndrome pregnancies. Eur J Hum Genet 2003;11: 5.
Jaques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996;93: 7-9.
Barkai G, Arbuzova S, Berkenstadt M, Heifetz S, Cuckle H. Frequency of Down syndrome and neural-tube defects in the same family. Lancet 2003;361: 1331-5.
Castilla EE, Lopez-Camelo JS. The surveillance of birth defects in South America: the search for time clusters: epidemics. Adv Mutagen Res 1990;2: 191-210.
Risch N. Linkage strategies for genetically complex traits. I: multilocus models. Am J Hum Genet 1990;46: 222-8.
K?llén B, Mastroiacovo P, Robert E. Major congenital malformations in Down syndrome. Am J Med Genet 1996;65: 160-6.(Márcia R Amorim, PhD stud)