Frequency of Down's syndrome and neural-tube defects in the same family

doi:10.1016/S0140-6736(03)13080-2

The Lancet

Volume 361, Issue 9366, 19 April 2003, Pages 1331-1335

https://doi.org/10.1016/S0140-6736(03)13080-2 Get rights and content

Summary

Background

There is evidence that some mothers of infants with Down's syndrome have abnormal metabolism of folate and methyl, as well as mutations in folate genes, which are features that are also seen in neural-tube defects (NTD). We therefore investigated whether Down's syndrome and NTD arise more often in the same family than would be expected from the incidence of each disorder considered separately.

Methods

We studied two series of families using information obtained from medical records about maternal age, pregnancy outcome, congenital malformations, and karyotype: the first, 493 families from Israel who were at high risk of NTD (445 with a history of NTD and 48 with isolated hydrocephalus); and the second, 516 families from the Ukraine at high risk of Down's syndrome.

Findings

In the families at risk of NTD, there were a total of 11 pregnancies affected by Down's syndrome in 1492 at-risk pregnancies (compared with 1·87 expected on the basis of maternal age), which was a significant increase (p<0·00001). In the families at risk of Down's syndrome, there were seven NTD pregnancies in 1847 at risk, compared with 1·37 expected (p<0·001).

Interpretation

In this study, we provide direct evidence of a link between Down's syndrome and NTD. Folate supplementation before conception has the potential to reduce the frequency of Down's syndrome.

Introduction

Despite substantial research, the cause of the non-disjunction leading to trisomy 21 in Down's syndrome remains unclear. Of the known risk factors, advanced maternal age is by far the strongest and, independently of age, genetic mapping has shown that some types of crossover at the first maternal meiosis confer a substantial susceptibility to non-disjunction, although the mechanisms predisposing to altered recombination are uncertain.¹

There is evidence that some mothers of infants with Down's syndrome have abnormal folate and methyl metabolism,² resulting in DNA hypomethylation, which is associated with chromosomal instability, impaired segregation, and aneuploidy.3, 4 These results have led several groups to investigate, in the mothers of affected individuals, polymorphisms in two genes for folate metabolism: 5,10-methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) (figure). Some workers have reported increased frequency of the C677T MTHFR and A66G MTRR polymorphisms, overall or in subgroups, but the results have not been consistent.2, 5, 6, 7, 8, 9 Both MTHFR and MTRR mutations could be critical for DNA methylation. MTHFR catalyses the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is the methyl donor in the remethylation of homocysteine to methionine by methionine synthase, which in turn is maintained in its active form by MTRR.

Abnormal folate intake or metabolism is known to have a role in the pathogenesis of neural-tube defects (NTD). Mothers of affected infants have impaired folate status,10, 11, 12 and several investigators have reported an increased frequency of mutations in the genes encoding MTHFR and MTRR, although as for Down's syndrome, not consistently so13, 14 Moreover, periconceptional folate supplementation reduces the risk of a pregnancy with NTD.15, 16 Thus, at least in a proportion of cases, Down's syndrome and NTD could have a common aetiological pathway. The two disorders also have shared epidemiological features such as large maternal contribution to both risk of occurrence and recurrence, high frequency in miscarriages, ethnic differences, and dependency on maternal age, albeit operating to a differing extent in each disorder. If there were a causal link, the two conditions should arise more often in affected families than in the population in general. We tested this hypothesis by investigating the frequency of Down's syndrome in a series of families referred for genetic counselling in Israel because of high NTD risk, and the incidence of NTD in a series of families in the Ukraine who were at high risk of Down's syndrome.

Section snippets

Families at high risk of NTD

All families were identified who had been referred to the Danek Gertner Institute of Human Genetics at the Sheba Medical Centre, Israel, between 1971 and 2001 because of a previous pregnancy affected by NTD or isolated hydrocephalus. NTD risk is 4% when a sibling has this disorder and 1–2% in cases of isolated hydrocephalus.¹⁷ Families were included if there was at least one other pregnancy in addition to the proband. For each pregnancy, we obtained information from medical records about

Results

547 families at risk of NTD (Israel series) were identified, of whom 54 did not have pregnancies other than the proband, and so the remaining 493 were included. In 445 of the 493, the proband had an NTD (264 anencephaly, 163 spina bifida, 13 encephalocele, and five cases of non-chromosomal, non-syndromic holoprosencephaly), and 48 had isolated hydrocephalus. There were 1492 pregnancies other than the proband. Table 1 shows the proportion of pregnancies according to maternal age, gravidity,

Discussion

We have noted a significantly high frequency of Down's syndrome in pregnancies at high risk of NTD because of a sibling with NTD or hydrocephalus. We also recorded an increase in NTD in those at high risk of Down's syndrome because of a family history of the disorder. Thus our findings provide evidence of an association between Down's syndrome and NTD, reinforcing the reasoning and circumstantial evidence of impaired folate status in the two disorders. This study is potentially subject to two

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Cited by (77)

Folic acid and primary prevention of neural tube defects: A review
2018, Reproductive Toxicology
Citation Excerpt :
There seems to be an increased risk of twinning associated with folic acid [125,126]. Reportedly, folic acid may decrease the risk of multiple congenital abnormalities [127–129], as well as of trisomy 21 [130,131]. The first controlled multi-center intervention project in women with a prior NTD-affected pregnancy, who were given a multivitamin preparation providing 3.6 mg folic acid once daily for ≤1 month before conception, was published in 1981 by Smithells.
With 4 mg folic acid daily, it may take 20 weeks to reach red-blood-cell folate levels between 1050 and 1340 nmol/L, optimal for reduction of the neural tube defect risk. Therefore, folic acid supplementation should be started 5–6 months before conception. The residual risk with optimal red-blood-cell folate levels is reportedly 4.5 per 10,000 total births. The residual risk in pooled data from countries with mandatory folic acid fortification is 7.5 per 10,000 pregnancies, regardless of pre-fortification rates. European monitoring of folate intake with questionnaires should be replaced by periodic measurements of red-blood-cell folate. The risk of folate intake >1 mg/day does not outweigh the benefits of folic acid fortification, provided un-metabolized folic acid, RBC folate and vitamin B₁₂ are monitored periodically. A European monitoring system, based on U.S. National Health and Nutrition Examination Surveys, should reside with the European Centre for Disease Prevention and Control.
Epidemiology and genetics of human aneuploidy
2018, Human Reproductive and Prenatal Genetics
By far the strongest epidemiological variable associated with aneuploidy is advancing maternal age, accounting for about two-thirds of Down syndrome births. Modern molecular methods applied to fetal material obtained at prenatal diagnosis or assisted reproduction show that this variable is present throughout pregnancy. Genetic and reproductive factors account for some of the nonmaternal cases. Environmental factors are unlikely to play a large role. The genetics of aneuploidy are generally understood but the underlying cause remains elusive. Research is now focusing on the role of cohesin, shugoshin, and spindle assembly checkpoint genes in ensuring the maintenance and segregation of chromosomes during germ cell division and maturation.
Health-related quality of life is compromised in individuals with spina bifida: Results from qualitative and quantitative studies
2014, European Journal of Obstetrics and Gynecology and Reproductive Biology
Citation Excerpt :
Through multifactorial inheritance these factors are usually a combination of genetics from both parents and environmental factors such as diabetes or certain prescribed medications. In addition, spina bifida can sometimes occur more frequently as part of a syndrome or chromosomal disorder along with other birth defects [17]. Folate is seen as a key preventative measure for those with and without a multifactorial inheritance pre-disposition and has the potential to reduce the frequency of other possible syndromes.
Spina bifida (SB) accounts for approximately 90% of total neural tube defects. According to the degree of SB severity, the range of associated symptoms and complications varies greatly. Given the complexity and diversity of these complications, individuals with SB might suffer from livelong impairment. This review presents an overview of the impact of SB on patients’ health-related quality of life (HRQoL) and explores results from published quantitative and qualitative studies regarding the HRQoL impact of SB on patients, as well as comparing results of existing studies to national norms.
A literature search using three electronic databases PUBMED, PsycINFO, and Embase was performed to identify relevant studies dating from January 1976 to November 2010. To satisfy the initial inclusion criteria, articles had to contain studies that were specific to HRQoL in patients with SB.
Findings highlight that HRQoL is significantly impaired in patients with SB. Making sure that the public is aware of the disease and how to minimise the risk of NTD, such as SB (e.g., through adequate folate levels at time of conception, etc.) is essential to ensure that fewer individuals face the burden of NTDs in the future.
Autosomal Trisomies
2013, Emery and Rimoin's Principles and Practice of Medical Genetics
Pathophysiology of Neural Tube Defects
2011, Fetal and Neonatal Physiology E-Book, Fourth Edition
Homocysteine and oxidative stress in Egyptian children with Down syndrome
2010, Clinical Biochemistry
To assess homocysteine, folic acid and vitamin B₁₂, trace element levels and oxidant/antioxidant status in Down syndrome (DS) mothers and children.
42 mothers with previous history of bearing DS baby with karyotypically confirmed full trisomy 21 were included. 48 healthy mothers with their healthy children were considered as control. Serum B₁₂, folic acid, total homocysteine (tHcy), vitamins E and C, TBARS and trace elements were estimated.
DS mothers showed higher levels of tHCy, lower levels of folic acid and vitamin B₁₂ than controls. tHCy and folic acid concentrations were significantly decreased, while vitamin B₁₂ exhibited a slight decrease in DS children versus control. Vitamins E and C, zinc and copper levels were markedly reduced in DS mothers. By contrast, TBARS showed significant elevation in them. Furthermore, DS children had severe reduction of vitamin C and zinc levels relative to healthy children. However, vitamin E showed slight reduction and TBARS displayed a slight rise in DS children.
Abnormal folic acid-homocysteine metabolism is a potent marker to identify women at risk for having DS child and it also exposes them to oxidant/antioxidant imbalance.

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ArticlesFrequency of Down's syndrome and neural-tube defects in the same family

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Families at high risk of NTD

Results

Discussion

Am J Clin Nutr

J Nutr

Am J Hum Genet

Metabolism

Am J Clin Nutr

Mol Genet Metab

Metabolism

Am J Clin Nutr

Lancet

Lancet

Down syndrome: genetic recombination and the origin of the extra chromosome 21

Clin Genet

Recommended dietary allowances (RDAs) for genomic stability

Mutat Res

A common mutation in the methylenetetrahydrofolate reductase gene is not a risk factor for Down syndrome in a population-based study

Am J Hum Genet

Methylenetetrahydrofolate reductase polymorphism in the etiology of Down syndrome

Pediatr Res

Articles
Frequency of Down's syndrome and neural-tube defects in the same family